Original Article
Comparison of Efficacy and Side Effects of Oral Baclofen Versus Tizanidine Therapy with Adjuvant Botulinum Toxin Type A in Children With Cerebral Palsy and Spastic Equinus Foot Deformity
Journal of Child Neurology 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815587030 jcn.sagepub.com
Alper I. Dai, MD1, Sefika N. Aksoy, MD2, and Abdullah T. Demiryu¨rek, PhD3
Abstract This retrospective study aimed to compare the therapeutic response, including side effects, for oral baclofen versus oral tizanidine therapy with adjuvant botulinum toxin type A in a group of 64 pediatric patients diagnosed with static encephalopathy and spastic equinus foot deformity. Following botulinum toxin A treatment, clinical improvement led to the gradual reduction of baclofen or tizanidine dosing to one-third of the former dose. Gross Motor Functional Measure and Caregiver Health Questionnaire scores were markedly elevated post–botulinum toxin A treatment, with scores for the tizanidine (Gross Motor Functional Measure: 74.45 + 3.72; Caregiver Health Questionnaire: 72.43 + 4.29) group significantly higher than for the baclofen group (Gross Motor Functional Measure: 68.23 + 2.66; Caregiver Health Questionnaire: 67.53 + 2.67, P < .001). These findings suggest that the combined use of botulinum toxin A and a low dose of tizanidine in treating children with cerebral palsy appears to be more effective and has fewer side effects versus baclofen with adjuvant botulinum toxin A. Keywords adverse effect, baclofen, botulinum toxin, cerebral palsy, tizanidine Received November 4, 2014. Received revised April 14, 2015. Accepted for publication April 21, 2015.
Children with cerebral palsy can present with a variety of motor problems, changing with growth and development. This disorder results from insult or injury to the brain before birth or in early childhood that causes neural connections to be formed in aberrant ways and leads to persistent abnormal limb strength, control, or both.1 Cerebral palsy is thought to affect 2.0-2.5 individuals per 1000 of the general population.2 The reported incidence, prevalence, and most common causes of cerebral palsy have varied over time because of changes in prenatal and pediatric care.3 There is no standardized approach to spasticity management of cerebral palsy. But adequate assessment of the specific impairments causing disability is necessary for appropriate interventions to be instituted.4 The treatment strategy depends on the degree of functional failure caused by the spasticity and its location. Botulinum toxin A has been used to treat focal dystonias and rigidity in hemiplegic or diplegic spasticity.5 Botulinum toxin A produces dose-related weakness of skeletal muscle by impairing the release of acetylcholine at the neuromuscular junction. Based on this mechanism, a number of clinical trials have investigated the effectiveness of botulinum toxin A in improving
lower extremity functions in children with cerebral palsy. Some studies have found botulinum toxin A to be effective,6-9 while others did not find the effect to be significant.10-12 Botulinum toxin A injection allows spasticity control for a 3- to 4-month period and, therefore, repeated treatments are generally necessary. The next injection takes place over 3 to 6 months, but an immunity phenomenon occurs, which decreases botulinum toxin A efficacy up to 50%.13 Described adverse events tend to be
1
Department of Pediatrics, Faculty of Medicine, Division of Pediatric Neurology, University of Gaziantep, Gaziantep, Turkey 2 Department of Biochemistry, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey 3 Department of Medical Pharmacology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey Corresponding Author: Alper I. Dai, MD, Department of Pediatrics, Faculty of Medicine, Division of Pediatric Neurology, University of Gaziantep, Gaziantep, 27310, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at University of Texas Libraries on August 31, 2015
2
Journal of Child Neurology
expected consequences of muscle relaxation, such as weakness or initial loss of function.14,15 Oral medications including baclofen and tizanidine are a systemic, rather than focal, treatment for spasticity in children with cerebral palsy.16 Baclofen, a derivative of g-aminobutyric acid (GABA), is a GABAB receptor agonist. Baclofen has both presynaptic and postsynaptic actions. At the presynaptic site, baclofen decreases calcium conduction with resultant decreased excitatory amino acid release. At the postsynaptic site, baclofen stimulates opening of potassium channels, leading to neuronal hyperpolarization. In addition, baclofen can inhibit the release of substance P.17 The clinical effects include decreased resistance to passive range of motion, decrease in hyperreflexia, and reduction in painful spasms.18 However, increased weakness of the spastic limbs can limit its usefulness. In addition, abrupt cessation of sustained treatment should be avoided because sudden withdrawal of baclofen has been associated with hallucinations and seizures.19 Tizanidine is a centrally acting a2-adrenoceptor agonist believed to reduce spasticity by blocking nerve impulses through presynaptic inhibition of motor neurons.20 The effects of tizanidine are linked mainly with its a2-adrenergic agonist properties, although its affect on imidazoline receptors can also play a role.21 Tizanidine acts predominantly at presynaptic level, reducing the release of the excitatory amino acids glutamate and aspartate from the presynaptic terminals of spinal cord interneurons. It can also decrease substance P release from small sensory afferents.21 The clinical effects of tizanidine include reduced muscle tone, spasm frequency, and hyperreflexia. Because of its adrenergic action, hypotension and orthostatic hypotension can occur. Increased sedation can be due to actions at the imidazoline receptors. Two previous studies report outcomes of tizanidine treatment in children with cerebral palsy. One study found that 30 diplegic children with severe form of cerebral palsy received tizanidine monotherapy, and showed improved motor ability.22 Other small placebo-controlled study showed a significant reduction of the spasticity in children with tizanidine.23 However, no functional measures were used in that study. The American Academy of Neurology practice parameter recommends that tizanidine can be considered for the treatment of spasticity in childhood cerebral palsy, but the evidence was deemed insufficient to comment on effects on function.5,24 Antispastic drugs are used as single therapies rather than combined approaches in the treatment of cerebral palsy and spastic equinus foot deformity. Spasticity can be alleviated to a small degree with oral medications including baclofen and tizanidine.5 The authors’ hypothesis is that the combined use of antispastic drugs with botulinum toxin A are beneficial, and increase the efficacy of the oral drug treatment in children with cerebral palsy and spastic equinus foot deformity. The authors also hypothesize that combined treatment approach leads to fewer side effects of the drugs. Therefore, the purpose of this study was to investigate the impact of botulinum toxin A injections in patients already receiving either tizanidine or baclofen. The authors have also aimed to compare the side effect profiles and oral drug reductions with these treatments.
Methods Sixty-four children with gastrocnemius tendon contracture from spasticity were included for this retrospective study. All of these children had spastic bilateral equinus foot deformity associated with cerebral palsy or static encephalopathy (spastic paraparesis); their diagnosis was confirmed by a pediatric neurologist. Diplegic or hemiplegic patients were not included to this study. The subjects were between the ages of 2 and 14 years old, with a mean age of 4.9 years, and were treated at Gaziantep University Hospital, Turkey, between 2009 and 2013. All the patients with spastic equinus foot deformity associated with cerebral palsy or spastic paraparesis were treated during these 5 years period and included to the study. A total of 31 children were treated with adjuvant oral baclofen, while 33 received oral tizanidine. Each had already been placed in a rehabilitation program, and was referred by their therapist to the authors’ center for botulinum toxin A treatment. The authors focused on patients who most likely to require gastrocnemius lengthening, but who had not yet reached the point at which surgery was neither clearly indicated nor willingly accepted by the child’s parents. The goal of botulinum toxin A injection was to increase the range of motion in the affected joint. Selection criteria for intramuscular botulinum toxin A injections include dynamic deformity interfering with function, producing pain or contributing to progressive deformity, and painful spasticity without fixed muscle contracture. In all cases, botulinum toxin A was added to the oral baclofen or tizanidine medication regimen, which had been only partially effective in ameliorating symptoms in the treatment of spastic equinus foot in cerebral palsy. The dosage range for tizanidine was 0.3-0.5 mg/kg/ day, taken in 4 divided doses.25 The maximum dose for baclofen was 40 mg/day in 3 divided doses if 8 years of age.26 The dosage of botulinum toxin A must be individualized for each patient. At the authors’ center, 20-24 units of botulinum toxin A (Botox, Allergan Pharma, Parsippany, NJ, USA) per kg of body weight with a maximum of 300 units per child on 1 occasion, double/triple level lower of gastrocnemius muscle, with a maximum dose of 50 units per injection site was used.27,28 Dosages of 16-24 units per kg body weight are now in use in experienced hands for double or triple level lower limb sites. However, the dose–efficiency relationship might only be linear for a distinct range. The short 1 ml ‘‘diabetic’’ all-in-1 syringe and needle was used for this purpose and injected more proximally as stated in the previous studies.28 Intranasal midazolam was used, as needed, as an anesthetic agent for the procedure.29 The authors palpated the gastrocnemius muscle using the skin as a fulcrum to determine needle placement without electromyography guidance. Patient follow-ups were at 2- to 4-week intervals, with evaluations lasting a total of 12 weeks. Laboratory tests were done monthly due to possible side effects. The authors checked complete blood count and differentiation, liver function test, thyroid function test, electrolytes, serum glucose, lipid, and albumin levels. Cardiac evaluations and electrocardiography were performed monthly for all patients to evaluate the possible cardiac effects of the medication. The therapeutic response in both groups, those orally receiving baclofen or tizanidine, were assessed by means of Gross Motor Functional Measure30 and the Modified Ashworth Scale31 by the same pediatric neurologist. The Gross Motor Functional Measure is designed to measure quantitative changes in gross motor function of children with cerebral palsy for skills from lying and rolling up to walking, running, and jumping; the modified 66-item scale is a compact version of the original 88-item scale.30 The primary outcome measure was the Gross Motor Functional Measure–66 for this
Downloaded from jcn.sagepub.com at University of Texas Libraries on August 31, 2015
Dai et al
3
Table 1. Demographic and Clinical Characteristics of the Treatment Groups.
Sex: male/female; n (%) Age (years) GMFM before BTX-A GMFM after BTX-A MAS before BTX-A MAS after BTX-A CHQ before BTX-A CHQ after BTX-A
Baclofen group (n ¼ 31)
Tizanidine group (n ¼ 33)
P
20/11 (64/36) 4.7 + 3.8 44.14 + 3.41 68.23 + 2.66** 3.61 + 2.35 2.68 + 2.84 56.11 + 4.25 67.53 + 2.67**
21/12 (63/37) 5.1 + 1.5 45.18 + 2.63 74.45 + 3.72** 3.79 + 4.78 1.94 + 2.21* 57.96 + 6.74 72.43 + 4.29**
1.000 .577 .175
Comparison of Efficacy and Side Effects of Oral Baclofen Versus Tizanidine Therapy with Adjuvant Botulinum Toxin Type A in Children With Cerebral Palsy and Spastic Equinus Foot Deformity
Journal of Child Neurology 1-6 ª The Author(s) 2015 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073815587030 jcn.sagepub.com
Alper I. Dai, MD1, Sefika N. Aksoy, MD2, and Abdullah T. Demiryu¨rek, PhD3
Abstract This retrospective study aimed to compare the therapeutic response, including side effects, for oral baclofen versus oral tizanidine therapy with adjuvant botulinum toxin type A in a group of 64 pediatric patients diagnosed with static encephalopathy and spastic equinus foot deformity. Following botulinum toxin A treatment, clinical improvement led to the gradual reduction of baclofen or tizanidine dosing to one-third of the former dose. Gross Motor Functional Measure and Caregiver Health Questionnaire scores were markedly elevated post–botulinum toxin A treatment, with scores for the tizanidine (Gross Motor Functional Measure: 74.45 + 3.72; Caregiver Health Questionnaire: 72.43 + 4.29) group significantly higher than for the baclofen group (Gross Motor Functional Measure: 68.23 + 2.66; Caregiver Health Questionnaire: 67.53 + 2.67, P < .001). These findings suggest that the combined use of botulinum toxin A and a low dose of tizanidine in treating children with cerebral palsy appears to be more effective and has fewer side effects versus baclofen with adjuvant botulinum toxin A. Keywords adverse effect, baclofen, botulinum toxin, cerebral palsy, tizanidine Received November 4, 2014. Received revised April 14, 2015. Accepted for publication April 21, 2015.
Children with cerebral palsy can present with a variety of motor problems, changing with growth and development. This disorder results from insult or injury to the brain before birth or in early childhood that causes neural connections to be formed in aberrant ways and leads to persistent abnormal limb strength, control, or both.1 Cerebral palsy is thought to affect 2.0-2.5 individuals per 1000 of the general population.2 The reported incidence, prevalence, and most common causes of cerebral palsy have varied over time because of changes in prenatal and pediatric care.3 There is no standardized approach to spasticity management of cerebral palsy. But adequate assessment of the specific impairments causing disability is necessary for appropriate interventions to be instituted.4 The treatment strategy depends on the degree of functional failure caused by the spasticity and its location. Botulinum toxin A has been used to treat focal dystonias and rigidity in hemiplegic or diplegic spasticity.5 Botulinum toxin A produces dose-related weakness of skeletal muscle by impairing the release of acetylcholine at the neuromuscular junction. Based on this mechanism, a number of clinical trials have investigated the effectiveness of botulinum toxin A in improving
lower extremity functions in children with cerebral palsy. Some studies have found botulinum toxin A to be effective,6-9 while others did not find the effect to be significant.10-12 Botulinum toxin A injection allows spasticity control for a 3- to 4-month period and, therefore, repeated treatments are generally necessary. The next injection takes place over 3 to 6 months, but an immunity phenomenon occurs, which decreases botulinum toxin A efficacy up to 50%.13 Described adverse events tend to be
1
Department of Pediatrics, Faculty of Medicine, Division of Pediatric Neurology, University of Gaziantep, Gaziantep, Turkey 2 Department of Biochemistry, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey 3 Department of Medical Pharmacology, Faculty of Medicine, University of Gaziantep, Gaziantep, Turkey Corresponding Author: Alper I. Dai, MD, Department of Pediatrics, Faculty of Medicine, Division of Pediatric Neurology, University of Gaziantep, Gaziantep, 27310, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at University of Texas Libraries on August 31, 2015
2
Journal of Child Neurology
expected consequences of muscle relaxation, such as weakness or initial loss of function.14,15 Oral medications including baclofen and tizanidine are a systemic, rather than focal, treatment for spasticity in children with cerebral palsy.16 Baclofen, a derivative of g-aminobutyric acid (GABA), is a GABAB receptor agonist. Baclofen has both presynaptic and postsynaptic actions. At the presynaptic site, baclofen decreases calcium conduction with resultant decreased excitatory amino acid release. At the postsynaptic site, baclofen stimulates opening of potassium channels, leading to neuronal hyperpolarization. In addition, baclofen can inhibit the release of substance P.17 The clinical effects include decreased resistance to passive range of motion, decrease in hyperreflexia, and reduction in painful spasms.18 However, increased weakness of the spastic limbs can limit its usefulness. In addition, abrupt cessation of sustained treatment should be avoided because sudden withdrawal of baclofen has been associated with hallucinations and seizures.19 Tizanidine is a centrally acting a2-adrenoceptor agonist believed to reduce spasticity by blocking nerve impulses through presynaptic inhibition of motor neurons.20 The effects of tizanidine are linked mainly with its a2-adrenergic agonist properties, although its affect on imidazoline receptors can also play a role.21 Tizanidine acts predominantly at presynaptic level, reducing the release of the excitatory amino acids glutamate and aspartate from the presynaptic terminals of spinal cord interneurons. It can also decrease substance P release from small sensory afferents.21 The clinical effects of tizanidine include reduced muscle tone, spasm frequency, and hyperreflexia. Because of its adrenergic action, hypotension and orthostatic hypotension can occur. Increased sedation can be due to actions at the imidazoline receptors. Two previous studies report outcomes of tizanidine treatment in children with cerebral palsy. One study found that 30 diplegic children with severe form of cerebral palsy received tizanidine monotherapy, and showed improved motor ability.22 Other small placebo-controlled study showed a significant reduction of the spasticity in children with tizanidine.23 However, no functional measures were used in that study. The American Academy of Neurology practice parameter recommends that tizanidine can be considered for the treatment of spasticity in childhood cerebral palsy, but the evidence was deemed insufficient to comment on effects on function.5,24 Antispastic drugs are used as single therapies rather than combined approaches in the treatment of cerebral palsy and spastic equinus foot deformity. Spasticity can be alleviated to a small degree with oral medications including baclofen and tizanidine.5 The authors’ hypothesis is that the combined use of antispastic drugs with botulinum toxin A are beneficial, and increase the efficacy of the oral drug treatment in children with cerebral palsy and spastic equinus foot deformity. The authors also hypothesize that combined treatment approach leads to fewer side effects of the drugs. Therefore, the purpose of this study was to investigate the impact of botulinum toxin A injections in patients already receiving either tizanidine or baclofen. The authors have also aimed to compare the side effect profiles and oral drug reductions with these treatments.
Methods Sixty-four children with gastrocnemius tendon contracture from spasticity were included for this retrospective study. All of these children had spastic bilateral equinus foot deformity associated with cerebral palsy or static encephalopathy (spastic paraparesis); their diagnosis was confirmed by a pediatric neurologist. Diplegic or hemiplegic patients were not included to this study. The subjects were between the ages of 2 and 14 years old, with a mean age of 4.9 years, and were treated at Gaziantep University Hospital, Turkey, between 2009 and 2013. All the patients with spastic equinus foot deformity associated with cerebral palsy or spastic paraparesis were treated during these 5 years period and included to the study. A total of 31 children were treated with adjuvant oral baclofen, while 33 received oral tizanidine. Each had already been placed in a rehabilitation program, and was referred by their therapist to the authors’ center for botulinum toxin A treatment. The authors focused on patients who most likely to require gastrocnemius lengthening, but who had not yet reached the point at which surgery was neither clearly indicated nor willingly accepted by the child’s parents. The goal of botulinum toxin A injection was to increase the range of motion in the affected joint. Selection criteria for intramuscular botulinum toxin A injections include dynamic deformity interfering with function, producing pain or contributing to progressive deformity, and painful spasticity without fixed muscle contracture. In all cases, botulinum toxin A was added to the oral baclofen or tizanidine medication regimen, which had been only partially effective in ameliorating symptoms in the treatment of spastic equinus foot in cerebral palsy. The dosage range for tizanidine was 0.3-0.5 mg/kg/ day, taken in 4 divided doses.25 The maximum dose for baclofen was 40 mg/day in 3 divided doses if 8 years of age.26 The dosage of botulinum toxin A must be individualized for each patient. At the authors’ center, 20-24 units of botulinum toxin A (Botox, Allergan Pharma, Parsippany, NJ, USA) per kg of body weight with a maximum of 300 units per child on 1 occasion, double/triple level lower of gastrocnemius muscle, with a maximum dose of 50 units per injection site was used.27,28 Dosages of 16-24 units per kg body weight are now in use in experienced hands for double or triple level lower limb sites. However, the dose–efficiency relationship might only be linear for a distinct range. The short 1 ml ‘‘diabetic’’ all-in-1 syringe and needle was used for this purpose and injected more proximally as stated in the previous studies.28 Intranasal midazolam was used, as needed, as an anesthetic agent for the procedure.29 The authors palpated the gastrocnemius muscle using the skin as a fulcrum to determine needle placement without electromyography guidance. Patient follow-ups were at 2- to 4-week intervals, with evaluations lasting a total of 12 weeks. Laboratory tests were done monthly due to possible side effects. The authors checked complete blood count and differentiation, liver function test, thyroid function test, electrolytes, serum glucose, lipid, and albumin levels. Cardiac evaluations and electrocardiography were performed monthly for all patients to evaluate the possible cardiac effects of the medication. The therapeutic response in both groups, those orally receiving baclofen or tizanidine, were assessed by means of Gross Motor Functional Measure30 and the Modified Ashworth Scale31 by the same pediatric neurologist. The Gross Motor Functional Measure is designed to measure quantitative changes in gross motor function of children with cerebral palsy for skills from lying and rolling up to walking, running, and jumping; the modified 66-item scale is a compact version of the original 88-item scale.30 The primary outcome measure was the Gross Motor Functional Measure–66 for this
Downloaded from jcn.sagepub.com at University of Texas Libraries on August 31, 2015
Dai et al
3
Table 1. Demographic and Clinical Characteristics of the Treatment Groups.
Sex: male/female; n (%) Age (years) GMFM before BTX-A GMFM after BTX-A MAS before BTX-A MAS after BTX-A CHQ before BTX-A CHQ after BTX-A
Baclofen group (n ¼ 31)
Tizanidine group (n ¼ 33)
P
20/11 (64/36) 4.7 + 3.8 44.14 + 3.41 68.23 + 2.66** 3.61 + 2.35 2.68 + 2.84 56.11 + 4.25 67.53 + 2.67**
21/12 (63/37) 5.1 + 1.5 45.18 + 2.63 74.45 + 3.72** 3.79 + 4.78 1.94 + 2.21* 57.96 + 6.74 72.43 + 4.29**
1.000 .577 .175
