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    • The passive movement increased significantly at all joints a

    2018-11-01

    The passive movement increased significantly at all joints at T1, and persisted at T2 and T3 for all joints, except for elbow flexion and forearm supination (Table 3). Note that PD 0332991 the passive range of motion for elbow extension and forearm supination for most of the patients was already within 10% of the maximum possible range at T0 (see Appendix A for figures of individual subject data). For elbow extension the change in passive movement was negatively correlated with the pre-injection movement; the greater the pre-injection elbow extension, the smaller its increase post-injection in both the short-term (r=−0.86, p<0.001) and long-term (r=−0.70, p=0.025). However, for forearm supination the opposite was seen; the more restricted the forearm supination pre-injection at T0, the smaller its increase post-injection in the short-term (r=0.57, p=0.03) (Table 4). Active movement showed more variability across patients. For patients who could perform active movements, the mean extent of movement increased significantly at all joints in the short-term, except for elbow extension, forearm pronation, and wrist extension (Table 3). However, over the long-term, the increase was significant at all joints except wrist extension. The change in active movement was negatively correlated with the pre-injection movement; the more restricted the pre-injection movement the greater its increase post-injection in the short-term for elbow flexion (r=−0.62, p=0.004), and in the long-term for elbow flexion (r=−0.58, p=0.04), forearm pronation (r=−0.65, p=0.017), and wrist flexion (r=−0.68, p=0.011) (Table 4). The median modified Ashworth scores decreased significantly across all the joint movements from pre- to post-injection assessments (Table 3). The change in stiffness was negatively correlated with the degree of pre-injection stiffness. The greater the pre-injection scores, the smaller the change for most movements (except shoulder flexion and wrist extension) in the short-term, and for shoulder abduction (r=−0.84, p<0.001), elbow extension (r=−0.85, p<0.001), and forearm supination (r=−0.67, p=0.013) in the long-term (Table 4). Table 5 shows that the modified Ashworth scores across all movements and subjects reduced from a score of 2 (51%) and 3 (44%) at T0 to mostly 0 (48%) and 1 (30%) at T1.
    Discussion In this case series, we report that intramuscular injections of the enzyme hyaluronidase increased passive and active joint movement and reduced muscle stiffness at upper limb joints in patients with spasticity of cerebral origin. The effect of treatment remained over at least three months of follow-up. These results suggest that accumulation of hyaluronan within muscles promotes the development of muscle stiffness in individuals with neurologic injury, and that intramuscular delivery of hyaluronidase is a promising direct treatment for muscle stiffness. The injections were safe and well tolerated, and without clinically significant adverse effects. Most importantly, the treatment did not produce weakness, which is a common adverse effect with current treatment options for spasticity (Phadke et al., 2015). Side effects of muscle weakness and fatigue are major impediments to recovery in patients with neurologic injury. The ability of hyaluronidase to reduce the resistance to movement without producing weakness suggests that it can potentially facilitate recovery of function after neurologic injury. There is no direct evidence yet that the change in mechanical properties of spastic muscles is due to the accumulation of hyaluronan. However, a study by Okita et al. (2004) showed that immobilization of the rat ankle joint led to increased hyaluronan accumulation in the endomysium of the rat soleus muscle compared to controls within 1week, with concomitant decrease in sarcomere length. This was followed by subsequent change in the arrangement of collagen fibrils and reduction in ankle range of motion. The authors suggested that increased hyaluronan in muscular tissue may induce muscle stiffness. There is now emerging evidence that the accumulation of hyaluronan precedes fibrosis in several organs including the lung, kidney, and liver (Bensadoun et al., 1996; Evanko et al., 2015; Jun et al., 1997; Hernnas et al., 1992; Halfon et al., 2005). Although the mechanisms underlying changes in muscle due to mechanical immobilization and spastic paralysis may be different, immobility is a consequence of spastic paralysis, and may trigger a cascade of events that leads to the accumulation of hyaluronan (Stecco et al., 2014).