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Management of Nerve Injuries in the Upper Extremity
Management of Nerve Injuries in the Upper Extremity
ROBERT A. CHASE, M.D. Yale University School of Medicine
A PEHIPHERAL nerve that has sustained crushing trauma or complete transection contains proximal and distal axones with entirely different potentials. The distal axones, sequestrated from the central cell bodies, undergo degeneration. The proximal axones are injured but living extremities of viable central cell bodies. After a short latent period they sprout anew with regenerative compulsion. This regenerative pressure produces new outgrowth until the axones reinnervate motor end plates or sensory end organs~unless they are interrupted by an equal resistance to growth. Resistance to outgrowth may occur in the nerve stump milieu in the form of fibrous tissue invasion. This fibrous tissue struggle with the insurgent axones results in neuroma formation. The nerve sheath cells retain their viability both distal and proximal to the sites of injury. Their behavior is of major importance in regrowth of the axones to final reinnervation of the end organs. As the peripheral axones degenerate, the sheath cells hypertrophy and orient themselves in a linear fashion to await regrowth of new axones. Ifaxones re-enter in a reasonable period of time, these sheath cells create a milieu for regrowth which is incomparably good. The physicochemical ultra structure provided directs regrowth of axones in proper orientation. 41 . 45. 46 Occasionally when a nerve gap of short measure is produced at the site of nerve division, the axones cross this and enter the distal segment. In 1905 this finding led CajaF to believe that the distal stump radiated a neurotrophic chemical agent which attracted regenerating nerve cylinders. This theory has now been effectively and substantially disproved experimentally,l0.43 If regenerating axis cylinders do not enter the expectant orderly distal sheath, the sheath slowly loses its receptivity. Morphologic evidence of this is shrinkage of the distal nerve, which is apparent during the first half year after transection. Clinically acceptable regeneration has been noted by several observers3. 10. 14. 27.34 when nerves are approximated
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over two years after injury. After the first year, however, the failure rate rises rapidly. If proper coaptation of proximal stump to distal stump is achieved, then regeneration occurs from the point of transection down the distal sheath. The rate of regrowth has been carefully studied. G, H, 30, 31 In man the initial rate is comparatively rapid with progressive deceleration as regrowth proceeds distally.30, 31 This growth rate is as high as 8 mm. per day initially.30 Clinically, repair of nerves in the hand and wrist results in a recovery rate which is roughly one digital phalanx length per month. For example, regeneration equal to a finger's length would take about three months. The rate of regrowth is faster after crushing injuries than after complete transection. H , 31 Research directed toward production of agents which would stimulate nerve regeneration has failed to show enhancement by vitamins, thyroid, cortisone, atropine, cytochromic C and other agents both chemical and physica1. 10 Some scar-inhibiting agents, such as Piromen, serum antilipase, serum antitrypsin and ACTH, remove a significant block to regeneration experimentally.lo, 22 The result has been improved regeneration in many experimental circumstances. RECOVERY OF FUNCTION AFTER NEURORRHAPHY
After denervation, muscles undergo atrophic changes which are not unlike those with disuse or following tenotomy.l6, 32 Electrical stimulation definitely inhibits denervation and disuse atrophy,13, 16 Atrophic changes are reversible for about one year, after which progressive irreversible fibrotic changes take place. Burrow 6 has shown that following sensory denervation and repair, the sensory modalities return in a fixed sequence. The earliest sign of recovery is Tinel's sign followed in succession by deep sensation, tingling, protopathic sensation, light touch, temperature and position sense. Normal sudomotor activity is found only after return of all other modalities. This fact supports the value of Moberg's23 recently reported technique for evaluation of sensory loss using finger-print documentation of return of sudomotor function. Development of sensation in skin grafts is slow, but partial return of sensation is the rule. Recovery is more accurate in full-thickness grafts than in split-thickness grafts.23 It has been the impression of some that motor functional recovery in median and ulnar nerve repairs was superior to that in radial nerve repairs,14 GuthlO subjected these data to statistical analysis, and concluded that no difference in functional results could be determined, using the reported measurements of function in these three nerves.
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EARLY MANAGEMENT OF NERVE TRANSECTION
Early accurate coaptation of distal and proximal segments of a severed nerve gives the best functional end result. Careful re-approximation of the nerve sheath with fine sutures is the most widely practiced method. Seddon27 endorses the delayed primary technique with accurate suture about three weeks after transection. He feels that the fibrosis in the stumps produced by injury is grossly manifested by this time, and that scarring of other adjacent repaired structures is confined at this time with less likely invasion of the nerve repair. In his experience the slight thickening of the nerve sheath which is established at three weeks makes nerve suture easier and more accurate. Seddon27 states that the final results are better in his series using the delayed suture technique. Choice of suture material for neurorrhaphy has led to debate among experts in the field. This led Sunderland and Smith35 to carry out controlled studies of the virtues of the materials available. The attributes most desired are: that the suture set up minimal fibroblastic reaction, that the reaction be as short in duration as possible, and that the material be of fine caliber. Silk, plain gut and human hair adhered most closely to this pattern. Sterility assurance, fine caliber, tensile strength and ease of use give silk a slight advantage over the other two. Tantalum and nylon both created severe fibroblastic reaction late after repair. Nerve anastomosis using sleeves of various materials around the site of juncture has been tried and results evaluated by many observers. 1. 8.39.42-45.47 The enthusiasm for tantalum cylinders has been effectively negated by the poor late results and morphologic evidence of reaction fibroplasia and strangulation at the repair site. The tireless investigations of Weiss39- 47 have shown that the use of an arterial sleeve at the anastomosis site creates a favorable milieu for nerve regeneration in animals. It seems logical to apply the same technique to nerve anastomoses in humans. Weiss has demonstrated high grade success in monkeys using frozen, dried homografts of artery as the sleeve. A promising inert foreign agent for use at the site of anastomosis is Milipore, 8 although it must withstand the test of time. The plasma clot method using plasma as an adhesive agent at the nerve ends is enthusiastically advocated by one school of surgeons. 38 Still another school combines the use of plasma and silk. 3 Tarlov states that he "recommends the plasma clot technique to the patient operator in the interest of improving functional results." A knowledge of the internal topography of a peripheral nerve is helpful in estimating the prognosis for a nerve repair at a specific level. Sunderland et al.a6. 37 have studied this topography in detail in humans. They demonstrate the percentage of cross-sectional area of nerves occupied by nerve fibers. Where the percentage is low, one might predict poorer func-
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tional results from repair. From the standpoint of topography, zones considered unfavorable for repair are radial nerve at the axilla and elbow, median nerve at the elbow and wrist and ulnar nerve at the wrist. Because the likelihood of axis cylinder regeneration into the non-neural component of the total nerve cross section is good, Sunderland 36 • 37 favors funicular suture. The identification of funiculi in small nerves can be greatly enhanced by injecting saline with very dilute dye through the perineurium. This technique contrasts the interneural tissue with the funiculi. It also identifies the proximal extent of scarring in neuromas. Various dyes are being investigated for their lack of toxicity.
RECOVERY MEASUREMENT Functional recovery after nerve interruption is very difficult to assess accurately. Clinically one can use electromyography, demonstrate reaction of degeneration, and record denervation fibrillation as objective qualitative indices of denervation. Reversal of the denervation picture is evidence of re-innervation. The degree of total re-innervation cannot be quantitatively measured because of the numerous biologic variables. Restoration of sensation is even more difficult to evaluate because one depends almost entirely on subjective response. Moberg 23 has relied on sudomotor functional return in his objective method for measure of sensory return. He has shown a parallel between sudomotor return and return of all important tactile gnosis. It is true that sudomotor function is the last of the modalities to recover after sensory nerve interruption. Functional recovery documented by Moberg's test would categorize the result as excellent. Scaled below this, however, are patients with acceptable and occasionally only protective sensation whose sudomotor result would be zero. Obviously, patients with brachial plexus injury proximal to the juncture with the sympathetic nerves or patients who have had sympathetic nerve interruption exclusively cannot be evaluated by sudomotor testing. As an index of excellence and as a test of simple application it is a fine contribution. Clinically one may roughly quantify a result using the combined tests outlined by Moberg, but an accurate method for comparison of results of nerve repair from clinic to clinic is still wanting. Seddon27 scaled results of motor recovery empirically from 0 (for no recovery) to 5 (for full recovery) and sensory recovery from 0 (for absent sensation) to 4 (for recovery of 2 point discrimination). An analysis of 330 cases gave gross recovery rates after nerve repair as follows: Median-;-useful motor recovery. . . . . . . . . .. -useful sensory recovery .......... Ulnar -useful motor recovery ........... Radial -useful motor recovery ...........
88.0% 79.4% 79.7% 75.0%
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Failure rate was highest in high level repairs, delayed repairs and where a significant gap had to be overcome. Sunderland34 has indicated the nature of the wounding agent as creating some variation in recovery. He demonstrates poorer recovery after high velocity missile wounds than after lacerations. PROBLEMS AFTER NERVE SURGERY
Neuroma
The symptomatic neuroma is the most frequent problem after peripheral nerve injury. The history of development of surgical methods for treatment of neuromas reflects the knotty nature of the problem. 2 , 5, 12 The experiments of Poth et al. 24 are most revealing and suggest that the pressure of axone regrowth must be met before such growth can be inhibited. Their experiments with various agents led them to conclude that a closed sleeve over the nerve end was effective in preventing neuroma formation. Edds 9 used methyl methacrylate polymer in acetone to cap the end of the nerve, creating a tailor-made fitted cap which doe,; not dislodge. This combines the fixative effect of acetone with the physical capping effect of the plastic. If no special treatment is given to the proximal nerve stump, it should be placed well away from scar and deep in soft tissue where the neuroma may not be bothersome. Nerve Gaps
The problem of bridging nerve gaps is one which has stirred considerable interest during the last several decades. Loss of nerve substance is not an uncommon problem facing one who is dealing with upper extremity trauma. Mobilization and transposition of nerves to overcome the defect is the most successful method of overcoming the deficit.lo, 34, 44 After mobilization and re-suture, the result is on a par with uncomplicated neurorrhaphy. The temptation to stretch peripheral nerves to overcome gaps must be resisted. Nerves will stretch a considerable distance without gross evidence of damage. Highet and Sanders l5 show well-documented evidence of severe degenerative changes and fibrosis after stretching. Liu et al. 20 studied the tensile strength of nerves in fresh specimens and noted histologic evidence of acute damage on stretching the ulnar nerve about 4 per cent of its total length. When manipulative procedures do not suffice, some grafting or bridging method must be used. Much of the reported success with homografting of nerves and tubulation techniques in animals cannot be duplicated in human clinical experience. Autografts in humans have been reported by some observers 4 , 17, 18, 26
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as hardly less successful than end-to-end suture. A suitable donor nerve for transfer is not available without some sacrifice. Autografts using medial cutaneous nerve of the forearm, sural nerve, superficial radial nerve and saphenous nerve as donors have been advocated. Hummell18 has used the phrenic nerve avulsed at the neck to provide segments as long as 20 cm. for autografting. Seddon26 reviewed a series of 52 cases of nerve autografting and concluded that the operation was of value in 67.3 per cent. Homografting of nerves, which has been quite successful in animals,40 has been a discouraging failure in humans. 25 The homograft series of Spurling and Barnes Woodha1l28 . 29 showed failure in all cases with gross and microscopic evidence of severe fibrous reaction. Heterografts and autografts fixed in various agents provoke even more severe fibrous tissue reaction. 4 The problem with homo grafted nerves appears to be one of specificity with tissue incompatibility similar to homografts of other adult tissue. There are no reports of nerve grafts in identical twins or individuals with agammaglobulinemia. Weiss 44 has demonstrated growth of axis cylinders across short gaps using longitudinally oriented fine fibers of glass, nylon, rayon or tantalum in blood-filled arterial tubes. More recently Campbe1l 8 has constructed tubes of Milipore and bridged 2.5 cm. gaps in the sciatic nerves of cats. A rupture along the course of such a tube resulted in neuroma formation at the rupture site. This supports the importance of fibroblastic invasion as the primary cause of neuroma formation. Milipore is brittle and will fracture, making it somewhat impractical for clinical use. Piromen, a pyrogenic drug, has been demonstrated to diminish fibrosis in areas surgically invaded. Animal experiments have been done noting its effect on nerve regeneration. McCullough22 concluded that less subcutaneous and perineural fibrosis occurred, neuroma formation was abated and in his experiments the functional return was superior. Clemente at the University of California at Los Angeles has used this agent as well as ACTH and DOCA with demonstrable improvement of neuronal growth across spinal cord transections in cats. These fascinating animal experiments should not be interpreted as any assurance that the procedures are applicable to human nerve gaps. The seasoned observers in this field have been repeatedly disappointed to find that techniques which are quite successful in animals are a failure when applied to humans. Another method to overcome the nerve gap dilemma is by nerve transfer.21 Peripheral nerves will regenerate down distal sheaths without regard to their original central connection. 47 Nerves of secondary importance can be sectioned and transferred to the distal stump of nerves of major importance. For example, Lurje21 reports success by transferring the musculocutaneous nerve sectioned proximal to the brachialis muscle and transfer of
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the proximal stump to the distal radial nerve injured high in the arm. Successful cross innervation by transfer of ulnar to median at the wrist is also reported. Sensation which returns is not of high quality as a general rule. This fact led Littler19 to utilize island transfers of normally innervated skin carried on neurovascular pedicles to re-surface areas of prime importance in the hand. With this technique full quality sensation is preserved.
Painful Sequelae The last of the late problems in peripheral nerve surgery are the painful sequelae after nerve injury. To discuss these in detail is not within the scope of this paper, but several generalizations can be drawn. The painful neuroma has been discussed above. Causalgia occurred in 34 of 282 major nerve lesions studied by Sunderland and Kelly.33 Frequency is highest in lesions of the medial cord of the brachial plexus and median nerve in the upper extremity. It is theorized that the reason for this is that the bulk of sensory and sympathetic fibers are carried by these trunks. The incidence of causalgia is higher the more proximal the lesion. Treatment benefit is sporadically reported but is unpredictable with nerve block, neurolysis, neurotomy and amputation. Posterior rhizotomy and ablation of the sensory cortex are sometinies effective. The most effective single measure appears to be sympathectomy. The reason for this is not clear. SUMMARY
1. The proximal end of a transected nerve has all the physiologic potential for regrowth and restoration of function at the end organs. Reduction of the deterrents to regeneration and the provision of a proper milieu for regrowth and geographic guidance are the aim of the surgeon. 2. End-to-end coaptation of severed nerve ends without prolonged delay, without tension, in a soft untraumatized bed by sheath suture, plasma clot, or arterial sleeve technique produces the finest results. 3. The most acceptable suture material for neurorrhaphy is fine silk. Fine plain catgut and human hair also meet the requisites for good epineural coaptation. 4. Factors modifying functional recovery are discussed. 5. Symptomatic neuromas may be successfully treated by a number of techniques. End capping with methyl methacrylate in acetone is reported as most successful. 6. Nerve gaps may be overcome by mobilization and joint positioning, nerve transfers, nerve autografting, or island transfers of skin. Research concerned with other methods is briefly reviewed. 7. Painful sequelae of nerve injury are discussed.
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REFERENCES 1. Alexander, E. and Weiss, P.: Arterial Tube Nerve Substitutes. Proc. Roy. Soc. Exper. Biol. & Med. 68: 380, 1948. 2. Bate, J. T.: Method of Treating Nerve Ends in Amputation Stumps. Am. J. Surg. 64: 373, 1944. 3. Bateman, J. E.: Plasma Silk Suture of Nerves. Ann. Surg. 1,''37: 456, 1948. 4. Bjorkesten, G.: Clinical Experience with Nerve Grafting. J. Neurosurg. 5: 450, 1948. 5. Boldrey, E.: Amputation Neuroma in Nerves Implanted in Bone. Ann. Surg. 118: 1652, 1943. 6. Burrow, J.: Phenomena of Regeneration in Peripheral Nerves After Suture. Proc. Royal Soc. Med. 25: 1103, 1932. 7. Cajal, D.: Studien ii.ber Nerveuregeneration. Leipzig, 1908. 8. Campbell, J. B., Bassett, A., Giardo, M., Seymour, R. J. and Rossi, J.: Monomolecular Filter for Bridging Nerve Gaps. J. Neurosurg. 13: 635, 1956. 9. Edds, M.: Preve:ltion of Nerve Regeneration and Neuroma Formation by Caps of Synthetic Resin. J. Neurosurg. 2: 507, 1945. 10. Guth, L.: Regeneration in Mammalian Peripheral Nervous System. Physiol. Rev. 36: 441, 1956. 11. Gutmann, E. and Gutmann, L.: Factors Affecting Recovery of Sensory Function After Nerve Lesions. J. Neurol. & Psychiat. 5: 117, 1942. 12. Gutmann, L. and Medawar, P. B.: Chemical Inhibition of Fiber Regeneration and Neuroma Formation in Peripheral Nerves. J. Neurol. & Psychiat. 5: 130, 1942. 13. Gutmann, E. and Gutmann, L.: Effect of Galvanic Exercise on Denervated and Re-innervated Muscles in Rabbit. J. Neurol. Neurosurg. & Psychiat. 7: 7, 1955. 14. Hamlin, E. and Watkins, A. L.: Regeneration in Ulnar, Median and Radial Nerves. S. CLIN. NORTH AMERICA 27: 1052, 1947. 15. Highet, W. B. and Sanders, F. K.: Effects of Stretching Nerves After ~uture. Brit. J. Surg. 30: 355, 1943. 16. Hines, H.: Neuromuscular Denervation, Atrophy and Regeneration. Federation Proc. 3: 231, 1944. 17. Holmes, W.: Histologic Observation on Repair of Nerves by Autograft. Brit. J. Surg. 35: 167, 1947. 18. Hummel, B.: Bridging Large Nerve Defects. Chirurg. 19: 253, 1948. 19. Littler, J. W.: Neurovascular Pedicle Transfer of Tissue in Reconstructive Surgery of the Hand. Reviewed in J. Bone & Joint Surg. 38.1: 917,1956. 20. Lin, C. T., Bends, C. E. and Sewey, F. H.: Tensile Strength of Human NervesExperimental, Physiologic and Histologic Study. Arch. Neurol. & Psychiat. 59: 322, 1948. 21. Lurje, A. S.: Use of N. Musculocutaneous for Neurotization of N. Radialis in Cases of Very Large Defects of Latter. Ann. Surg. 128: 110, 1948. 22. McCullough, A. W.: Gross Observation of Peripheral Nerve Degeneration in White Rat with Small Dose of Drug Piromen. Anat. Record 118: 328, 1954. 23. Moberg, E.: Objective Methods of Determining the Functional Value of E'ensibility in Hand. J. Bone & Joint Surg. 40B: 454, 1958. 24. Poth, E. S., Fernandez, E. B. and Drager, G. A.: Prevention of Neuroma Formation by Encasement of Severed Nerve End in Rigid Tubes. Proc. Soc. Exper. Biol. & Med. 56: 7, 1944. 25. Seddon, H. J. and Holmes, W.: Late Condition of Nerve Homografts. Surg. Gynec. & Obst. 79: 342, 1944. 26. Seddon, H. J.: Use of Autogenous Grafts for Repair of Large Gaps in Peripheral Nerves. Brit. J. Surg. 35: 151, 1947. 27. Seddon, H. J.: Practical Value of Peripheral Nerve Repair. Proc. Royal E'oc. Med.42:427,1949. 28. Spurling, R. G. and Woodhall, B.: Experience with Early Nerve Surgery in Peripheral Nerve Injuries. Ann. Surg. 123: 731, 1946. 29. Spurling, R. G., Lyons, W. R., Whitcomb, B. B. and Woodhall, B.: Failure of Whole Fresh Homogenous Nerve Grafts in Man. J. Neurosurg. 2: 79, 1945.
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30. Sunderland, S. and Bradley, K. C.: Rates of Advance of Hoffmann-Tinel Sign in Regenerating Nerves. Arch. Neurol. & Psychiat. 67: 650, 1952. 31. Sunderland, S.: Rates of Regeneration in Human Peripheral Nerves. Arch. Neurol. & Psychiat. 58: 251, 1947. 32. Sunderland, S.: In: Weiss, Genetic Neurology, Chicago Univ. Press, 1950. 33. Sunderland, S. and Kelly, M.: Painful Sequelae of Injuries to Peripheral Nerves. Australian and New Zealand .J. Surg. 18: 75, 1948. 34. Sunderland, S.: Observations on Course of Recovery and Late End Results in a Series of Cases of Peripheral Nerve Suture. Australian and New Zealand J. Surg. 28: 264, 1949. 35. Sunderland, S. and Smith, G. K.: Relative Merits of Various Suture Materials for Repair of Severed Nerves. Australian and New Zealand J. Surg. 20: 85, 1950. 36. Sunderland, H. and Bedbrook, G. M.: Cross-Sectional Area of Peripheral Nerve Trunks Occupied by Fibers Representing Individual Muscular and Cutaneous Branches. Brain 72: 613, 1949. 37. Sunderland, S. and Bradley, K. C.: Cross Sectional Area of Peripheral Nerve Trunks Devoted to Nerve Fibers. Brain 72: 428, 1949. 38. Tarlov, 1. M.: Plasma Clot Suture of Peripheral Nerves and Nerve Roots. Springfield, IlL, C. C Thomas, 1950. 39. Weiss, P.: Nerve Reunion with Sleeves of Frozen Dried Artery in Rabbits, Cats and Monkeys. Proc. Soc. Exper. BioI. & Med. 54: 274, 1943. 40. Weiss, P.: Nerve Regeneration Through Frozen Dried Nerve Grafts in Cats and Monkeys. Proc. Soc. Exper. BioI. & Med. 54: 277, 1943. 41. Weiss, P.: In Vitro Experiments on Factors Determining Course of Outgrowing Nerve Fibers. J. Exper. Zool. 68: 393, 1934. 42. Weiss, P.: Nerve Regeneration in Rat Following Tubular Splicing of Severed Nerves. Arch. Surg. 46: 525, 1943. 43. Weiss, P.: Further Experimental Evidence Against N eurotropian in Nerve Regeneration. J. Exper. Zool. 95: 233, 1944. 44. Weiss, P.: Technology of Nerve Regeneration: A Review-Sutureless Tubulation and Related Methods of Nerve Repair. J. Neurosurg. 1: 400,1944. 45. WeisA, P. : Sutureless Reunion of Severed Nerves with Elastic Cuffs of Tantalum. J. N eurosurg. 1: 219, 1944. <16. Weiss, P.: Cell Orientation in Vitro. J. Exper. Zoo!. 100: 353, 1945. 47. Weiss, P.: Competitive Re-innervation of Rat Muscles by Their Own and Foreign Nerves. J. Neurophysio!. 9: 413, 1946.
Yale University School of Medicine New Haven, Connecticut
ROBERT A. CHASE, M.D. Yale University School of Medicine
A PEHIPHERAL nerve that has sustained crushing trauma or complete transection contains proximal and distal axones with entirely different potentials. The distal axones, sequestrated from the central cell bodies, undergo degeneration. The proximal axones are injured but living extremities of viable central cell bodies. After a short latent period they sprout anew with regenerative compulsion. This regenerative pressure produces new outgrowth until the axones reinnervate motor end plates or sensory end organs~unless they are interrupted by an equal resistance to growth. Resistance to outgrowth may occur in the nerve stump milieu in the form of fibrous tissue invasion. This fibrous tissue struggle with the insurgent axones results in neuroma formation. The nerve sheath cells retain their viability both distal and proximal to the sites of injury. Their behavior is of major importance in regrowth of the axones to final reinnervation of the end organs. As the peripheral axones degenerate, the sheath cells hypertrophy and orient themselves in a linear fashion to await regrowth of new axones. Ifaxones re-enter in a reasonable period of time, these sheath cells create a milieu for regrowth which is incomparably good. The physicochemical ultra structure provided directs regrowth of axones in proper orientation. 41 . 45. 46 Occasionally when a nerve gap of short measure is produced at the site of nerve division, the axones cross this and enter the distal segment. In 1905 this finding led CajaF to believe that the distal stump radiated a neurotrophic chemical agent which attracted regenerating nerve cylinders. This theory has now been effectively and substantially disproved experimentally,l0.43 If regenerating axis cylinders do not enter the expectant orderly distal sheath, the sheath slowly loses its receptivity. Morphologic evidence of this is shrinkage of the distal nerve, which is apparent during the first half year after transection. Clinically acceptable regeneration has been noted by several observers3. 10. 14. 27.34 when nerves are approximated
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over two years after injury. After the first year, however, the failure rate rises rapidly. If proper coaptation of proximal stump to distal stump is achieved, then regeneration occurs from the point of transection down the distal sheath. The rate of regrowth has been carefully studied. G, H, 30, 31 In man the initial rate is comparatively rapid with progressive deceleration as regrowth proceeds distally.30, 31 This growth rate is as high as 8 mm. per day initially.30 Clinically, repair of nerves in the hand and wrist results in a recovery rate which is roughly one digital phalanx length per month. For example, regeneration equal to a finger's length would take about three months. The rate of regrowth is faster after crushing injuries than after complete transection. H , 31 Research directed toward production of agents which would stimulate nerve regeneration has failed to show enhancement by vitamins, thyroid, cortisone, atropine, cytochromic C and other agents both chemical and physica1. 10 Some scar-inhibiting agents, such as Piromen, serum antilipase, serum antitrypsin and ACTH, remove a significant block to regeneration experimentally.lo, 22 The result has been improved regeneration in many experimental circumstances. RECOVERY OF FUNCTION AFTER NEURORRHAPHY
After denervation, muscles undergo atrophic changes which are not unlike those with disuse or following tenotomy.l6, 32 Electrical stimulation definitely inhibits denervation and disuse atrophy,13, 16 Atrophic changes are reversible for about one year, after which progressive irreversible fibrotic changes take place. Burrow 6 has shown that following sensory denervation and repair, the sensory modalities return in a fixed sequence. The earliest sign of recovery is Tinel's sign followed in succession by deep sensation, tingling, protopathic sensation, light touch, temperature and position sense. Normal sudomotor activity is found only after return of all other modalities. This fact supports the value of Moberg's23 recently reported technique for evaluation of sensory loss using finger-print documentation of return of sudomotor function. Development of sensation in skin grafts is slow, but partial return of sensation is the rule. Recovery is more accurate in full-thickness grafts than in split-thickness grafts.23 It has been the impression of some that motor functional recovery in median and ulnar nerve repairs was superior to that in radial nerve repairs,14 GuthlO subjected these data to statistical analysis, and concluded that no difference in functional results could be determined, using the reported measurements of function in these three nerves.
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EARLY MANAGEMENT OF NERVE TRANSECTION
Early accurate coaptation of distal and proximal segments of a severed nerve gives the best functional end result. Careful re-approximation of the nerve sheath with fine sutures is the most widely practiced method. Seddon27 endorses the delayed primary technique with accurate suture about three weeks after transection. He feels that the fibrosis in the stumps produced by injury is grossly manifested by this time, and that scarring of other adjacent repaired structures is confined at this time with less likely invasion of the nerve repair. In his experience the slight thickening of the nerve sheath which is established at three weeks makes nerve suture easier and more accurate. Seddon27 states that the final results are better in his series using the delayed suture technique. Choice of suture material for neurorrhaphy has led to debate among experts in the field. This led Sunderland and Smith35 to carry out controlled studies of the virtues of the materials available. The attributes most desired are: that the suture set up minimal fibroblastic reaction, that the reaction be as short in duration as possible, and that the material be of fine caliber. Silk, plain gut and human hair adhered most closely to this pattern. Sterility assurance, fine caliber, tensile strength and ease of use give silk a slight advantage over the other two. Tantalum and nylon both created severe fibroblastic reaction late after repair. Nerve anastomosis using sleeves of various materials around the site of juncture has been tried and results evaluated by many observers. 1. 8.39.42-45.47 The enthusiasm for tantalum cylinders has been effectively negated by the poor late results and morphologic evidence of reaction fibroplasia and strangulation at the repair site. The tireless investigations of Weiss39- 47 have shown that the use of an arterial sleeve at the anastomosis site creates a favorable milieu for nerve regeneration in animals. It seems logical to apply the same technique to nerve anastomoses in humans. Weiss has demonstrated high grade success in monkeys using frozen, dried homografts of artery as the sleeve. A promising inert foreign agent for use at the site of anastomosis is Milipore, 8 although it must withstand the test of time. The plasma clot method using plasma as an adhesive agent at the nerve ends is enthusiastically advocated by one school of surgeons. 38 Still another school combines the use of plasma and silk. 3 Tarlov states that he "recommends the plasma clot technique to the patient operator in the interest of improving functional results." A knowledge of the internal topography of a peripheral nerve is helpful in estimating the prognosis for a nerve repair at a specific level. Sunderland et al.a6. 37 have studied this topography in detail in humans. They demonstrate the percentage of cross-sectional area of nerves occupied by nerve fibers. Where the percentage is low, one might predict poorer func-
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tional results from repair. From the standpoint of topography, zones considered unfavorable for repair are radial nerve at the axilla and elbow, median nerve at the elbow and wrist and ulnar nerve at the wrist. Because the likelihood of axis cylinder regeneration into the non-neural component of the total nerve cross section is good, Sunderland 36 • 37 favors funicular suture. The identification of funiculi in small nerves can be greatly enhanced by injecting saline with very dilute dye through the perineurium. This technique contrasts the interneural tissue with the funiculi. It also identifies the proximal extent of scarring in neuromas. Various dyes are being investigated for their lack of toxicity.
RECOVERY MEASUREMENT Functional recovery after nerve interruption is very difficult to assess accurately. Clinically one can use electromyography, demonstrate reaction of degeneration, and record denervation fibrillation as objective qualitative indices of denervation. Reversal of the denervation picture is evidence of re-innervation. The degree of total re-innervation cannot be quantitatively measured because of the numerous biologic variables. Restoration of sensation is even more difficult to evaluate because one depends almost entirely on subjective response. Moberg 23 has relied on sudomotor functional return in his objective method for measure of sensory return. He has shown a parallel between sudomotor return and return of all important tactile gnosis. It is true that sudomotor function is the last of the modalities to recover after sensory nerve interruption. Functional recovery documented by Moberg's test would categorize the result as excellent. Scaled below this, however, are patients with acceptable and occasionally only protective sensation whose sudomotor result would be zero. Obviously, patients with brachial plexus injury proximal to the juncture with the sympathetic nerves or patients who have had sympathetic nerve interruption exclusively cannot be evaluated by sudomotor testing. As an index of excellence and as a test of simple application it is a fine contribution. Clinically one may roughly quantify a result using the combined tests outlined by Moberg, but an accurate method for comparison of results of nerve repair from clinic to clinic is still wanting. Seddon27 scaled results of motor recovery empirically from 0 (for no recovery) to 5 (for full recovery) and sensory recovery from 0 (for absent sensation) to 4 (for recovery of 2 point discrimination). An analysis of 330 cases gave gross recovery rates after nerve repair as follows: Median-;-useful motor recovery. . . . . . . . . .. -useful sensory recovery .......... Ulnar -useful motor recovery ........... Radial -useful motor recovery ...........
88.0% 79.4% 79.7% 75.0%
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Failure rate was highest in high level repairs, delayed repairs and where a significant gap had to be overcome. Sunderland34 has indicated the nature of the wounding agent as creating some variation in recovery. He demonstrates poorer recovery after high velocity missile wounds than after lacerations. PROBLEMS AFTER NERVE SURGERY
Neuroma
The symptomatic neuroma is the most frequent problem after peripheral nerve injury. The history of development of surgical methods for treatment of neuromas reflects the knotty nature of the problem. 2 , 5, 12 The experiments of Poth et al. 24 are most revealing and suggest that the pressure of axone regrowth must be met before such growth can be inhibited. Their experiments with various agents led them to conclude that a closed sleeve over the nerve end was effective in preventing neuroma formation. Edds 9 used methyl methacrylate polymer in acetone to cap the end of the nerve, creating a tailor-made fitted cap which doe,; not dislodge. This combines the fixative effect of acetone with the physical capping effect of the plastic. If no special treatment is given to the proximal nerve stump, it should be placed well away from scar and deep in soft tissue where the neuroma may not be bothersome. Nerve Gaps
The problem of bridging nerve gaps is one which has stirred considerable interest during the last several decades. Loss of nerve substance is not an uncommon problem facing one who is dealing with upper extremity trauma. Mobilization and transposition of nerves to overcome the defect is the most successful method of overcoming the deficit.lo, 34, 44 After mobilization and re-suture, the result is on a par with uncomplicated neurorrhaphy. The temptation to stretch peripheral nerves to overcome gaps must be resisted. Nerves will stretch a considerable distance without gross evidence of damage. Highet and Sanders l5 show well-documented evidence of severe degenerative changes and fibrosis after stretching. Liu et al. 20 studied the tensile strength of nerves in fresh specimens and noted histologic evidence of acute damage on stretching the ulnar nerve about 4 per cent of its total length. When manipulative procedures do not suffice, some grafting or bridging method must be used. Much of the reported success with homografting of nerves and tubulation techniques in animals cannot be duplicated in human clinical experience. Autografts in humans have been reported by some observers 4 , 17, 18, 26
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as hardly less successful than end-to-end suture. A suitable donor nerve for transfer is not available without some sacrifice. Autografts using medial cutaneous nerve of the forearm, sural nerve, superficial radial nerve and saphenous nerve as donors have been advocated. Hummell18 has used the phrenic nerve avulsed at the neck to provide segments as long as 20 cm. for autografting. Seddon26 reviewed a series of 52 cases of nerve autografting and concluded that the operation was of value in 67.3 per cent. Homografting of nerves, which has been quite successful in animals,40 has been a discouraging failure in humans. 25 The homograft series of Spurling and Barnes Woodha1l28 . 29 showed failure in all cases with gross and microscopic evidence of severe fibrous reaction. Heterografts and autografts fixed in various agents provoke even more severe fibrous tissue reaction. 4 The problem with homo grafted nerves appears to be one of specificity with tissue incompatibility similar to homografts of other adult tissue. There are no reports of nerve grafts in identical twins or individuals with agammaglobulinemia. Weiss 44 has demonstrated growth of axis cylinders across short gaps using longitudinally oriented fine fibers of glass, nylon, rayon or tantalum in blood-filled arterial tubes. More recently Campbe1l 8 has constructed tubes of Milipore and bridged 2.5 cm. gaps in the sciatic nerves of cats. A rupture along the course of such a tube resulted in neuroma formation at the rupture site. This supports the importance of fibroblastic invasion as the primary cause of neuroma formation. Milipore is brittle and will fracture, making it somewhat impractical for clinical use. Piromen, a pyrogenic drug, has been demonstrated to diminish fibrosis in areas surgically invaded. Animal experiments have been done noting its effect on nerve regeneration. McCullough22 concluded that less subcutaneous and perineural fibrosis occurred, neuroma formation was abated and in his experiments the functional return was superior. Clemente at the University of California at Los Angeles has used this agent as well as ACTH and DOCA with demonstrable improvement of neuronal growth across spinal cord transections in cats. These fascinating animal experiments should not be interpreted as any assurance that the procedures are applicable to human nerve gaps. The seasoned observers in this field have been repeatedly disappointed to find that techniques which are quite successful in animals are a failure when applied to humans. Another method to overcome the nerve gap dilemma is by nerve transfer.21 Peripheral nerves will regenerate down distal sheaths without regard to their original central connection. 47 Nerves of secondary importance can be sectioned and transferred to the distal stump of nerves of major importance. For example, Lurje21 reports success by transferring the musculocutaneous nerve sectioned proximal to the brachialis muscle and transfer of
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the proximal stump to the distal radial nerve injured high in the arm. Successful cross innervation by transfer of ulnar to median at the wrist is also reported. Sensation which returns is not of high quality as a general rule. This fact led Littler19 to utilize island transfers of normally innervated skin carried on neurovascular pedicles to re-surface areas of prime importance in the hand. With this technique full quality sensation is preserved.
Painful Sequelae The last of the late problems in peripheral nerve surgery are the painful sequelae after nerve injury. To discuss these in detail is not within the scope of this paper, but several generalizations can be drawn. The painful neuroma has been discussed above. Causalgia occurred in 34 of 282 major nerve lesions studied by Sunderland and Kelly.33 Frequency is highest in lesions of the medial cord of the brachial plexus and median nerve in the upper extremity. It is theorized that the reason for this is that the bulk of sensory and sympathetic fibers are carried by these trunks. The incidence of causalgia is higher the more proximal the lesion. Treatment benefit is sporadically reported but is unpredictable with nerve block, neurolysis, neurotomy and amputation. Posterior rhizotomy and ablation of the sensory cortex are sometinies effective. The most effective single measure appears to be sympathectomy. The reason for this is not clear. SUMMARY
1. The proximal end of a transected nerve has all the physiologic potential for regrowth and restoration of function at the end organs. Reduction of the deterrents to regeneration and the provision of a proper milieu for regrowth and geographic guidance are the aim of the surgeon. 2. End-to-end coaptation of severed nerve ends without prolonged delay, without tension, in a soft untraumatized bed by sheath suture, plasma clot, or arterial sleeve technique produces the finest results. 3. The most acceptable suture material for neurorrhaphy is fine silk. Fine plain catgut and human hair also meet the requisites for good epineural coaptation. 4. Factors modifying functional recovery are discussed. 5. Symptomatic neuromas may be successfully treated by a number of techniques. End capping with methyl methacrylate in acetone is reported as most successful. 6. Nerve gaps may be overcome by mobilization and joint positioning, nerve transfers, nerve autografting, or island transfers of skin. Research concerned with other methods is briefly reviewed. 7. Painful sequelae of nerve injury are discussed.
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REFERENCES 1. Alexander, E. and Weiss, P.: Arterial Tube Nerve Substitutes. Proc. Roy. Soc. Exper. Biol. & Med. 68: 380, 1948. 2. Bate, J. T.: Method of Treating Nerve Ends in Amputation Stumps. Am. J. Surg. 64: 373, 1944. 3. Bateman, J. E.: Plasma Silk Suture of Nerves. Ann. Surg. 1,''37: 456, 1948. 4. Bjorkesten, G.: Clinical Experience with Nerve Grafting. J. Neurosurg. 5: 450, 1948. 5. Boldrey, E.: Amputation Neuroma in Nerves Implanted in Bone. Ann. Surg. 118: 1652, 1943. 6. Burrow, J.: Phenomena of Regeneration in Peripheral Nerves After Suture. Proc. Royal Soc. Med. 25: 1103, 1932. 7. Cajal, D.: Studien ii.ber Nerveuregeneration. Leipzig, 1908. 8. Campbell, J. B., Bassett, A., Giardo, M., Seymour, R. J. and Rossi, J.: Monomolecular Filter for Bridging Nerve Gaps. J. Neurosurg. 13: 635, 1956. 9. Edds, M.: Preve:ltion of Nerve Regeneration and Neuroma Formation by Caps of Synthetic Resin. J. Neurosurg. 2: 507, 1945. 10. Guth, L.: Regeneration in Mammalian Peripheral Nervous System. Physiol. Rev. 36: 441, 1956. 11. Gutmann, E. and Gutmann, L.: Factors Affecting Recovery of Sensory Function After Nerve Lesions. J. Neurol. & Psychiat. 5: 117, 1942. 12. Gutmann, L. and Medawar, P. B.: Chemical Inhibition of Fiber Regeneration and Neuroma Formation in Peripheral Nerves. J. Neurol. & Psychiat. 5: 130, 1942. 13. Gutmann, E. and Gutmann, L.: Effect of Galvanic Exercise on Denervated and Re-innervated Muscles in Rabbit. J. Neurol. Neurosurg. & Psychiat. 7: 7, 1955. 14. Hamlin, E. and Watkins, A. L.: Regeneration in Ulnar, Median and Radial Nerves. S. CLIN. NORTH AMERICA 27: 1052, 1947. 15. Highet, W. B. and Sanders, F. K.: Effects of Stretching Nerves After ~uture. Brit. J. Surg. 30: 355, 1943. 16. Hines, H.: Neuromuscular Denervation, Atrophy and Regeneration. Federation Proc. 3: 231, 1944. 17. Holmes, W.: Histologic Observation on Repair of Nerves by Autograft. Brit. J. Surg. 35: 167, 1947. 18. Hummel, B.: Bridging Large Nerve Defects. Chirurg. 19: 253, 1948. 19. Littler, J. W.: Neurovascular Pedicle Transfer of Tissue in Reconstructive Surgery of the Hand. Reviewed in J. Bone & Joint Surg. 38.1: 917,1956. 20. Lin, C. T., Bends, C. E. and Sewey, F. H.: Tensile Strength of Human NervesExperimental, Physiologic and Histologic Study. Arch. Neurol. & Psychiat. 59: 322, 1948. 21. Lurje, A. S.: Use of N. Musculocutaneous for Neurotization of N. Radialis in Cases of Very Large Defects of Latter. Ann. Surg. 128: 110, 1948. 22. McCullough, A. W.: Gross Observation of Peripheral Nerve Degeneration in White Rat with Small Dose of Drug Piromen. Anat. Record 118: 328, 1954. 23. Moberg, E.: Objective Methods of Determining the Functional Value of E'ensibility in Hand. J. Bone & Joint Surg. 40B: 454, 1958. 24. Poth, E. S., Fernandez, E. B. and Drager, G. A.: Prevention of Neuroma Formation by Encasement of Severed Nerve End in Rigid Tubes. Proc. Soc. Exper. Biol. & Med. 56: 7, 1944. 25. Seddon, H. J. and Holmes, W.: Late Condition of Nerve Homografts. Surg. Gynec. & Obst. 79: 342, 1944. 26. Seddon, H. J.: Use of Autogenous Grafts for Repair of Large Gaps in Peripheral Nerves. Brit. J. Surg. 35: 151, 1947. 27. Seddon, H. J.: Practical Value of Peripheral Nerve Repair. Proc. Royal E'oc. Med.42:427,1949. 28. Spurling, R. G. and Woodhall, B.: Experience with Early Nerve Surgery in Peripheral Nerve Injuries. Ann. Surg. 123: 731, 1946. 29. Spurling, R. G., Lyons, W. R., Whitcomb, B. B. and Woodhall, B.: Failure of Whole Fresh Homogenous Nerve Grafts in Man. J. Neurosurg. 2: 79, 1945.
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30. Sunderland, S. and Bradley, K. C.: Rates of Advance of Hoffmann-Tinel Sign in Regenerating Nerves. Arch. Neurol. & Psychiat. 67: 650, 1952. 31. Sunderland, S.: Rates of Regeneration in Human Peripheral Nerves. Arch. Neurol. & Psychiat. 58: 251, 1947. 32. Sunderland, S.: In: Weiss, Genetic Neurology, Chicago Univ. Press, 1950. 33. Sunderland, S. and Kelly, M.: Painful Sequelae of Injuries to Peripheral Nerves. Australian and New Zealand .J. Surg. 18: 75, 1948. 34. Sunderland, S.: Observations on Course of Recovery and Late End Results in a Series of Cases of Peripheral Nerve Suture. Australian and New Zealand J. Surg. 28: 264, 1949. 35. Sunderland, S. and Smith, G. K.: Relative Merits of Various Suture Materials for Repair of Severed Nerves. Australian and New Zealand J. Surg. 20: 85, 1950. 36. Sunderland, H. and Bedbrook, G. M.: Cross-Sectional Area of Peripheral Nerve Trunks Occupied by Fibers Representing Individual Muscular and Cutaneous Branches. Brain 72: 613, 1949. 37. Sunderland, S. and Bradley, K. C.: Cross Sectional Area of Peripheral Nerve Trunks Devoted to Nerve Fibers. Brain 72: 428, 1949. 38. Tarlov, 1. M.: Plasma Clot Suture of Peripheral Nerves and Nerve Roots. Springfield, IlL, C. C Thomas, 1950. 39. Weiss, P.: Nerve Reunion with Sleeves of Frozen Dried Artery in Rabbits, Cats and Monkeys. Proc. Soc. Exper. BioI. & Med. 54: 274, 1943. 40. Weiss, P.: Nerve Regeneration Through Frozen Dried Nerve Grafts in Cats and Monkeys. Proc. Soc. Exper. BioI. & Med. 54: 277, 1943. 41. Weiss, P.: In Vitro Experiments on Factors Determining Course of Outgrowing Nerve Fibers. J. Exper. Zool. 68: 393, 1934. 42. Weiss, P.: Nerve Regeneration in Rat Following Tubular Splicing of Severed Nerves. Arch. Surg. 46: 525, 1943. 43. Weiss, P.: Further Experimental Evidence Against N eurotropian in Nerve Regeneration. J. Exper. Zool. 95: 233, 1944. 44. Weiss, P.: Technology of Nerve Regeneration: A Review-Sutureless Tubulation and Related Methods of Nerve Repair. J. Neurosurg. 1: 400,1944. 45. WeisA, P. : Sutureless Reunion of Severed Nerves with Elastic Cuffs of Tantalum. J. N eurosurg. 1: 219, 1944. <16. Weiss, P.: Cell Orientation in Vitro. J. Exper. Zoo!. 100: 353, 1945. 47. Weiss, P.: Competitive Re-innervation of Rat Muscles by Their Own and Foreign Nerves. J. Neurophysio!. 9: 413, 1946.
Yale University School of Medicine New Haven, Connecticut