Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.

The effect of physical manipulation on the outcome of neurotoxin (NT) injection was studied in a rat tibialis anterior (TA) model system where dorsiflexion torque could be measured precisely. After determination of initial torque, all rats received a one-time botulinum toxin A (BTX-A) injection (dose 6.0 units/kg in a volume of 100μL) into the TA midbelly. Four experimental groups were studied: one group was subjected to BTX-A injection alone (BTX-A only, n=8), one was subjected to BTX-A injection followed immediately by 10 isometric contractions (ISO; n=9), and the third was subjected to BTX-A followed immediately by 10 muscle passive stretch/release cycles (PS; n=10). After 1 month, maximum dorsiflexion torque of the injected and contralateral legs was determined followed by quantification of TA fiber area. Post-injection torque was significantly reduced by around 80% in all NT-treated extremities 1 month after injection (p<0.05). While all NT-treated extremities demonstrated a significant torque decrease relative to their pre-injection levels, ISO and PS groups demonstrated significantly lower torques compared with the BTX-A only group which received no physical manipulation (p<0.05) indicating greater efficacy. Perhaps even more surprising was that the ISO and PS groups both demonstrated a significantly smaller contralateral effect compared with the BTX-A only group that received no manipulation (p<0.05) indicating a decreased systemic-effect. Muscle fiber size generally correlated with dorsiflexion torque. These data demonstrate that both neuromuscular activity (seen in the ISO group) and muscle movement (seen in the PS group) increased the efficacy of BTX-A and decreased the systemic side effects.Neurotoxins (NT) that block neuromuscular transmission are used to treat muscular spasticity secondary to cerebral palsy, stroke, and head injury. 1-3 Therapeutic effects of NT treatment on spasticity include improved muscle function, facilitation of the effects of physical therapy, and delayed surgery. However, there are immediate and long-term negative side effects related to NT treatments, including systemic weakness and resistance to the toxin. [4][5][6]

The data demonstrate that, after a single BT-A injection, although gross muscle morphology recovered over a 12-month time period, loss of contractile function did not recover. Muscle Nerve 57: 435-441, 2018.

Summary The effects of botulinum neurotoxin A on the passive mechanical properties of skeletal muscle have not been investigated, but may have significant impact in the treatment of neuromuscular disorders including spasticity. Single fiber and fiber bundle passive mechanical testing was performed on rat muscles treated with botulinum neurotoxin A. Myosin heavy chain and titin composition of single fibers was determined by gel electrophoresis. Muscle collagen content was determined using a hydroxyproline assay. Neurotoxin-treated single fiber passive elastic modulus was reduced compared to control fibers (53.00 kPa versus 63.43 kPa). Fiber stiffness and slack sarcomere length were also reduced compared to control fibers and myosin heavy chain composition shifted from faster to slower isoforms. Average titin molecular weight increased 1.77% after treatment. Fiber bundle passive elastic modulus increased following treatment (168.83 kPa versus 75.14 kPa). Bundle stiffness also increased while collagen content per mass of muscle tissue increased 38%. Injection of botulinum neurotoxin A produces an effect on the passive mechanical properties of normal muscle that is opposite to the changes observed in spastic muscles.

Introduction Botulinum toxin serotype A (BT-A) is used for a variety of motor and sensory disorders related to abnormal muscle activity. Methods We developed a high-resolution rodent model to allow precise determination of the effect of BT-A dose (measured in units) and injectate volume (measured in μL) on the efficacy of the injection and systemic side effects. Dorsiflexion is the best indicator of injected and contralateral muscle function. Results One month after injection, dorsiflexion torque of BT-A-injected limbs was decreased significantly in all experimental groups compared with saline controls (P<0.05). Torque was also compared among the BT-A groups, which demonstrated a significant effect of dose (P<0.001), but no effect of volume (P>0.2) and no dose x volume interaction (P>0.3). Similar results were observed for other parameters measured. Discussion These data demonstrate that injection dose and not volume or concentration is the primary determinant of neurotoxin efficacy in a rodent model.