Pharmacologic interventions for reducing spasticity in cerebral palsy
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《美国医学杂志》
Michigan State University, Kalamazoo Center for Medical Studies, Kalamazoo, Michigan 49008, USA
Abstract
Motor function abnormalities are a key feature of cerebral palsy. Spasticity is one of the main motor abnormalities seen in children with cerebral palsy. Spasticity is a velocity dependent increased resistance to movement. While in some children, spasticity may adversely impact the motor abilities, in others, it may help maintain posture and ability to ambulate. Thus, treatment to reduce spasticity requires careful consideration of various factors. Non-pharmacologic interventions used to reduce spasticity include physiotherapy, occupational therapy, use of adaptive equipment, various orthopedic surgical procedures and neurosurgical procedures. Pharmacologic interventions used for reducing spasticity in children with cerebral palsy reviewed in this article include oral administration of baclofen, diazepam, dantrolene and tizanidine, intrathecal baclofen, and local injections of botulinum toxin, phenol, and alcohol.
Keywords: Spasticity; Baclofen; Dantolene; Botulinum toxin; Phenol
Motor function abnormalities are a key feature of cerebral palsy.[1],[2],[3] As described by JP. Lin, the disordered motor skills experienced by children with cerebral palsy include delayed motor development, muscle weakness, impaired movement sequencing, dexterity, anticipatory control, abnormal posturing, exaggerated reflexes, muscle spasms, muscle stiffness, and joint deformities.[4]
A clinical finding seen in children with cerebral palsy as part of the motor disorder is the development of clasp-knife spasticity. According to the Taskforce on Childhood Motor Disorders, spasticity is defined as "hypertonia in which one or both of the following signs are present: (1) Resistance to externally imposed movement increases with increasing speed of stretch and varies with the direction of joint movement. (2) Resistance to externally imposed movement rises rapidly above threshold speed or joint angle."[5] In other words, spasticity refers to a velocity- dependent increase in resistance to movement. Spasticity is associated with both positive (hypertonia, clonus, increased deep tendon reflexes, persistence of primitive reflexes, Babinski sign) and negative (decreased coordination, decreased ability for motor planning, weakness, decreased muscular endurance) features of the upper motor neuron syndrome.[6],[7],[8],[9] Most treatment modalities aimed at reducing spasticity do so by affecting the positive symptoms of spasticity.
Spasticity can be aggravated by pain, stress, fatigue, fever, cold, systemic illness, lack of sleep, constipation, diarrhea, tight fitting clothes, improperly fitted orthoses, immobility, and hormonal changes.[2],[4],[10],[11] In addition to cerebral palsy, spasticity can also be seen in children with multiple sclerosis, traumatic brain injury, stroke, anoxic brain injury, spinal cord injury, hemispherectomy and neurodegenerative diseases.[4],[5],[7]
Clinically, the degree of spasticity noted varies depending upon the state of arousal of the child at the time as well as the duration since the original insult to the brain.[4] The natural history of reflex excitability following acute stroke was described by R. Herman, cited by Lin, progresses through the following four phases: "(1) flaccid and inexcitable, (2) hyperrefelxia and clonus in first few months, lasting a few years (3) reduction in reflex excitability, and (4) stiff, inexcitable and shortened muscles: fixed contracture."[4],[12]
Reduction of spasticity is only one of the many facets of the overall management of motor disorders of cerebral palsy. While in some children spasticity may interfere with motor function, in others it may in fact be useful to maintain posture and the capacity to ambulate. Thus it is essential to carefully weigh the potential benefits vs adverse effects on motor function of reducing spasticity. Factors to be considered in selecting the child for the treatment to reduce spasticity include: cognitive and emotional maturity of the child, growth potential, presence or absence of positive and negative features of upper motor neuron syndrome, distribution of the spasticity, likely underlying cause of the spasticity, whether the spasticity is acute or chronic, static or progressive, and psychosocial factors that might affect treatment adherence.[1],[2],[4],[5],[6],[9] For objectivity, the severity of spasticity can be assessed by standardized instruments, for example, the Ashworth Scale, Modified Ashworth Scale, or the Tardieu Scale.[1]
Once a decision is made to treat a child, the age of the child at the time of treatment is an important consideration in selecting the appropriate therapeutic intervention or a combination thereof. It is generally agreed that children treated before the age of 4-5 have significantly less occurrence of progressive joint contractures and limb deformities.[2],[5],[9] Early and aggressive physiotherapy and occupational therapy have been shown to be very effective, and may obviate the later need for other therapeutic interventions to reduce spasticity.[1],[2] Optimal benefit from the injection of botulinum toxin is seen in children aged 2 to 6 yr. Surgical procedures on the other hand should be delayed until after 6-8 yr of age, and phenol injections until skeletal maturity is reached.[1] Other factors influencing the choice of specific intervention include distribution and severity of spasticity, associated medical conditions, side effects, ease of administration and prior treatments.[1],[2],[4],[5] Various therapeutic modalities used to reduce spasticity are listed in table1. An overview of the pharmacologic interventions is presented further in this review.
Oral Drugs
In general, the use of oral medications is limited to children with generalized spasticity who may benefit from mild reduction of spasticity.[13] Higher dosages are associated with systemic side effects like sedation, weakness, behavior changes, and other central side effects limiting their usefulness.
Baclofen
Baclofen is a gamma-amino butyric acid (GABA) agonist. Baclofen reduces the release of excitatory neurotransmitters and substance P by binding to the GABAB receptors.[5],[7],[10] Because its primary action is at the spinal cord level, baclofen is especially useful in treating spasticity of spinal cord origin, such as in patients with spinal cord injury and demyelinating myelopathies. Although the use of baclofen in children with cerebral palsy is not well established, it may be useful in selected patients. Starting dose is 2.5mg daily, which can be titrated up gradually to a maximum of 20-60mg/day, based on the response.[6],[7],[10]
Side effects include weakness, sedation, ataxia, nausea, impaired cognition, orthostatic hypotension, dizziness, and, in some cases, depression.[5],[6],[7],[13] Baclofen overdose can cause severe flaccidity and coma requiring intensive care and assisted ventilation until, baclofen is metabolized by the body. As such baclofen is non-toxic to neural tissue.
Sudden withdrawal of baclofen may result in a withdrawal syndrome which can be potentially serious.[5],[8],[10],[13] Withdrawal syndrome has been reported after sudden discontinuation of oral as well as intrathecal baclofen. The syndrome is characterized by seizures, hallucinations, hyperthermia, dysesthesia, pruritis, and rebound spasticity. Neuroleptic malignant syndrome and death have been reported with sudden withdrawal of baclofen. Treatment of baclofen withdrawal syndrome is immediate administration of oral baclofen.
Benzodiazepines
Diazepam and clonazepam have been used in children with cerebral palsy to improve tone. Benzodiazepines act both at the brain stem as well as spinal cord levels to increase the affinity of GABA to the GABAA receptor complex presynaptically and postsynaptically.[5],[13],[14] Benzodiazepines increase the GABA-mediated inhibition supraspinally and in the spinal cord. Benzodiazepines have been shown to reduce generalized spasticity, hyperreflexia, and painful muscle spasms.[14],[15] Improvement is also seen in passive range of joint motion and spontaneous movements.
Diazepam has been shown to improve sleep and reduce anxiety. Diazepam has been used in the dosage range from 1 to 10 mg per dose administered 3 to 4 times per day.[7],[10] Sedation is the most common side effect. Other less common side effects include increased drooling, ataxia, and cognitive dullness. In some cases, tolerance and dependence is seen with prolonged use. Clonazepam is rapidly absorbed after oral administration, has a half-life of 18-28 hrs, and has been used to reduce night time muscle spasms. Typical dosage in children is 0.01-0.3 mg/ kg/day given 2 to 3 times per day.[10],[11],[13]
Dantrolene Sodium
Dantrolene acts at the level of the skeletal muscle to reduce spasticity by inhibiting calcium release from the sarcoplasmic reticulum, thus uncoupling electrical excitation from contraction.[1],[4],[6],[7],[13] Dantrolene sodium reaches peak blood levels in 3-6 hrs, while its active metabolite 5-hydroxydantrolene reaches peak levels in 4-8 hrs after oral administration.[10],[13] In children, dantrolene is started at a low dose, typically 0.5 mg/kg given twice daily, increasing by 0.5 mg/kg every 5-7 days to a maximum dose of 12 mg/kg/day or 400 mg/day. Dantrolene reduces spasticity by inducing skeletal muscle weakness, which is its most significant side effect. Other side effects include weakness, fatigue, drowsiness and diarrhea.[10] Hepatotoxicity has been reported with the use of dantrolene, and hepatic function must be monitored periodically in patients on dantrolene.
Alpha[2] Adrenergic Agonists
Tizanidine and clonidine have been used in the treatment of spasticity. Alpha[2] noradrenergic agonists act at receptors in the brain and spinal cord.[5],[10],[13] Postulated mechanisms of action include hyperpolarization of motoneurons, prevention of release of excitatory amino acids from the presynaptic terminal of spinal interneurons, and facilitation of the action of inhibitory neurotransmitter gylcine.[4],[5],[6],[10] Both tizanidine and clonidine exert antinociceptive effects mediated by release of substance P in the spinal cord.[10],[16]
Sedation is the most common side effect. Sedative effect may also be helpful in some patients who have difficulty with sleeping. Other side effects include hypotension especially with clonidine, depression, dry mouth, dizziness, and hepatotoxiciy.
Tizanidine is started at a dose of 1 mg given at bedtime for children under 10 yrs and 2 mg for children of 10 yrs or more; maintenance dose is 0.3-0.5 mg/kg/day divided four times daily.[16] Clonidine is given at a starting dose of 0.05 mg per day and increased by 0.05 mg every week to a maximum of 0.3 mg per day given in three divided doses.[13] Clonidine is available as tablets and transderdemal patch.
Local drug injections
Local intramuscular injections of alcohol or phenols exert their effects by causing chemodenervation, while local injection of botulinum toxin casues neuromuscular blockade.[1] In either case nerve muscle impulse transmission is interrupted.
Botulinum Toxin
Botulinum toxin is an exotoxin produced by the bacterium Clostridium botulinum. Seven immunogenically distinct serotypes have been identified named A to G. Botulinum toxin A is serotype used clinically with well-established efficacy. Botulinum toxin works by inhibiting presynaptic acetylcholine release at the neuromuscular junction causing reversible partial flaccid paralysis of the muscle in which it is injected.[1],[17],[18] Its effects are usually noticeable within 12-72 hrs following injection in the affected muscle with effects lasting for 3-6 months. The effects of botulinum toxin injection are reversed over time because of proximal nerve sprouting followed by recovery of vesicle turnover and gradual regression of sprouts.
With repeated injections, effectiveness may be lost as there may be development of resistance to the botulinum toxin due to formation of antibodies against the toxin. Use of minimum effective dose, use of different serotypes, and not giving repeated doses sooner then every 3 months reduce the chances of development of resistance.[17],[19],[20]
Dose of injection vary depending up on the type of commercial preparation used. Injections of botulinum toxin usually need to be repeated every 3-6 months to maintain optimal therapeutic effectiveness.
The most common side effects of botulinum toxin injection are local pain and bruising. Other reported side effects include excessive weakness of muscles, constipation, fever, and incontinence. Botulinum toxin injection has a well-established safety record, and serious side effects such as dysphagia and aspiration pneumonia, especially with injection in the head and neck region, are rare.[1],[17],[18],[20]
Botulinum toxin is used most effectively in the treatment of focal spasticity. Optimal effectiveness has been reported when used between 1 and 6 yr of age for the treatment of lower extremity spasticity, and between 5 and 15 yr of age for the treatment of children with hemiplegia.[17],[18],[20] Botulinum toxin has been shown to be effective in reducing spasticity in lower extremity, improve joint range of motion and gait, improve equinus deformity, and improve adductor tone. It has been shown to be effective in reducing upper extremity spasticity, dystonia and function.[18],[19] Use of botulinum toxin is not recommended in the presence of fixed joint or muscle contracture because of its ineffectiveness in these cases.
Alcohol and Phenol Injections
Injections of phenol or alcohol are given in the specific nerve or muscle after identifying the nerve and muscle affected by electrical stimulation. Alcohol and phenol injections result in local neuronal necrosis secondary to denaturation of proteins.[1],[17] The onset of action following alcohol injection is noted within hours, lasting from 2 weeks to 36 weeks.[17] The onset and duration of phenol injections are variable; generally, reported duration is between 1 month and 36 months.[17] Factors influencing the onset and duration of action of phenol include: concentration of the medication, duration of exposure, method of delivery, and history of prior injections. With regeneration of the neuromuscular junction the effects of alcohol and phenol injections wear off. Alcohol and phenol injections are not as common as that of botulinum toxin. Disadvantages of alcohol and phenol injections include need for special skills, electrical stimulation procedure, sedation, and anesthesia.
Intrathecal baclofen
Intrathecal delivery of baclofen allows much higher cerebrospinal fluid (CSF) concentration while reducing the likelihood of generalized side effects that are associated with oral administration.[1],[17] The baclofen pump is implanted subcutaneously in the abdomen, and the catheter extending from the pump is positioned intrathecally at appropriate level.
A trial dose of baclofen is given to assess the response of intrathecal baclofen before insertion of the pump. Intrathecal baclofen has been shown to be effective in reducing lower extremity spasticity as well as upper extremity spasticity. The effectiveness has been shown to last for many years.
Dose dependent side effects include weakness, fatigue, confusion, hypotonia and lethargy. Sudden discontinuation can lead to a withdrawal syndrome as discussed earlier. This can occur from pump malfunction. Similarly, overdose from incorrect programming for delivery of appropriate dose can lead to respiratory depression and coma. Complications associated with pump include CSF leakage, catheter infections and meningitis[21].
Conclusion
Spasticity is one of the main clinical features seen in children with cerebral palsy. Before considering treatment to reduce spasticity, a careful assessment should be done weighing the risks of treatment versus the benefits of reducing the spasticity. In some children spasticity may serve to maintain posture and ambulation. Early physiotherapy and occupational therapy interventions are quite effective in prevention and treatment of spasticity. In addition to various non-pharmacologic measures, several pharmacologic agents are effective in spasticity management. Many factors influence the choice of a particular intervention and treatment decisions should be made on an individual basis. For generalized treatment, oral drugs such as baclofen, diazepam, and tizinadine have been used. Local spasticity can be effectively reduced by intramuscular injections of botulinum toxin.
References
1. Koman LA, Smith BP, Shilt JS. Cerebral palsy. Lancet 2004; 363 : 1619-1631.
2. Singhi PD. Cerebral palsy management. Indian J Pediatr 2004; 71 : 635-639
3. Bax M, Goldstein M, Rosenbaum P et al. Proposed definition and classification of cerebral palsy. Dev Med Child Neurol 2005; 47 : 571-576.
4. Lin JP. The assessment and management of hypertonus in cerebral palsy: a physiological atlas (road map). Clinics in Developmental Medicine 2003; 161 : 85-104.
5. Sanger TD. Pathophysiology of pediatric movement disorders. J Child Neurol 2003; 18 : S9-S24.
6. Goldstein EM. Spasticity management: an overview. J Child Neurol 2001; 16 : 16-23.
7. Matthews DJ, Wilson P. Cerebral palsy. In Molnar GE, Alexander MA, eds. Pediatric Rehabilitation . 3rd edn. Philadelphia; Hanley and Belfus, 1999; 193-218.
8. Tilton AH. Management of spasticity in children with cerebral palsy. Semin Pediatr Neurol 2004; 11(1) : 58-65.
9. Tilton AH, Maria BL. Consensus statement on pharmacotherapy for spasticity. J Child Neurol 2003
10. Krach LE: Pharmacotherapy of spasticity: oral medications and intrathecal baclofen. J Child Neurol 2001; 16(1):31-36.
11. Thompson AJ, Jarrett L, Lockley L, Marsden J, Stevenson VL: Clinical management of Spasticity. J Neurol Neurosurg Psychiatry 2005; 76(4) : 459-463.
12. Herman R. The myotatic reflex: clinico-physiological aspects of spasticity and contracture Brain 1970; 93 : 273-312.
13. Edgar TS. Oral pharmacotherapy of childhood movement disorders. J Child Neurol 2003; 18 : S40-S49.
14. Matthew A, Matthew MC. The efficacy of diazepam in enhancing motor function in children with spastic cerebral palsy. J Trop Pediatr 2005; 51(2) : 109-113.
15. Matthew A, Matthew MC. Bedtime diazepam enhances well-being in children with spastic cerebral palsy. Pediatr Rehabil 2005; 8(1) : 63-66.
16. Wagstaff AJ, Bryson HM. Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs 1997; 53(3) : 435-452.
17. Tilton AH. Injectable neuromuscular blockade in the treatment of spasticity and movement disorders. J Child Neurol 2003; 18 : S50-S66.
18. Jefferson RJ. Botulinium toxin in the management of cerebral palsy. Dev Med Child Neurol 2004; 46(7) : 491-499.
19. Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy. Cochrane Database Syst Rev 2004; 18(4) : CD003469.
20. Edgar TS. Clinical utility of botulinum toxin in the treatment of cerebral palsy: comprehensive review. J Child Nerurol 2001; 16 : 37-46.
21. Pidcock FS. The emerging role of therapeutic botulinum toxin in the tretement of cerebral palsy. Journal of Pediatrics 2004; 145 : S33-S35.(Patel Dilip R, Soyode Olu)
Abstract
Motor function abnormalities are a key feature of cerebral palsy. Spasticity is one of the main motor abnormalities seen in children with cerebral palsy. Spasticity is a velocity dependent increased resistance to movement. While in some children, spasticity may adversely impact the motor abilities, in others, it may help maintain posture and ability to ambulate. Thus, treatment to reduce spasticity requires careful consideration of various factors. Non-pharmacologic interventions used to reduce spasticity include physiotherapy, occupational therapy, use of adaptive equipment, various orthopedic surgical procedures and neurosurgical procedures. Pharmacologic interventions used for reducing spasticity in children with cerebral palsy reviewed in this article include oral administration of baclofen, diazepam, dantrolene and tizanidine, intrathecal baclofen, and local injections of botulinum toxin, phenol, and alcohol.
Keywords: Spasticity; Baclofen; Dantolene; Botulinum toxin; Phenol
Motor function abnormalities are a key feature of cerebral palsy.[1],[2],[3] As described by JP. Lin, the disordered motor skills experienced by children with cerebral palsy include delayed motor development, muscle weakness, impaired movement sequencing, dexterity, anticipatory control, abnormal posturing, exaggerated reflexes, muscle spasms, muscle stiffness, and joint deformities.[4]
A clinical finding seen in children with cerebral palsy as part of the motor disorder is the development of clasp-knife spasticity. According to the Taskforce on Childhood Motor Disorders, spasticity is defined as "hypertonia in which one or both of the following signs are present: (1) Resistance to externally imposed movement increases with increasing speed of stretch and varies with the direction of joint movement. (2) Resistance to externally imposed movement rises rapidly above threshold speed or joint angle."[5] In other words, spasticity refers to a velocity- dependent increase in resistance to movement. Spasticity is associated with both positive (hypertonia, clonus, increased deep tendon reflexes, persistence of primitive reflexes, Babinski sign) and negative (decreased coordination, decreased ability for motor planning, weakness, decreased muscular endurance) features of the upper motor neuron syndrome.[6],[7],[8],[9] Most treatment modalities aimed at reducing spasticity do so by affecting the positive symptoms of spasticity.
Spasticity can be aggravated by pain, stress, fatigue, fever, cold, systemic illness, lack of sleep, constipation, diarrhea, tight fitting clothes, improperly fitted orthoses, immobility, and hormonal changes.[2],[4],[10],[11] In addition to cerebral palsy, spasticity can also be seen in children with multiple sclerosis, traumatic brain injury, stroke, anoxic brain injury, spinal cord injury, hemispherectomy and neurodegenerative diseases.[4],[5],[7]
Clinically, the degree of spasticity noted varies depending upon the state of arousal of the child at the time as well as the duration since the original insult to the brain.[4] The natural history of reflex excitability following acute stroke was described by R. Herman, cited by Lin, progresses through the following four phases: "(1) flaccid and inexcitable, (2) hyperrefelxia and clonus in first few months, lasting a few years (3) reduction in reflex excitability, and (4) stiff, inexcitable and shortened muscles: fixed contracture."[4],[12]
Reduction of spasticity is only one of the many facets of the overall management of motor disorders of cerebral palsy. While in some children spasticity may interfere with motor function, in others it may in fact be useful to maintain posture and the capacity to ambulate. Thus it is essential to carefully weigh the potential benefits vs adverse effects on motor function of reducing spasticity. Factors to be considered in selecting the child for the treatment to reduce spasticity include: cognitive and emotional maturity of the child, growth potential, presence or absence of positive and negative features of upper motor neuron syndrome, distribution of the spasticity, likely underlying cause of the spasticity, whether the spasticity is acute or chronic, static or progressive, and psychosocial factors that might affect treatment adherence.[1],[2],[4],[5],[6],[9] For objectivity, the severity of spasticity can be assessed by standardized instruments, for example, the Ashworth Scale, Modified Ashworth Scale, or the Tardieu Scale.[1]
Once a decision is made to treat a child, the age of the child at the time of treatment is an important consideration in selecting the appropriate therapeutic intervention or a combination thereof. It is generally agreed that children treated before the age of 4-5 have significantly less occurrence of progressive joint contractures and limb deformities.[2],[5],[9] Early and aggressive physiotherapy and occupational therapy have been shown to be very effective, and may obviate the later need for other therapeutic interventions to reduce spasticity.[1],[2] Optimal benefit from the injection of botulinum toxin is seen in children aged 2 to 6 yr. Surgical procedures on the other hand should be delayed until after 6-8 yr of age, and phenol injections until skeletal maturity is reached.[1] Other factors influencing the choice of specific intervention include distribution and severity of spasticity, associated medical conditions, side effects, ease of administration and prior treatments.[1],[2],[4],[5] Various therapeutic modalities used to reduce spasticity are listed in table1. An overview of the pharmacologic interventions is presented further in this review.
Oral Drugs
In general, the use of oral medications is limited to children with generalized spasticity who may benefit from mild reduction of spasticity.[13] Higher dosages are associated with systemic side effects like sedation, weakness, behavior changes, and other central side effects limiting their usefulness.
Baclofen
Baclofen is a gamma-amino butyric acid (GABA) agonist. Baclofen reduces the release of excitatory neurotransmitters and substance P by binding to the GABAB receptors.[5],[7],[10] Because its primary action is at the spinal cord level, baclofen is especially useful in treating spasticity of spinal cord origin, such as in patients with spinal cord injury and demyelinating myelopathies. Although the use of baclofen in children with cerebral palsy is not well established, it may be useful in selected patients. Starting dose is 2.5mg daily, which can be titrated up gradually to a maximum of 20-60mg/day, based on the response.[6],[7],[10]
Side effects include weakness, sedation, ataxia, nausea, impaired cognition, orthostatic hypotension, dizziness, and, in some cases, depression.[5],[6],[7],[13] Baclofen overdose can cause severe flaccidity and coma requiring intensive care and assisted ventilation until, baclofen is metabolized by the body. As such baclofen is non-toxic to neural tissue.
Sudden withdrawal of baclofen may result in a withdrawal syndrome which can be potentially serious.[5],[8],[10],[13] Withdrawal syndrome has been reported after sudden discontinuation of oral as well as intrathecal baclofen. The syndrome is characterized by seizures, hallucinations, hyperthermia, dysesthesia, pruritis, and rebound spasticity. Neuroleptic malignant syndrome and death have been reported with sudden withdrawal of baclofen. Treatment of baclofen withdrawal syndrome is immediate administration of oral baclofen.
Benzodiazepines
Diazepam and clonazepam have been used in children with cerebral palsy to improve tone. Benzodiazepines act both at the brain stem as well as spinal cord levels to increase the affinity of GABA to the GABAA receptor complex presynaptically and postsynaptically.[5],[13],[14] Benzodiazepines increase the GABA-mediated inhibition supraspinally and in the spinal cord. Benzodiazepines have been shown to reduce generalized spasticity, hyperreflexia, and painful muscle spasms.[14],[15] Improvement is also seen in passive range of joint motion and spontaneous movements.
Diazepam has been shown to improve sleep and reduce anxiety. Diazepam has been used in the dosage range from 1 to 10 mg per dose administered 3 to 4 times per day.[7],[10] Sedation is the most common side effect. Other less common side effects include increased drooling, ataxia, and cognitive dullness. In some cases, tolerance and dependence is seen with prolonged use. Clonazepam is rapidly absorbed after oral administration, has a half-life of 18-28 hrs, and has been used to reduce night time muscle spasms. Typical dosage in children is 0.01-0.3 mg/ kg/day given 2 to 3 times per day.[10],[11],[13]
Dantrolene Sodium
Dantrolene acts at the level of the skeletal muscle to reduce spasticity by inhibiting calcium release from the sarcoplasmic reticulum, thus uncoupling electrical excitation from contraction.[1],[4],[6],[7],[13] Dantrolene sodium reaches peak blood levels in 3-6 hrs, while its active metabolite 5-hydroxydantrolene reaches peak levels in 4-8 hrs after oral administration.[10],[13] In children, dantrolene is started at a low dose, typically 0.5 mg/kg given twice daily, increasing by 0.5 mg/kg every 5-7 days to a maximum dose of 12 mg/kg/day or 400 mg/day. Dantrolene reduces spasticity by inducing skeletal muscle weakness, which is its most significant side effect. Other side effects include weakness, fatigue, drowsiness and diarrhea.[10] Hepatotoxicity has been reported with the use of dantrolene, and hepatic function must be monitored periodically in patients on dantrolene.
Alpha[2] Adrenergic Agonists
Tizanidine and clonidine have been used in the treatment of spasticity. Alpha[2] noradrenergic agonists act at receptors in the brain and spinal cord.[5],[10],[13] Postulated mechanisms of action include hyperpolarization of motoneurons, prevention of release of excitatory amino acids from the presynaptic terminal of spinal interneurons, and facilitation of the action of inhibitory neurotransmitter gylcine.[4],[5],[6],[10] Both tizanidine and clonidine exert antinociceptive effects mediated by release of substance P in the spinal cord.[10],[16]
Sedation is the most common side effect. Sedative effect may also be helpful in some patients who have difficulty with sleeping. Other side effects include hypotension especially with clonidine, depression, dry mouth, dizziness, and hepatotoxiciy.
Tizanidine is started at a dose of 1 mg given at bedtime for children under 10 yrs and 2 mg for children of 10 yrs or more; maintenance dose is 0.3-0.5 mg/kg/day divided four times daily.[16] Clonidine is given at a starting dose of 0.05 mg per day and increased by 0.05 mg every week to a maximum of 0.3 mg per day given in three divided doses.[13] Clonidine is available as tablets and transderdemal patch.
Local drug injections
Local intramuscular injections of alcohol or phenols exert their effects by causing chemodenervation, while local injection of botulinum toxin casues neuromuscular blockade.[1] In either case nerve muscle impulse transmission is interrupted.
Botulinum Toxin
Botulinum toxin is an exotoxin produced by the bacterium Clostridium botulinum. Seven immunogenically distinct serotypes have been identified named A to G. Botulinum toxin A is serotype used clinically with well-established efficacy. Botulinum toxin works by inhibiting presynaptic acetylcholine release at the neuromuscular junction causing reversible partial flaccid paralysis of the muscle in which it is injected.[1],[17],[18] Its effects are usually noticeable within 12-72 hrs following injection in the affected muscle with effects lasting for 3-6 months. The effects of botulinum toxin injection are reversed over time because of proximal nerve sprouting followed by recovery of vesicle turnover and gradual regression of sprouts.
With repeated injections, effectiveness may be lost as there may be development of resistance to the botulinum toxin due to formation of antibodies against the toxin. Use of minimum effective dose, use of different serotypes, and not giving repeated doses sooner then every 3 months reduce the chances of development of resistance.[17],[19],[20]
Dose of injection vary depending up on the type of commercial preparation used. Injections of botulinum toxin usually need to be repeated every 3-6 months to maintain optimal therapeutic effectiveness.
The most common side effects of botulinum toxin injection are local pain and bruising. Other reported side effects include excessive weakness of muscles, constipation, fever, and incontinence. Botulinum toxin injection has a well-established safety record, and serious side effects such as dysphagia and aspiration pneumonia, especially with injection in the head and neck region, are rare.[1],[17],[18],[20]
Botulinum toxin is used most effectively in the treatment of focal spasticity. Optimal effectiveness has been reported when used between 1 and 6 yr of age for the treatment of lower extremity spasticity, and between 5 and 15 yr of age for the treatment of children with hemiplegia.[17],[18],[20] Botulinum toxin has been shown to be effective in reducing spasticity in lower extremity, improve joint range of motion and gait, improve equinus deformity, and improve adductor tone. It has been shown to be effective in reducing upper extremity spasticity, dystonia and function.[18],[19] Use of botulinum toxin is not recommended in the presence of fixed joint or muscle contracture because of its ineffectiveness in these cases.
Alcohol and Phenol Injections
Injections of phenol or alcohol are given in the specific nerve or muscle after identifying the nerve and muscle affected by electrical stimulation. Alcohol and phenol injections result in local neuronal necrosis secondary to denaturation of proteins.[1],[17] The onset of action following alcohol injection is noted within hours, lasting from 2 weeks to 36 weeks.[17] The onset and duration of phenol injections are variable; generally, reported duration is between 1 month and 36 months.[17] Factors influencing the onset and duration of action of phenol include: concentration of the medication, duration of exposure, method of delivery, and history of prior injections. With regeneration of the neuromuscular junction the effects of alcohol and phenol injections wear off. Alcohol and phenol injections are not as common as that of botulinum toxin. Disadvantages of alcohol and phenol injections include need for special skills, electrical stimulation procedure, sedation, and anesthesia.
Intrathecal baclofen
Intrathecal delivery of baclofen allows much higher cerebrospinal fluid (CSF) concentration while reducing the likelihood of generalized side effects that are associated with oral administration.[1],[17] The baclofen pump is implanted subcutaneously in the abdomen, and the catheter extending from the pump is positioned intrathecally at appropriate level.
A trial dose of baclofen is given to assess the response of intrathecal baclofen before insertion of the pump. Intrathecal baclofen has been shown to be effective in reducing lower extremity spasticity as well as upper extremity spasticity. The effectiveness has been shown to last for many years.
Dose dependent side effects include weakness, fatigue, confusion, hypotonia and lethargy. Sudden discontinuation can lead to a withdrawal syndrome as discussed earlier. This can occur from pump malfunction. Similarly, overdose from incorrect programming for delivery of appropriate dose can lead to respiratory depression and coma. Complications associated with pump include CSF leakage, catheter infections and meningitis[21].
Conclusion
Spasticity is one of the main clinical features seen in children with cerebral palsy. Before considering treatment to reduce spasticity, a careful assessment should be done weighing the risks of treatment versus the benefits of reducing the spasticity. In some children spasticity may serve to maintain posture and ambulation. Early physiotherapy and occupational therapy interventions are quite effective in prevention and treatment of spasticity. In addition to various non-pharmacologic measures, several pharmacologic agents are effective in spasticity management. Many factors influence the choice of a particular intervention and treatment decisions should be made on an individual basis. For generalized treatment, oral drugs such as baclofen, diazepam, and tizinadine have been used. Local spasticity can be effectively reduced by intramuscular injections of botulinum toxin.
References
1. Koman LA, Smith BP, Shilt JS. Cerebral palsy. Lancet 2004; 363 : 1619-1631.
2. Singhi PD. Cerebral palsy management. Indian J Pediatr 2004; 71 : 635-639
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