AAN Reviews Evidence for Spasticity Treatments for Childhood Cerebral Palsy
A comprehensive review of published medical research by a special panel of the AAN has found botulinum toxin-A to be effective and generally safe for treating localized or segmental spasticity in children with cerebral palsy (CP), but there was limited or no evidence in favor of most other medications and treatments, with the exception of diazepam.
The Quality Standards Subcommittee's multidisciplinary review, which was developed in full collaboration with the Practice Committee of the Child Neurology Society and published in the Jan. 26 issue of Neurology, also found a critical lack of research on the efficacy of current spasticity treatment options in children with CP.
Neurology Today asked lead author Mauricio R. Delgado, MD, professor of neurology at the University of Texas Southwestern Medical Center and medical director for pediatric neurology at Texas Scottish Rite Hospital for Children in Dallas, to help explain the panel's findings.
WHAT IS THE PREVALENCE OF CP AND RELATED SPASTICITY?
Cerebral palsy is the most common cause of spasticity in children, and a majority of children with CP are affected by spasticity. The prevalence of CP was recently reported to be 3.6 cases per 1000 in 8-year-olds, with very little variation among Western nations. CP will affect more than 10,000 infants born in the United States each year.
SHOULD ALL PATIENTS WITH SPASTICITY RECEIVE SOME TYPE OF DRUG TREATMENT TO REDUCE SYMPTOMS?
Not always. Spasticity is only one component of CP and may not be the main factor interfering with a patient's ability to function or participate in activities of daily living. Also, alleviating spasticity may not always be desirable because some patients experience a decline in function with spasticity reduction.
Reasons to treat spasticity include reducing pain and muscle spasms, facilitating brace use, improving posture, minimizing contractures and deformity, facilitating mobility and dexterity, and improving patient ease of care as well as hygiene or self-care. The decision to use antispasticity medications, however, requires careful assessment of the patient's other impairments, such as weakness and movement disorders.
WHAT DRUGS ARE CURRENTLY BEING USED?
A number of medications have been used, including oral medications like benzodiazepines, dantrolene, baclofen, and tizanidine; neuromuscular blocking agents such as botulinum toxin A and B (BoNT-A and BoNT-B); chemical denervation using phenol and alcohol; and intrathecal baclofen (ITB). Oral medications are used when a generalized antispasticity effect is desired, while chemical denervation agents and ITB are used to treat localized spasticity in one extremity, or severe segmental spasticity.
DID THE PANEL FIND ANY MAJOR CHANGES IN THE AVAILABLE TREATMENT OPTIONS?
The data are not sufficient to support or refute the use of any of the medications that most physicians use to treat children with generalized spasticity. For patients with localized or segmental spasticity that warrants treatment, BoNT-A is an effective and generally safe treatment to reduce spasticity.
HOW DID THE DRUGS THAT WERE REVIEWED COMPARE FROM A SAFETY AND EFFICACY STANDPOINT?
For localized spasticity BoNT-A was found to be an effective treatment to reduce spasticity in the upper and lower extremities. However, there is conflicting evidence regarding functional improvement. BoNT-A was found to be generally safe in children with CP, but the FDA is presently investigating isolated cases of generalized weakness resulting in poor outcomes in some children. There is insufficient evidence to support or refute the use of BoNT-B, phenol, and alcohol injections as a treatment for localized spasticity in children with spastic CP.
For generalized spasticity, diazepam is probably effective in reducing spasticity, but there are insufficient data on its functional benefits and side effects for the panel to make any recommendations. Tizanidine is possibly effective, but there are insufficient data on its effect on function and the drug's side-effect profile. There is also insufficient evidence to support or refute the use of dantrolene, oral baclofen, or ITB.
HOW MANY PUBLISHED STUDIES DID THE PANEL REVIEW?
The authors looked at a total of 978 abstracts initially, and from these 528 were identified as potentially pertinent and reviewed in full. Of these, 218 articles were selected that fulfilled the inclusion/exclusion criteria. Each one was then reviewed, abstracted, and classified by at least two authors, and disagreements were resolved by reaching consensus between the reviewers, the first author, and at least two other authors.
WERE THERE ANY FINDINGS IN THE LITERATURE THAT MIGHT COME AS A SURPRISE TO CLINICIANS?
The most striking finding is the lack of data. For example, none of the pharmacological treatments for generalized spasticity — diazepam, tizanidine, dantrolene, baclofen, and ITB — have been adequately tested for safety and efficacy in children with spasticity due to CP. There is very little information on the functional effects of reducing spasticity.
THE PANEL FOUND CONFLICTING EVIDENCE REGARDING THE EFFECTIVENESS OF DANTROLENE AND ORAL BACLOFEN. WHAT ARE THE CONCERNS?
One Class I study and one Class II dantrolene study reached conflicting results using similar doses. The Class I study found no spasticity improvement and no functional gain, while the Class II study found spasticity improvement associated with improvement in activities of daily living.
In the case of oral baclofen, two Class II studies found opposite findings regarding the antispasticity effect of this drug. Interestingly, the study that found spasticity improvement did not find significant functional gain. Furthermore, a patient who relied on the spastic “crutch” to ambulate showed walking impairment after treatment. The other study, using a similar dose and age group, did not find a significant spasticity reduction but reported significant improvement in achieving a set of goals.
WHAT ABOUT TIZANIDINE?
There is very limited information on the benefits or toxicity profile of this drug in children. The panel found one small Class II study in 10 patients that showed a significant reduction of spasticity, noticed two weeks after starting treatment, but no functional assessments were done.
WHAT DID THE PANEL RECOMMEND FOR FUTURE STUDIES?
There is a need to develop, standardize, and validate clinically relevant spasticity scales — for example, the Tardieu Spasticity Scale — that quantify spasticity according to its current definition. There is also an urgent need for studies to establish efficacy of the current therapies and find additional safer and effective treatments to help children affected by generalized spasticity due to CP. A first step could be to investigate medications that have shown antispasticity effect in adult patients, such as gabapentin. We also need to know more about long-term effects of these treatments and how they may improve function, ease of caregiving, and quality of life.
Dr. Delgado has received research support from Abbott Labs, UCB Pharma, and Allergan and estimates that 2 percent of his clinical effort is spent on intrathecal baclofen trials and 20 percent on botulinum toxin injections. For a complete list of other panel members and their disclosures, see the original Jan. 26 paper online at www.neurology.org.