Botulinum Toxin in the Management of Children with Cerebral Palsy

Abstract

During the past 25 years, botulinum toxin type A (BoNT-A) has become the most widely used medical intervention in children with cerebral palsy. In this review we consider the gaps in our knowledge in the use of BoNT-A and reasons why muscle morphology and function in children with cerebral palsy are impaired. We review limitations in our knowledge regarding the mechanisms underlying the development of contractures and the difficulty in preventing them. It is clear from this review that injection of BoNT-A in the large muscles of both the upper and lower limbs of children with cerebral palsy will result in a predictable decrease in muscle activity, which is usually reported as a reduction in spasticity, for between 3 and 6 months. These changes are noted by the use of clinical tools such as the Modified Ashworth Scale and the Modified Tardieu Scale. Decreased muscle over-activity usually results in improved range of motion in distal joints. Injection of the gastrocnemius muscle for toe-walking in a child with hemiplegia or diplegia usually has the effect of increasing the passive range of dorsiflexion at the ankle. In our review, we found that this may result in a measurable improvement in gait by the use of observational gait scales or gait analysis, in some children. However, improvements in gait function are not always achieved and are small in magnitude and short lived. We found that some of the differences in outcomes in clinical trials may relate to the use of adjunctive interventions such as serial casting, orthoses, night splints and intensive therapy. We note that the majority of clinical trials of the use of BoNT-A in children with cerebral palsy have focussed on a single injection cycle and this is insufficient to understand the balance between benefit and harm. Most outcomes were reported in terms of changes in muscle tone and there were fewer studies with robust methodology that reported improvements in function. Changes in the domains of activities and participation have rarely been reported in studies to date. There were no clinical reviews to date that consider the findings of studies in human volunteers and in experimental animals and their relevance to clinical protocols. In this review we found that studies in human volunteers and in experimental animals show muscle atrophy after an injection of BoNT-A for at least 12 months. Muscle atrophy was accompanied by loss of contractile elements in muscle and replacement with fat and connective tissue. It is not currently known if these changes, mediated at a molecular level, are reversible. We conclude that there is a need to revise clinical protocols by using BoNT-A more thoughtfully, less frequently and with greatly enhanced monitoring of the effects on injected muscle for both short-term and long-term benefits and harms.

Fig. 1

Schematic of the interaction between the positive and negative features of the upper motor neuron (UMN) syndrome, leading to spasticity with dynamic contractures and fixed muscle–tendon contractures. Dynamic or flexible contractures are often treated by injection of botulinum toxin type A (BoNT-A). Fixed contractures are usually treated by orthopaedic surgery. LMN lower motor neuron

Fig. 2

Staging the musculoskeletal pathology in children with cerebral palsy. Younger children have spasticity which is dynamic and which reduces at rest and disappears under the relaxation of a general anaesthetic. This is the stage when injections of botulinum toxin type A (BoNT-A) or neurosurgical procedures such as selective dorsal rhizotomy (SDR) may be helpful. At Stage 2 and 3, the musculoskeletal pathology is fixed and correction requires orthopaedic surgery

Fig. 3

Schematic of the World Health Organisation’s (WHO) International Classification of Functioning (ICF) and potential outcome measures. AM activity monitor, CHQ Child Health Questionnaire, FMS Functional Mobility Scale, GMFM66 Gross Motor Function Measure, GOAL ^® Gait Outcomes Assessment List, MAS Modified Ashworth Scale, MTS Modified Tardieu Scale, ROM range of motion (goniometry), 3DGA 3-dimensional gait analysis

Fig. 4

Botulinum toxin type A (BoNT-A) mechanism of action. The BoNT-A heavy chain is shown in green and the light chain in yellow, linked by a disulphide bond. Acetylcholine (Ach), the neurotransmitter which is blocked by BoNT-A, is shown as red dots within a circular vesicle in the nerve terminal. The effects of chemodenervation by injection of BoNT-A are summarised at macroscopic, microscopic and molecular levels. SNAP 25 soluble N-ethylmaleimide fusion protein, attachment protein,VAMP vesicle associated membrane protein

Fig. 5

Algorithm as to the timing of the use of botulinum toxin type A (BoNT-A) and orthopaedic surgery for ambulant children with cerebral palsy (CP). The peak age for the use of BoNT-A is between 2 and 6 years. The peak age for the use of orthopaedic surgery is between 6 and 12 years. It is desirable to have a ‘washout’ period with no injections when the response of the target muscle is limited

Fig. 6

Risk versus benefit for injection of botulinum toxin type A (BoNT-A) in the ambulant child with cerebral palsy (CP). The benefits (decreased spasticity, increased range of motion and improvements in gait may outweigh the harms (weakness, muscle atrophy and fibrosis). The understanding of risk to benefit may change with further studies, both clinical and in animal models. The endpoint is orthopaedic surgery for gait improvement. GMFCS Gross Motor Function Classification System

Fig. 7

Risk versus benefit for injection of botulinum toxin type A (BoNT-A) in the non-ambulant child with cerebral palsy (CP). The harms are the risk of serious/fatal adverse events and the benefits are modest. There may not be a defined endpoint and intermittent, life-long injections are not an ideal proposition.GMFCS Gross Motor Function Classification System

Fig. 8

Historical view of changes in the gastrocnemius muscle after injection of botulinum toxin type A (BoNT-A) for equinus gait. The spastic gastrocsoleus muscle is shown as a tightly coiled spring, causing the child to walk on their toes. After injection the spring (spasticity) is relaxed and the child achieves foot-flat. After 3–6 months, the effects of injection wear off and the equinus returns

Fig. 9

Contemporary view of changes in the gastrocnemius muscle after injection of botulinum toxin type A (BoNT-A) for equinus gait. The gastrocnemius is small before injection with dynamic shortening and equinus at the ankle. After injection of BoNT-A there is acute atrophy, a decrease in spasticity and foot-flat. After 6–12 months there is partial recovery of the muscle and the equinus returns