Long-Term Effects With Potential Clinical Importance of Botulinum Toxin Type-A on Mechanics of Muscles Exposed

Abstract

Botulinum toxin type-A (BTX-A) is widely used for spasticity management and mechanically aims at reducing passive resistance at the joint and widening joint range of movement. However, recent experiments on acute BTX-A effects showed that the injected rat tibialis anterior (TA) muscle's passive forces increased, and the length range of active force exertion (l range) did not change. Additionally, BTX-A was shown to spread into non-injected muscles in the compartment and affect their mechanics. Whether those effects persist in the long term is highly important, but unknown. The aim was to test the following hypotheses with experiments conducted in the anterior crural compartment of the rat: In the long term, BTX-A (1) maintains l range , (2) increases passive forces of the injected TA muscle, and (3) spreads into non-injected extensor digitorum longus (EDL) and the extensor hallucis longus (EHL) muscles, also affecting their active and passive forces. Male Wistar rats were divided into two groups: BTX-A and Control (0.1 units of BTX-A or only saline was injected into the TA). Isometric forces of the muscles were measured simultaneously 1-month post-injection. The targeted TA was lengthened, whereas the non-targeted EDL and EHL were kept at constant length. Hydroxyproline analysis was done to quantify changes in the collagen content of studied muscles. Two-way ANOVA test (for muscle forces, factors: TA length and animal group) and unpaired t or Mann-Whitney U test (for l range and collagen content, where appropriate) were used for statistical analyses (P < 0.05). BTX-A caused significant effects. TA: active forces decreased (maximally by 75.2% at short and minimally by 48.3%, at long muscle lengths), l range decreased (by 22.9%), passive forces increased (by 12.3%), and collagen content increased (approximately threefold). EDL and EHL: active forces decreased (up to 66.8%), passive force increased (minimally by 62.5%), and collagen content increased (approximately twofold). Therefore, hypothesis 1 was rejected and 2 and 3 were confirmed indicating that previously reported acute BTX-A effects persist and advance in the long term. A narrower l range and an elevated passive resistance of the targeted muscle are unintended mechanical effects, whereas spread of BTX-A into other compartmental muscles indicates the presence of uncontrolled mechanical effects.

Comparative Effectiveness of Botulinum Toxin Injections and Extracorporeal Shockwave Therapy for Post-Stroke Spasticity: A Systematic Review and Network Meta-Analysis

“…However, the major concern for BoNT injections is the formation of neutralizing antibodies (ranging from 0 to 3.6 %) after repeated treatments, which may jeopardize its therapeutic effects [67] . Alteration of muscle mechanics and intramuscular connective tissue contents were observed in the rat model following BoNT injections [68] . Unintended botulism-like syndrome is possible when hematogenic systemic spread occurs, particularly using a high injection dose [69] .…”

“…67 Alteration of muscle mechanics and intramuscular connective tissue contents were observed in the rat model following BoNT injections. 68 Unintended botulism-like syndrome is possible when hematogenic systemic spread occurs, particularly using a high injection dose. 69 On the contrary, the side effects of ESWT are usually mild, encompassing skin petechial or transient localized pain.…”

Comprehensive Assessment of the Time Course of Biomechanical, Electrophysiological and Neuro-Motor Effects after Botulinum Toxin Injections in Elbow Flexors of Chronic Stroke Survivors with Spastic Hemiplegia: A Cross Sectional Observation Study

“…BoNT injections cause chemodenervation effects on the injected spastic muscles via presynaptic blockade of neurotransmitters at the neuromuscular junctions [19][20][21]. Animal studies have shown adaptive changes in the muscles after BoNT injections, including increased collagen content and passive resistance [40,41], muscle fiber loss and atrophy [30]. Collectively, these changes contribute to increased passive stiffness after BoNT.…”

Passive Properties of the Wrist and Fingers Following Chronic Hemiparetic Stroke: Interlimb Comparisons in Persons With and Without a Clinical Treatment History That Includes Botulinum Neurotoxin

“…This altered motor drive and associated limb use, over time, may change muscle structure and function, further amplifying the brain injury induced motor impairments. Botulinum neurotoxin (BoNT) chemical denervation, which is widely used to treat muscle hypertonia and spasticity (20)(21)(22), may also alter muscle properties (23)(24)(25)(26)(27)(28)(29)(30). One particularly detrimental sequelae of these muscle adaptations are that muscles can become increasingly stiff, making movement progressively more difficult.…”