Invited Discussion

``Sensory protection'' is a relatively new concept that has been introduced to the peripheral nerve surgeon as a potential method to ameliorate irreversible skeletal muscle denervation changes seen in proximal nerve injuries or after prolonged denervation.[1] [2] [3] The importance of the clinical problem need not be reiterated to the readership, as many have sought solutions to the problem by performing distal motor neurotizations,[4] stimulating the muscle electrically during the denervation period, treating the muscle pharmacologically, applying physiotherapy techniques, etc. Although some of these techniques have met with limited success, wider application of these techniques is still controversial.

The idea of transferring a sensory nerve to a denervated distal motor target was termed a ``foreign nerve crossover'' by the physiologists. Weiss, Guttman, and other renowned neuroscientists investigated these nerve transfers in the 1940's and '50's and concluded with only negative results: ``the sensory nerve wouldn't evoke a motor response in the denervated muscle.''[5] [6] [7] Subtle but significant changes were, however, observed. Muscle was seen to have increased mass. Sensory nerve fibers sprouted throughout the denervated muscle, but did not make functional neuromuscular junctions. No attempt at secondary reinnervation by a motor nerve was attempted in these early investigations. We built upon this work, repeating some of the original experiments; however, after varying periods of sensory neurotization of denervated muscle, we reinnervated the muscle with a motor nerve. We described our observations as ``sensory protection''.[1] [2]

Papakonstantinou et al. have further investigated sensory protection in the upper limb model of denervation established in their laboratory. They have used both qualitative and quantitative evaluations of nerve regeneration and muscle function to confirm the earlier described findings from our laboratory,[1] that skeletal muscle temporarily reinnervated by a sensory nerve during a period of prolonged denervation, when subsequently reinnervated by the original motor nerve, has significantly improved function (up to an 8-fold increase in twitch and tetanic force in our study). They also discuss an important concept of the model design, that a sufficient period of denervation be used, so that the control group does undergo irreversible changes (i.e., 3 months were insufficient to see a significant effect).

The authors had significant evidence to support their hypothesis. Particularly, the significant increase in the biceps muscle weight following sensory protection, and some temporal improvement in the grooming test support sensory protection as a clinically relevant method to improve muscle function following prolonged denervation. However, due to the small numbers and the lack of quantitative electrophysiologic evaluation, limited conclusions, particularly regarding the mechanisms of this effect, can be drawn.

They discuss the proposed mechanisms for these observation on the denervated muscle, either through action on the distal motor nerve sheath and/or an effect directly on the muscle, probably through myotrophic or neurotrophic factors. Given that they did not observe any differences in the distal musculocutaneous nerve, this favors the neurotrophic hypothesis. Fu and Gordon, through their work on prolonged muscle denervation and delayed reinnervation, have proposed that the collapse of the endoneurial sheath results in decreased motor reinnervation and significantly decreased number of motor units.[8] Our current work evaluating the mechanism of sensory protection has implicated both a neurotrophic pathway (Veltri et al. in preparation) and an effect upon the distal motor sheath. We have seen ultrastructural improvements of the distal motor nerve following sensory protection (supporting the nerve hypothesis) and a direct effect of the sensory nerve on the muscle itself, independent of the distal motor sheath (supporting the neurotrophic hypothesis). Other investigators, using differing methods of introducing sensory input into denervated muscle, found superior results with a direct sensory nerve coaptation to the distal motor nerve.[9] The specific mechanism will likely be elucidated only from changes observed in the molecular profiles of muscles under varying conditions.

It is exciting to review work from other laboratories investigating sensory protection, since further understanding will permit a clinical application of this work. By designing and critically evaluating the outcomes in a clinical trial, we will complete the cycle for the clinician investigator: clinical problem, research question, experimental hypothesis, experimental investigations, clinical trial, (hopefully) improved standard of care for our patients.

REFERENCES

• 1 Bain J R, Veltri K L, Chamberlain D, Fahnestock M. Improved functional recovery of denervated skeletal muscle after temporary sensory nerve innervation.  Neuroscience . 2001;  103 503-510
• 2 Hynes N M, Bain J R, Thoma A. Preservation of denervated muscle by sensory protection in rats.  J Reconstr Microsurg . 1997;  13 337-343
• 3 Papakonstantinou K C, Kamin E, Terzis J K. Muscle preservation by prolonged sensory protection.  J Reconstr Microsurg . 2002;  18 173-182
• 4 Mackinnon S, Novak C B. Nerve transfers. New options for reconstruction following nerve injury.  Hand Clinics . 1999;  15 643-666
• 5 Weiss P, Edds M V. Sensory-motor nerve crosses in the rat.  J Neurophysiol . 1945;  8 173-193
• 6 Gutmann E, Young J Z. The re-innervation of muscle after various periods of atrophy.  J Anatomy . 1943;  78 15-43
• 7 Karpati G, Carpenter S, Charron L. Experimental reinnervation attempts of skeletal muscle cells by non-motor nerves. In: Gorio A, et al., eds. Posttraumatic Peripheral Nerve Regeneration; Experimental Basis and Clinical Implications New York: Raven Press 1981: 495-506
• 8 Fu S Y, Gordon T. Contributing factors to poor functional recovery after delayed nerve repair: prolonged denervation.  J Neurosci . 1995;  15 3886-3895
• 9 Wang H, Gu Y, Xu J. Comparative study of different surgical procedures using sensory nerves or neurons for delaying atrophy of denervated skeletal muscle.  J Hand Surg . 2001;  26A 326-331