This is the current release of the guideline.

Adult spasticity and spasticity in pediatric cerebral palsy

Assessment of Therapeutic Effectiveness
Technology Assessment
Treatment

Neurology
Orthopedic Surgery
Pediatrics
Pharmacology
Physical Medicine and Rehabilitation

Pharmacists
Physicians

• To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of adult and childhood spasticity
• To make evidence-based recommendations

Adults with spasticity and children with spasticity due to cerebral palsy

Botulinum neurotoxin (BoNT) injection

Note: BoNT has been approved for adult and childhood spasticity by regulatory agencies in many European countries, but has not yet been approved for these indications in the United States by the U.S. Food and Drug Administration.

• Reduction in muscle tone
• Functional improvement

Hand-searches of Published Literature (Primary Sources)
Searches of Electronic Databases

The literature search used MEDLINE and Current Contents for relevant, fully published, peer-reviewed articles up to April 2007 and was supplemented through manual searches by panel members. The search terms used were botulinum toxin and movement disorders, dystonia, tics, tremors, hemifacial spasm, blepharospasm, cerebral palsy, spasticity, autonomic, Frey's syndrome, sweating, hyperhydrosis, drooling, headache, back pain, pain, laryngeal disorders, dysphonia, and urologic disorders. The following criteria were used: 1) relevant to the clinical questions of efficacy, safety, tolerability, or mode of use; 2) limited to human subjects; 3) limited to therapeutic studies. Abstracts, reviews, and meta-analyses were excluded.

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Classification of Evidence for Therapeutic Intervention

Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required: a) concealed allocation, b) primary outcome(s) clearly defined, c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion, or a case report.

* Objective outcome measurement: An outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

Systematic Review with Evidence Tables

The panel was comprised of specialists with experience in the therapeutic use of botulinum neurotoxin (BoNT) for the indications under consideration or with expertise in guideline methodology. Each article was reviewed by at least two panelists who did not participate in the trial reported. The articles were classified as Class I through IV using the American Association of Neurology (AAN) guideline process (see "Rating Scheme for the Strength of the Evidence"). Disagreements on article classification were resolved by discussion and consensus.

Other

Conclusions and recommendations were made according to the American Academy of Neurology (AAN) criteria for translating the quality of evidence for therapeutic interventions into recommendations.

Classification of Recommendations

The strength of practice recommendations is linked directly to the level of evidence:

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies.*)

Level B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or at least two consistent Class II studies.)

Level C = Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. (Studies not meeting criteria for Class I–Class III).

* In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Draft guidelines were reviewed for accuracy, quality, and thoroughness by the American Academy of Neurology members, topic experts, and pertinent physician organizations.

The guideline was approved by the Therapeutics and Technology Assessment Subcommittee on March 31, 2007; by the Practice Committee on July 12, 2007; and by the American Academy of Neurology Board of Directors on January 30, 2008.

Definitions of the levels of the recommendations (A, B, C, U) and classification of the evidence (Class I through Class IV) are provided at the end of the "Major Recommendations" field.

Upper Extremity Spasticity and Lower Extremity Spasticity in Adults

Conclusions

Botulinum neurotoxin (BoNT) is established as effective in the treatment of adult spasticity in the upper and lower limb in reducing muscle tone and improving passive function (14 Class I studies). While relatively few studies examined active function, recent data suggest that BoNT is probably effective in improving active function (one Class I study). There are inadequate data to determine if electrical stimulation or electromyography (EMG) techniques for optimal muscle localization improves outcome.

Recommendations

• BoNT should be offered as a treatment option to reduce muscle tone and improve passive function in adults with spasticity (Level A), and should be considered to improve active function (Level B).
• There is insufficient evidence to recommend an optimum technique for muscle localization at the time of injection (Level U).

Spasticity Due to Cerebral Palsy in Children

Conclusions

BoNT injection of the gastrocnemius-soleus muscles is established as effective in the treatment of spastic equinus in patients with cerebral palsy (CP) (four Class I studies). There is insufficient evidence to support or refute the benefit of additional casting to BoNT injection of the gastrocnemius-soleus muscles (inconsistent Class II and III studies) and the injection of BoNT into the hamstrings (only Class IV studies). In patients with adductor spasticity, BoNT injection is probably effective in improving adductor spasticity and range of motion (one Class I study), as well as postoperative pain in children undergoing adductor muscle lengthening surgery (one Class I study). In patients with upper extremity symptoms, BoNT injection is probably effective in improving spasticity and range of motion (two Class II studies and one Class III study).

Recommendations

• BoNT injection of the calf muscles should be offered as a treatment option for equinus varus deformity in children with cerebral palsy (Level A).
• BoNT injection should be considered as a treatment option for treatment of adductor spasticity and for pain control in children undergoing adductor-lengthening surgery (Level B).
• BoNT injection should be considered as a treatment option in children with upper extremity spasticity (Level B).

Definitions:

Classification of Recommendations

Level A = Established as effective, ineffective, or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. (Level A rating requires at least two consistent Class I studies*)

Level B = Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. (Level B rating requires at least one Class I study or two consistent Class II studies.)

Level C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. (Level C rating requires at least one Class II study or two consistent Class III studies.)

Level U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. (Studies not meeting criteria for Class I–III.)

*In exceptional cases, one convincing Class I study may suffice for an "A" recommendation if 1) all criteria are met, 2) the magnitude of effect is large (relative rate improved outcome >5 and the lower limit of the confidence interval is >2).

Classification of Evidence for Therapeutic Intervention

Class I: Randomized, controlled clinical trial with masked or objective outcome assessment in a representative population. Relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences. The following are required: a) concealed allocation, b) primary outcome(s) clearly defined, c) exclusion/inclusion criteria clearly defined, and d) adequate accounting for drop-outs (with at least 80% of enrolled subjects completing the study) and cross-overs with numbers sufficiently low to have minimal potential for bias.

Class II: Prospective matched group cohort study in a representative population with masked outcome assessment that meets b-d above OR a randomized controlled trial in a representative population that lacks one criteria a-d.

Class III: All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome is independently assessed, or independently derived by objective outcome measurement.*

Class IV: Studies not meeting Class I, II, or III criteria, including consensus, expert opinion, or a case report.

* Objective outcome measurement: An outcome measure that is unlikely to be affected by an observer's (patient, treating physician, investigator) expectation or bias (e.g., blood tests, administrative outcome data).

None provided

The type of supporting evidence is identified and graded for each recommendation (see "Major Recommendations").

Appropriate use of botulinum neurotoxin for treatment of adult and pediatric spasticity

• Undesirable effects associated with administration of botulinum neurotoxin (BoNT) fall into three broad categories. First, diffusion of the toxin from the intended sites of action can lead to unwanted inhibition of transmission at neighboring nerve endings. Second, sustained blockade of transmission can produce effects similar to anatomic denervation, including muscle atrophy. The third undesirable effect is immunoresistance to BoNT.
• Adverse events reported for BoNT in the treatment of spasticity include:
  • Focal weakness
  • Pain
  • Falls
  • Incontinence
  • Dysphagia

This statement is provided as an educational service of the American Academy of Neurology (AAN). It is based on an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN recognizes that specific patient care decisions are the prerogative of the patient and the physician caring for the patient, based on all of the circumstances involved. The clinical context section is made available in order to place the evidence-based guideline(s) into perspective with current practice habits and challenges. No formal practice recommendations should be inferred.

An implementation strategy was not provided.

Getting Better
Living with Illness

Effectiveness
Patient-centeredness
Safety

Not applicable: The guideline was not adapted from another source.

2008 May 6

American Academy of Neurology - Medical Specialty Society

American Academy of Neurology (AAN)

Therapeutics and Technology Assessment Subcommittee

Primary Authors: D.M. Simpson, MD; J-M. Gracies, MD, PhD; H.K. Graham, MD; J.M. Miyasaki, MD, Med; M. Naumann, MD; B. Russman, MD; L.L. Simpson, PhD; Y. So, MD, PhD

American Academy of Physical Medicine and Rehabilitation - Medical Specialty Society

This is the current release of the guideline.

This summary was completed by ECRI Institute on October 31, 2008. The information was verified by the guideline developer on December 30, 2008. This summary was updated by ECRI Institute on May 26, 2009, following the U.S. Food and Drug Administration advisory on Botox, Botox Cosmetic (Botulinum toxin Type A), and Myobloc (Botulinum toxin Type B).

This NGC summary is based on the original guideline, which is copyrighted by the American Academy of Neurology.