ABSTRACT: A modified surgical technique is introduced, enabling resto-ration of muscle function with direct muscular neurotization. Reliable clinicaloutcomes result from this technique. We report on a series of 10 patients inwhom the supplying motor nerve had been lost at the level of the neuro-muscular junction as the result of trauma or tumor resection. Our modifica-tion of the operative technique ensures a wide distribution of nerve fibersthroughout the remaining muscle tissue and produces a mean motor recov-ery of M4 after a period of 1 to 2 years.

© 2002 Wiley Periodicals, Inc. Muscle Nerve 26: 362–366, 2002

REFINEMENTS IN NERVE TOMUSCLE NEUROTIZATION

MICHAEL BECKER, MD,1 FRANZ LASSNER, MD,1 HISHAM FANSA, MD, PhD,2 CHRISTIAN MAWRIN, MD,3 and

NORBERT PALLUA MD, PhD1

1 Clinic of Plastic and Hand Surgery, Burn Center, Rheinisch Westfahlische Technische Hochschule,Aachen, Germany2Department of Plastic, Reconstructive and Hand Surgery, Otto-von-Guericke University, Magdeburg, Germany3 Institute of Neuropathology, Otto-von-Guericke University, Magdeburg, Germany

Accepted 19 April 2002

Muscular neurotization (or, nerve to muscle neuro-tization) describes the regenerative anatomical andphysiological phenomena arising when peripheralnerves are introduced into muscle.13,14 The surgicalprocedure of inserting peripheral nerves directlyinto denervated muscle is (with the exception of freeneurovascular muscle transplantation) the only re-constructive option when loss of motor nerve func-tion has occurred at the level of the neuromuscularjunction.2,20 However, the functional value of thisprocedure remains a matter of controversy. Thetechnique of reinnervating skeletal muscles by inser-tion of a donor nerve into the muscle tissue wasdeveloped at the beginning of the 20th cen-tury.5,8,22,23 Nevertheless, few reports of clinicallysuccessful reinnervation exist, and a high failure ratein other cases has been observed. For this reason,clinical application of the method during the follow-ing decades was only limited.

In the middle of the 20th century, several inves-tigators1,6,7 resumed animal experiments on directmuscular neurotization, obtaining good results. Sub-sequently, Sorbie and Porter21 and Sakellarides et

al.20 made force measurements of muscles reinner-vated in this way under experimental conditions. Ina dog model, Sorbie and Porter21 grafted a motornerve fascicle of the flexor carpi ulnaris muscle intothe muscle belly of the flexor carpi radialis muscle.This resulted in data which were relatively unpredict-able, with a wide scatter of regeneration results,ranging from 44–94% of the original muscular force.Macroscopically, the regenerated muscles stillshowed a substantial proportion of degenerated fi-bers. Histologically, motor end-plates were found tobe concentrated around the stump of the donornerve. In contrast, Sakellarides et al.20 achieved ahighly consistent 60–75% of original muscle func-tion in the dog. Prior to implantation, he divided thedonor nerve into two or three fascicles. This resultedin the regenerated muscles having a macroscopicappearance hardly distinguishable from normalmuscles.

Brunelli et al.3,4 addressed the question as towhether new motor end-plates were generated fol-lowing the ingrowth of axons into a denervatedmuscle. In rabbits, he grafted the motor branch ofthe peroneal nerve into the “aneural” zone of thelateral head of the gastrocnemius muscle where, un-der physiological conditions, no motor end-platesare detectable. Four weeks postoperatively, whenmotor function had recovered, motor end-plateswere found in histological sections. Subsequently, heapplied this technique to clinical cases with good

Key words: direct neurotization; motor end-plates; muscular regenera-tion; nerve regeneration; neuromuscular junctionCorrespondence to: M. Becker, University of Witten-Herdecke, Clinic forPlastic and Hand Surgery, Amenbergerstr. 11, 42177 Wuppertal, Ger-many; e-mail: becker.pch@gmx.de

© 2002 Wiley Periodicals, Inc.Published online 29 July 2002 in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mus.10205

362 Nerve to Muscle Neurotization MUSCLE & NERVE September 2002

results.3 Payne and Brushart18 confirmed these ob-servations, namely, that new motor end-plates formin the region of axonal ingrowth into a denervatedmuscle. This was by implantation of the tibial nerveproximally and distally into the soleus muscle of therat. A majority of end-plates were detectable proxi-mally after proximal implantation (not differentfrom the physiological situation). However, follow-ing distal implantation, end-plates were detected inthe previously aneural zone. Zhang et al.24 experi-mentally compared muscle weight following eitherconventional nerve grafting or intramuscular neuro-tization and, when only a single nerve stump hadbeen introduced into the muscle, found no signifi-cant differences. No functional evaluation was per-formed.

Physiologically, the neuromuscular junction ischaracterized by extensive branching of the nerveendings. Improvement in the clinical results of nerveto muscle neurotization appears to require a similarsetting in a reconstructive operation. We have ac-cordingly modified the surgical technique of directmuscular neurotization2–5 to ensure widespread dis-tribution of motor axons throughout the denervatedmuscle. Good motor function was restored in 10clinical cases by this method.

MATERIALS AND METHODS

Surgical Procedure. The sural nerve has a longproximal and medial segment with no significantbranching. At the distal third of the lower leg, thesural nerve divides into three branches for sensorysupply of the lateral calcaneus, the region below theankle, and the lateral midfoot. Further distally, morebranches of the sural nerve occur almost at skinlevel. The distal portion of the sural nerve can there-fore be harvested to the appropriate length, thusproviding the branching necessary to a wide distri-bution of axons throughout the muscle. Furthergrafts are needed in the commonly encounteredclinical context in which the nerve defect may be7–15 cm long and require three to five sural nervegrafts (Table 1). The remaining proximal parts ofthe sural nerve are cut to the appropriate length.The distal end of each segment is then microsurgi-cally dissected to separate the fascicles in a proximaldirection, thus creating the desired neural branch-ing. Additional nerve stumps (three or four) are cre-ated as axonal sources by dissecting the transversefibers between the fascicles. However, interfasciculardissection deviates axons on their way to the distalstump into the adjacent muscle tissue. To ensurethat a substantial number of axons reaches the distal

stump, our procedure was limited to a maximal seg-ment of 3–6 cm (Fig. 1). After coaptation of thenerve grafts to the proximal nerve stump, the distalbranches of the grafts were evenly distributedthroughout the muscle tissue. Tunnels were createdby blunt dissection along the axis of the muscle fi-bers, and the grafts were inserted far enough intothese tunnels so that all nerve stumps were locatedintramuscularly. The grafts were secured with 10.0nylon sutures. This resembles the terminal branch-ing of the motor nerves entering the skeletal muscle(Fig. 2). Surgery was performed by three differentsurgeons.

Patients. Over the last 2.5 years, 10 patients havebeen treated according to this technique. In none ofthe patients was a distal nerve stump available forneural coaptation. All patients were informed aboutthe direct insertion of nerve stumps into the muscleas an alternative to neurovascular muscle transfer.Surgery was performed primarily for the benefit ofthe patients and was a modification of an existingtechnique. Informed consent was obtained on thebasis that a less difficult operation could be expectedto provide a similar result to the more complex neu-rovascular muscle transfer in terms of function. Ofthe 10 patients, in 8 instances trauma had resulted indestruction of the neurovascular bundle where theperipheral nerve enters the muscle head. In 2 cases,tumor infiltration necessitated resection of themuscle head and the motor branch.

Evaluation. Five of the patients were evaluated af-ter 1 year, two patients after 1.5 years, and threepatients after 2 years. Evaluation included clinicalexamination of muscular force according to theHighet classification.9 Neurophysiological measure-ments were conducted on all patients at the end ofthe observation period. In one patient (Patient 5,Table 1), scar correction was necessary after 1 year,enabling us to obtain a muscle biopsy for histologicalevaluation. A segment of the material was snap-frozen and the remainder embedded in paraffin.The cryostat sections were stained for adenosine tri-phosphatase at pH 10.4, 9.4, and 4.1, and also foracetylcholinesterase. The paraffin sections werestained with hematoxylin-eosin and trichrome inlongitudinal and cross sections.

RESULTS

Reconstruction of the neuromuscular junction wasperformed as a primary procedure in the two tumorpatients and also in one posttraumatic case. All ofthe remaining seven patients except one (Patient 4,

Nerve to Muscle Neurotization MUSCLE & NERVE September 2002 363

Table 1) were operated within a 6-month interval,the mean denervation time of the secondary casesbeing 5.3 months. Active muscle movement was re-stored in all patients, with a resulting muscular force

of M4 in all muscles except two (graded M3); detailsare listed in Table 1.

Regeneration was confirmed electrophysiologi-cally, with similar findings obtained for all patients.

Table 1. Clinical results.*

Patient M/F Age Clinical setting Denervation Reconstructive procedure Regeneration result

1 M 19 Shoulder subluxation withaxillary nerve avulsionat the neuromuscularjunction

5 months 5 nerve grafts of 10 cm,each divided into 3 or 4fascicles, resulting in atotal of 17 nerveendings

1 year: full range of activeshoulder movement;deltoid muscle M4

2 M 52 Fibromatosis of the headof the triceps suraemuscle, completeresection

Primary reconstruction 3 nerve grafts of 15 cm;12 nerve endingsdistributed into tricepssurae muscle

1.5 years: M4 of tricepssurae muscle; norecurrence of tumor

3 M 33 Desmoid tumor of thehead of the pectoralismajor muscle, leadingto resection of head ofpectoralis major,pectoralis minor, lateralclavicle, long head ofbiceps, and anteriorglenoid

Primary reconstruction 3 nerve grafts of 12 cmfrom lateral fascicle intothe remaining pectoralismajor; 12 nerveendings. Pedicledscapular flap fortissue coverage

1 year: full range ofmovement; pectoralismajor muscle M4

4 M 45 Fracture of proximalradius with avulsioninjury to deep branchesof radial nerve

9 months 3 nerve grafts of 7–10 cm;12 nerve endings, toEDC and ECR

2 years: EDC M3 andECR M4

5 F 40 Fracture of radius andulna with avulsion injuryof deep branches ofradial nerve

6 months 4 nerve grafts of 10 cm;14 nerve endings toEDC and ECR

1 year: EDC and ECR M4

6 M 45 Circular saw injury of theproximal forearm withloss of the heads ofECR and EDC

Primary reconstruction 4 nerve grafts of 4 cm; 12nerve endings to EDCand ECR

1 year: ECD and ECR M4

7 M 24 Avulsion of the muscularbranches FCU, FDP4/5,and defect of the ulnarnerve distal of theelbow

4 months 1 nerve graftof 10 cm with 6 nerveendings to FDP4/5

1 year: FDP 4/5 M4

8 M 53 Subtotal avulsion of theupper arm with avulsioninjury ofmusculocutaneousnerve and tricepsbranch of radial nerve

3 months 3 nerve grafts of 8 cm forthe musculocutaneousnerve; 3 nerve grafts of11 cm for the tricepsbranch of the radialnerve

1.5 years: triceps muscleM4 and biceps muscleM3

9 M 28 Shoulder subluxation withavulsion of axillarynerve

6 months 2 × 7 cm, 1 × 10 cm, and1 × 13 cm nerve grafts

2 years: deltoid muscleM4

10 M 35 Scapular fracture.Avulsion of axillarynerve, neural fibrosisgrade B16 of superiortrunk andsuprascapular nerve

4 months 4 × 10 cm nerve graftsinto the deltoid muscle

2 years: deltoid muscleM4

ECR, extensor carpi radialis muscle; EDC, extensor digitorum communis muscle; FCU, flexor carpi ulnaris; FDP 4/5, flexor digitorum profundus muscleof the ring and small finger.*Grading of muscular force was according to Highet and Holmes9: M3, muscle can move joint through full range of motion against gravity; M4, fullrange of movement against gravity and some resistance.

364 Nerve to Muscle Neurotization MUSCLE & NERVE September 2002

No abnormal spontaneous electrophysiological activ-ity was recorded, and the voluntary activity of actionpotentials was close to normal. Occasionally, abnor-mal findings such as excessive polyphasic motor unitpotentials were seen during maximal voluntary con-traction only, and these were of long duration andlow amplitude, indicative of reinnervation.

The paraffin sections showed large areas of nor-mal and hypertrophied muscle fibers and also smallareas of partially atrophied fibers. In the cryostat sec-tions, typical signs of fiber type grouping was evi-dent. Target fibers, indicative of fresh regeneration,were not present (Fig. 3).

DISCUSSION

In all patients, muscular function was restored bythis surgical modification aimed at enhancement of

direct nerve to muscle neurotization, thus ensuringthat a maximum of nerve fibers are evenly distrib-uted throughout the muscle tissue.

In the clinical situation in which no distal nervestump is available for neural coaptation and wherethere is a loss of nerve or muscle at the level of theneuromuscular junction, intramuscular neurotiza-tion provides a good reconstructive option. In cer-tain cases, the nerve may still be present in the vicin-ity of the neuromuscular junction although havingundergone fibrotic degeneration as a result of a par-tial avulsion. This applied to two of our patients withshoulder subluxation (Patients 1 and 9, Table 1) aswell as the patient with brachial plexus injury (Pa-tient 10, Table 1). When additional loss of muscletissue has occurred, a major part of the end-plate–bearing area is absent. Reconstruction requires the

FIGURE 1. Schematic drawing of interfascicular preparation ofsural nerve grafts. Nerve stumps are present not only at the distalend of the sural nerve, but also at those points where interfas-cicular connections have been dissected (arrowhead), constitut-ing additional sources of neurotization (arrow).

FIGURE 2. Intraoperative situation after distribution of suralnerve grafts into the denervated muscle tissue.

FIGURE 3. Micrographs of frozen section of the reinnervatedmuscle. (A) ATPase at pH 10.4 demonstrating predominance ofType I fibers and occasional atrophy of Type II fibers, with fibertype grouping (bar = 50 µm). (B) Acetylcholinesterase activity atthe plasma membrane (bar = 20 µm).

Nerve to Muscle Neurotization MUSCLE & NERVE September 2002 365

ingrowth of axons into the denervated muscle andformation of new neuromuscular junctions. Inser-tion of peripheral nerves into a skeletal muscle re-sults in the reestablishment of a certain number ofneuromuscular junctions, as demonstrated by vari-ous authors.3,4,11,12,17,19 In view of the anatomicalstructure of the neuromuscular junction with exten-sive branching of the nerve endings, our aim hasbeen to establish a maximum of neuromatousstumps within the muscle tissue. To achieve the bestclinical result, the neuromuscular connections needto be distributed as widely as possible, as alreadydemonstrated by others.2,3 Our surgical techniqueprovides a refined method to achieve this.

The present patient population was operated onby three different surgeons with no apparent differ-ences in outcome, a strong argument for the reliabil-ity of the method. In agreement with this, the litera-ture provides evidence of pronounced histologicaldegeneration of large areas of muscle when only asingle or a few nerve stumps were inserted into de-nervated muscle. In cases in which the major end-plate–bearing area of the muscles are lost, successfulmotor recovery after direct neurotization presum-ably requires that motor end-plates form in the vi-cinity of ingrowing axons. Experimental evidencehas shown that new end-plates do indeed form in thevicinity of ingrowing axons,3,10,18 the increased sen-sitivity of denervated muscles to cholinesterase beingone possible contributing factor to this phenom-enon.6 Among our patients, the end-plate–bearingarea had been lost in three patients (Patients 2, 3,and 6, Table 1). Regeneration outcomes in thesepatients did not differ from those in patients inwhom the end-plate–bearing area remained intact,thus indicating new formation of motor end-platesduring regeneration.

In addition to surgical technique, the final out-come in terms of function depends on a number ofother factors, including the quality of the donornerve, and on less important factors, such as the ageof the patient, the size of the nerve defect (regen-erative distance), the quantity of remaining musclemass, and the time interval between trauma and re-construction.15

In conclusion, the direct insertion of nerves intomuscle seems to be a reliable method for functionalreconstruction of denervated muscles, provided thatcertain preconditions are met. These are: short re-generation distance (7–15 cm) combined with ashort period of denervation, healthy donor nerves,and a surgical technique ensuring wide distributionof fibers in the muscle.

This work was presented in part at the annual meeting of theAmerican Society for Peripheral Nerve, San Diego, California,January 2001 and the 5th International Muscle Symposium, Vi-enna, Austria, May 2000.

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