Botulinum toxin within the muscle – MRI follow up in children with spastic cerebral palsy supports neurogenic atrophy in healthy muscle one year after a single injection of botulinum toxin

Introduction: Botulinum toxin is widely used as a therapeutic option to reduce (multi-) focal muscle hypertension as well as for cosmetic indications. Recommendations on reinjection intervals (3–12months) are based on clinical observation and basic science research using animal models. Morphologic long-term alterations following a single injection of botulinum toxin are scarce. With the development of short tau inversion recovery (STIR) sequences Magnetic resonance imaging (MRI) is able to detect neurogenic muscle atrophy over the course of time.

The aim of this study was to investigate the neurogenic atrophy induced by a single injection of botulinum toxin in healthy adult muscle and the induced atrophy in primarily altered spastic muscle in children with cerebral palsy (CP). Methods: Prospective, double blind, placebo-controlled case study with two healthy adults and prospective case study in two children with unilateral spastic CP. Ultrasound guided injection of botulinum toxin type A (BOTOX or XEOMIN) in therapeutic dosage according to actual guidelines. MRI examination in healthy volunteers prior, and immediately after injection, and 3, 6, 9, and 12 months after injection, as well as in children with CP 6 weeks, 6 and 12 months after injection. Muscle biopsy was taken in one healthy adult 12 months after injection from both injected lateral heads of gastrocnemius muscle (GCL, BoNT/A versus placebo). The (ultra-) fine structural examination was correlated with the MRI findings.

Fig.1: Healthy adult volunteer

Fig.2: Child with unilateral spastic CPAxial T2-STIR-MR sequence, lower leg over the course of time:a-c: healthy volunteer: a=prior to injection, b=6 months, c=12 months after injectiond-f: 8 year old boy with unilateral spastic CP of his right body side: d=6 weeks after injection, e=6 months, f=12 months after injection.

Results: MRI reveals a high signal intensity pattern (HSIP) in STIR sequences and a reduction of muscle cross sectional area in the BoNT/A injected, but not in the saline (placebo) injected muscle of both healthy volunteers. Histology in one volunteer 12 months after injection showed neurogenic atrophy in approximately 30% of the muscle fibres in the BoNT/A injected muscle with signs of regeneration. Also in the children with CP as MRI correlate of neurogenic atrophy an increasing HISP could be detected until 6 months after injection that was decreasing again at 12 months. Conclusion: MRI proved to be a sensitive and objective method to show neurogenic muscle atrophy and alteration. The time course of neurogenic muscle atrophy and reinnervation following a single BoNT/A injection is inconsistent with the clinically driven recommendations concerning reinjection frequency. Visualization of BoNT/A related morphologic muscle alteration in correlation to the duration of clinical effect is necessary to further improve botulinum toxin intervention.