Long-term BTX-A effects on bi-articular muscle: Higher passive force, limited length range of active force production and unchanged intermuscular interactions.

Botulinum toxin type-A (BTX-A) is commonly used for spasticity management aiming at reducing joint stiffness and increasing joint range of motion in CP patients. However, previous animal studies showed acutely increased passive forces and a narrowerlength range of active force exertion (lrange) for muscles exposed. BTX-A can spread affecting mechanics of several muscles in a compartment, but it was shown acutely to diminishepimuscular myofascial force transmission (EMFT). Yet, our understanding of these effects in the long-term is limited and they need to be tested in a bi-articular muscle. The goal was to test the following hypotheses in a long-term rat model: exposure to BTX-A (i) has no effects onlrangeand passive forces of bi-articular extensor digitorum longus (EDL) muscle and (ii) diminishes EMFT. 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 tibialis anterior). Isometric proximal and distal EDL forces were measured simultaneously, one-month post-injection. Proximally and distally lengthening the muscle showed that BTX-A causes a significantly narrowerlrange(by 14.7% distally and 32.2% proximally) and significantly increased passive muscle forces (over 2-fold both distally and proximally). Altering muscle position at constant length showed that BTX-A does not change EMFT. The findings reject both hypotheses showing that long-term exposure to BTX-A compromises bi-articular muscle's contribution to motion for both joints and the muscle's mechanical interaction with the surroundings remains unaffected. These effects which may compromise long-term spasticity management should be studied in CP patients.

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

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.

Intraoperative testing of passive and active state mechanics of spastic semitendinosus in conditions involving intermuscular mechanical interactions and gait relevant joint positions.

In cerebral palsy (CP) patients suffering pathological knee joint motion, spastic muscle's passive state forces have not been quantified intraoperatively. Besides, assessment of spastic muscle's active state forces in conditions involving intermuscular mechanical interactions and gait relevant joint positions is lacking. Therefore, the source of flexor forces limiting joint motion remains unclear. The aim was to test the following hypotheses: (i) in both passive and active states, spastic semitendinosus (ST) per se shows its highest forces within gait relevant knee angle (KA) range and (ii) due to intermuscular mechanical interactions, the active state forces elevate. Isometric forces (seven children with CP, GMFCS-II) were measured during surgery over a range of KA from flexion to full extension, at hip angle (HA) = 45° and 20°, in four conditions: (I) passive state, (II) individual stimulation of the ST, simultaneous stimulation of the ST (III) with its synergists, and (IV) also with an antagonist. Gait analyses: intraoperative data for KA = 17-61° (HA = 45°) and KA = 0-33° (HA = 20°) represent the loading response and terminal swing, and mid/terminal stance phases of gait, respectively. Intraoperative tests: Passive forces maximally approximated half of peak force in condition II (HA = 45°). Added muscle activations did increase muscle forces significantly (HA = 45°: on average by 42.0% and 72.5%; HA = 20°: maximally by 131.8% and 123.7%, respectively in conditions III and IV, p < 0.01). In conclusion, intermuscular mechanical interactions yield elevated active state forces, which are well above passive state forces. This indicates that intermuscular mechanical interactions may be a source of high flexor forces in CP.

Intraoperative experiments combined with gait analyses indicate that active state rather than passive dominates the spastic gracilis muscle's joint movement limiting effect in cerebral palsy.

BACKGROUND: In cerebral palsy, spastic muscle's passive forces are considered to be high but have not been assessed directly. Although activated spastic muscle's force-joint angle relations were studied, this was independent of gait relevant joint positions. The aim was to test the following hypotheses intraoperatively: (i) spastic gracilis passive forces are high even in flexed knee positions, (ii) its active state forces attain high amplitudes within the gait relevant knee angle range, and (iii) increase with added activations of other muscles. METHODS: Isometric forces (seven children with cerebral palsy, gross motor function classification score = II) were measured during surgery from knee flexion to full extension, at hip angles of 45° and 20° and in four conditions: (I) passive state, after gracilis was stimulated (II) alone, (III) simultaneously with its synergists, and (IV) also with an antagonist. FINDINGS: Directly measured peak passive force of spastic gracilis was only a certain fraction of the peak active state forces (maximally 26%) measured in condition II. Conditions III and IV caused gracilis forces to increase (for hip angle = 45°, by 32.8% and 71.9%, and for hip angle = 20°, by 24.5% and 45.1%, respectively). Gait analyses indicated that intraoperative data for knee angles 61-17° and 33-0° (for hip angles 45° and 20°, respectively) are particularly relevant, where active state force approximates its peak values. INTERPRETATION: Active state muscular mechanics, rather than passive, of spastic gracilis present a capacity to limit joint movement. The findings can be highly relevant for diagnosis and orthopaedic surgery in individuals with cerebral palsy.

Effects of inter-synergistic mechanical interactions on the mechanical behaviour of activated spastic semitendinosus muscle of patients with cerebral palsy.

Previous physiological experiments and finite element modelling indicate that inter-synergistic epimuscular myofascial force transmission (EMFT) between co-activated muscles has a potential to affect healthy muscle's contribution to joint moment and joint range of movement. This is quite relevant for patients with cerebral palsy (CP) since, amplitude of spastic muscle's force and the joint range of force exertion are central to the joint movement limitation. Stiffness of activated spastic muscle is also a determinant for pathological joint movement. However, assessments of effects of inter-synergistic EMFT on the mechanical behaviour of spastic muscle are lacking. Those assessments require measurement during surgery of activated spastic muscle's forces directly at its tendon and as a function of joint angle. Employing this methodology, the aim was to test the following study hypotheses: added activation of semimembranosus (SM) and gracilis (GRA) muscles of patients with CP changes (1) force, (2) stiffness and (3) joint range of force exertion of activated spastic semitendinosus (ST) due to inter-synergistic EMFT. Isometric spastic ST forces were measured intraoperatively (12 limbs of 7 patients (mean age 8 years 9 months) for knee angles from flexion (120°) to full extension (0°). Conditions I and II: spastic ST was activated alone, and simultaneously with its synergists SM and GRA muscles, respectively. Condition II did increase activated spastic ST's forces significantly (by 33.3%), but did not change its stiffness and joint range of force exertion, confirming only study hypothesis 1. Therefore, we conclude that inter-synergistic EMFT affects forces exerted at spastic ST tendon, but not other characteristics of its angle-force relationship.