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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 (lrange) 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 lrange, (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 lrange 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), lrange 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 lrange 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.
Highlights
A widely used technique for management of spasticity arising from a wide range of conditions such as cerebral palsy (CP) (Graham et al, 2000; Criswell et al, 2006; Lukban et al, 2009), spinal cord injury (Adams and Hicks, 2005; Marciniak et al, 2008), multiple sclerosis (Hyman et al, 2000; Van Der Walt et al, 2012) and stroke (Bakheit et al, 2000; Bhakta et al, 2000) is injection of botulinum toxin type-A (BTX-A)
A line segment was drawn between the two markers and the injection location over the tibialis anterior (TA) muscle was determined as a point 5 mm lateral to the second marker
The present data indicate a reduced lrange for the injected TA muscle
Summary
A widely used technique for management of spasticity arising from a wide range of conditions such as cerebral palsy (CP) (Graham et al, 2000; Criswell et al, 2006; Lukban et al, 2009), spinal cord injury (Adams and Hicks, 2005; Marciniak et al, 2008), multiple sclerosis (Hyman et al, 2000; Van Der Walt et al, 2012) and stroke (Bakheit et al, 2000; Bhakta et al, 2000) is injection of botulinum toxin type-A (BTX-A). Spread of BTX-A through muscle fascia was reported (Shaari et al, 1991) Such spread has been reported to reduce forces (Yaraskavitch et al, 2008; Frasson et al, 2012) and cause changes in length-force characteristics of the non-injected muscles (Yucesoy et al, 2012; Ates and Yucesoy, 2014, 2018; Yucesoy and Ates, 2018). Those changes in the short term include effects contradicting treatment aims (i.e., decreased lrange, increased passive forces and elevated intramuscular collagen content) (Ates and Yucesoy, 2014). Finite element analyses of that indicated that they do ascribed to a continuing elevated stiffness the exposed muscles’ extracellular matrix (Turkoglu and Yucesoy, 2016), testing of which deserves major attention
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