What are the long-term consequences of botulinum toxin injections in spastic cerebral palsy?

Abstract

Muscle spasticity, defined as a velocity dependent resistance to stretch, is the primary impairment of spastic cerebral palsy (CP) and is neural in origin. However, spastic muscle also undergoes significant morphological and structural alterations secondary to spasticity which contribute to muscle weakness, muscle stiffness, restricted joint range of motion, and skeletal deformity. These secondary alterations can progress with age and contribute to a gradual loss of functional capacity during development, including the ability to ambulate independently. There is consensus that intra-muscular botulinum toxin A (BoNT-A) injections can be effective in the management of lower limb spasticity in children with spastic CP. BoNT-A injections can improve gait and delay and reduce the requirement for surgical interventions to treat musculoskeletal deformities when combined with conservative treatments. The study by Alhusaini et al. is one of the first that begins to address the important clinical question of how BoNT-A injections influence the secondary effects of spasticity on joint-level mechanical properties in children with spastic CP. An attractive feature of the study was that the authors assessed ankle joint stiffness and not just joint range of motion. Alhusaini et al. showed that BoNT-A has relatively minor effects on passive mechanical properties of the ankle plantar-flexor muscles at 6-weeks post injection in children with spastic CP aged 4– 10 years with high ankle joint stiffness. This study therefore does not support the efficacy of BoNT-A for treating contractures. What remains unclear at the present time is how BoNT-A might influence other structural and neuro-mechanical properties of the muscle and ⁄or tendon, especially in the longer term. For example, how does BoNT-A affect muscle size, strength, force-length-velocity behaviour, moment arms, co-activation, and tendon compliance? Of increasing concern is evidence from animal studies that intra-muscular BoNT-A injections adversely influence muscle growth in the injected muscle as well as muscles remote from the injection site. For example, Fortuna et al. recently reported up to 95% reductions in rabbit hind limb quadriceps muscle strength following 6 months of repeated BoNT-A injections, which was accompanied by up to 60% reductions in muscle mass. Reductions in strength and mass were also reported for quadriceps muscles in the contralateral limb. These findings point to the possibility that the short-term functional benefits of BoNT-A injections reported in clinical studies in spastic CP may be offset by accelerated structural weakening of muscle. This is important because children aged 2–5 years with spastic CP that have not undergone orthopaedic surgery or commenced BoNT-A injections already have significantly lower calf muscle volume relative to their typically developed peers. BoNT-A is routinely administered to children in this age group and is often repeated over many cycles. Further muscle weakening by BoNT-A would therefore be expected to adversely influence functional capacity. BoNT-A acts to weaken overactive muscles through chemical blockade of the neuromuscular junction. It might be expected that any associated muscle atrophy could contribute to observed improvements in gait following BoNT-A injections. However, during maturation in childhood and adolescence, muscles must increase in size to cope with the increased mechanical loading associated with motor function in activities such as gait. Muscle weakening from BoNT-A could therefore be beneficial in the short-term but detrimental in the longerterm because of impeded muscle growth. Aside from the study by Alhusaini et al., to our knowledge no detailed in vivo studies of the effects of BoNT-A on the active and passive mechanical properties of muscle in children with spastic CP have been conducted. In spite of the widespread use of BoNT-A injections in children with spastic CP for almost two decades, the long-term efficacy of this treatment for improving functional outcomes in children with spastic CP remain relatively unknown. In using a short-term solution we may be creating a long-term problem which could lead to increased costs of care in spastic CP. Long-term trials of the structural and neuro-mechanical responses of muscle to BoNT-A and their consequences for motor function in spastic CP are required. New developments in musculoskeletal modeling and simulation may prove fruitful in linking muscletendon adaptation with gait function in spastic CP.