Nerves have a structure of considerable complexity with features of special relevance to nerve injury and nerve regeneration. These include variations in the cross-sectional areas devoted to fascicular and epineurial tissue, the fascicular redistribution and mixing of different branch fibers brought about by fascicular plexuses, and the numbers of nerve fibers representing individual branches. The elasticity and tensile strength of nerve trunks and their capacity to resist traction deformation reside in the fascicular tissue, while the epineurium provides a protective cushion against compression. The microstructure of nerve trunks provides the basis for a classification of nerve injuries into five degrees of severity with partial and mixed types-each with a clearly defined pathology and distinguishing clinical features. Following a transection injury, changes occur in the severed axons, endoneurial tubes, fasciculi, and nerve trunk. The type of injury and the nature of these changes determine the outcome of axon regeneration. Key words: nerve injury nerve regeneration. MUSCLE & NERVE 13:771-784 1990
THE ANATOMY AND PHYSIOLOGY OF NERVE INJURY SIR SYDNEY SUNDERLAND, MD, DSc, FRACS, FRACP
Although it is true that many of the problems of nerve injury and nerve repair must wait on the molecular biologist for their solution, it is equally clear that, for the time being, we cannot afford to overlook the use of somewhat old fashioned but well-tried methods and techniques that still have much to offer. It is such an approach that forms the substance of this article. THE MICROSTRUCTURE OF NERVE TRUNKS
A convenient starting point for our purposes is a transverse section of a peripheral nerve trunk. This reveals those structural features that have special relevance to nerve injury (Fig 1). Such a section shows that nerve fibers are collected into fasciculi, each fasciculus being (1) surrounded by a thin but distinctive lamellated sheath of perineurial cells interspersed with fine collagen fibers, and (2) occupied by a framework of endoneurial tissue
From the Department of Anatomy, University of Melbourne, Australia. Dr. Sunderland is Professor Emeritus of Experimental Neurology. Second Annual Reiner Memorial Lecture presented at AAEE (now AAEM) Annual Meeting, International Symposium on Peripheral Nerve Regeneration, Washington, DC, September 17, 1989. Address reprint requests to Dr. Sunderland at the Department of Anatomy, University of Melbourne, Parkville, Victoria, 3052, Australia. Accepted for publication December 13, 1989 CCC 0148-639W90/090771-014 $04.00 Q 1990 John Wiley & Sons,Inc.
Anatomy and Physiology of Nerve Injury
that is organized around each nerve fiber to form its outer endoneurial sheath. T h e endoneurial tissue has some tensile strength. T h e main component giving tensile strength and elasticity to the nerve, however, is the perineurium. This sheath also constitutes a diffusion barrier and resists and maintains an intrafascicular pressure. The term perineural is often used incorrectly to apply to the perineurium. Perineural means around the nerve trunk and perineurial means around a fasciculus; the two terms are not interchangeable. The fasciculi are, in turn, set in an areolar connective tissue packing, the epineurium, which protects them from compression. The superficial epineurium forms an external sheath for the nerve, which gives it a cord-like appearance and consistency and which permits it to be easily separated from the surrounding tissues. The deep fascia1 or paraneural tissue refers to the unnamed, nonspecialized loose meshwork of areolar connective tissue that fills the space between specialized structures, such as muscles, nerves, and vessels, connecting them loosely together and permitting the movement of one on the other. Though this tissue is associated in this way with nerve trunks, it is not regarded as a component of the nerve trunk whose outer limits are clearly outlined by a definitive sheath of epineurial tissue. T o inspection and palpation, the nerve is a
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FIGURE 1. Diagrammatic representation of a transverse section of a nerve trunk. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
cord-like structure; the light microscope examination of a single transverse section reveals the structural features just outlined, while the electron microscope reveals details of only a fragment of the nerve at very high magnifications. All miss the significant point that the structure of a nerve is constantly changing along its entire length because the fasciculi are repeatedly dividing and uniting to form complex fascicular plexuses (Fig. 2). No fasciculus runs an independent unaltered course along the entire length of a nerve. The examination of successive transverse sections reveals that these plexus formations are responsible for bringing about:
FIGURE 2. Fascicular plexus formations in a 3 cm length of the musculocutaneous nerve reconstructed from a serially sectioned specimen. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
1. Repeated changes in the size, number, and ar-
rangement of the fasciculi so that sections taken more than a few millimetres apart fail to present fascicular patterns that are identical in every respect (Figs. 3 and 4). 2. The fascicular redistribution, dispersal, and intermingling of different branch fiber systems as they are traced along the nerve (Fig. 5). Features of this fascicular behavior are: a. The number of fasciculi varies from 1 to more than 100 depending on the nerve and the level. The following give some idea of the range of variation of fascicular numbers in 4 specimens of each nerve: Median: 3-22, 5- 16, 4- 13, 15-36. Ulnar: 1-8, 1-18, 3-8, 12-36.
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Radial: 1-20, 2- 13, 2-36, 8-29. Sciatic nerve: medial popliteal: 11-27, 16-33, 28-93, 32-83.
b.
c. d.
e.
lateral popliteal: 1-15, 1-21, 5-20, 824. Generalizing, the fasciculi in the median and ulnar nerves are larger and fewer in number above the elbow compared with the forearm. T h e size and number of fasciculi are inversely related at any level. T h e fasciculi are smaller and more numerous where a nerve crosses a joint. For a given total fascicular area, the tensile
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E picondyle
Supracondylar
FIGURE 3. Variations in the size and number of fasciculi in a specimen of the radial nerve. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
strength of a nerve increases with the number of fasciculi. Cables of the same size are stronger and more flexible if composed of many strands. The Cross-Sectional Areas of Nerves Devoted to Fascicular and Epineurial Tissue. The relative
amounts of fascicular and epineurial tissue con-
@@ A
f-
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B
tributing to the cross-sectional area of the nerve varies from level to level along the same nerve. In general, the fascicular contribution varies from about 30% to 70%. The sciatic nerve in the gluteal region is an exception in that the fascicular tissue in most of these nerves occupies only 20% to 30% of the nerve; in one specimen examined, this area was as low as 12%. As we shall see, the connective tissue component of a nerve trunk and features of the fascicular anatomy of nerves provide an important line of defense against compression injury. The Fascicular Redistribution, Dispersal, and Mixing of the Different Branch Fiber Systems. Fascicular
A on 6
FIGURE 4. The fascicular patterns present in transverse sections from a radial nerve taken 2 mm apart. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve Injury
FIGURE 5. Diagrammatic representation of the fascicular redistribution of nerve fibers brought about by the fascicular plexus. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
plexuses bring about the fascicular redistribution, dispersal, and intermingling of different branch fiber systems as they are traced along the nerve (Fig. 6). Thus the arrangement, considered from distal to proximal, is one-in which the localization of any particular branch system is at first discrete, then discrete in combination with other branch fiber% and finally a predominant one only until fiber scattering ultimately reaches a degree at the
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13 mm
63mm
85mm
127mm
i8omm
FIGURE 6. The fascicular redistribution of branch fiber systems in a radial nerve affected by fascicular plexus formations. The figures give the level of the section in mm above the lateral humeral epicondyle. APL and M indicate anterior, posterior, lateral, and medial aspects of the nerve. o superficial radial; 0 combined posterior interosseous fibers, S, supinator; + extensor carpi radialis brevis; x extensor carpi radialis longus; * combined radial extensor fibers; A brachioradialis; A brachialis. (From Sunderland S: Nerves and Nerve lnjuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
root of the limb where there is no segregation or localization of the branch fiber system. Expressed in another way, this means that, at the root, the nerve fibers representing the distal branches are intermingled and widely distributed through the fasciculi of the nerve. On the other hand, the fibers of proximal branches are concentrated in that sector of the nerve from which branching is about to occur, though the fibers will be mixed with those for distally destined branches. As the nerve proceeds distally, the fascicular plexuses effect a sorting out of the different branch fiber systems until, finally, the fibers for a particular branch are collected into their own fasciculus, or group of fasciculi, which then leaves the nerve as a definitive branch. The fascicular composition of the fibers representing any particular branch can be expressed in terms of three levels:
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1. At the root of the limb, the fibers of branches at and below the elbow and knee are widely distributed over many, if not all, of the fasciculi. They are mixed with the fibers of other more distal branches in varying combinations and proportions, though each fasciculus does not necessarily contain fibers from every branch. T h e fibers of high branches, though mixed with those from distal sources, are relatively localized and superficially placed because they are shortly to leave the nerve. 2 An intermediate zone where the fibers of a particular branch are contained in fasciculi that, though not devoted exclusively to them, occupy a relatively localized position in the nerve. 3. A distal zone where,-for a variable, but usually short, distance above the site of branching, the fibers of a branch are contained in a fasciculus or group of fasciculi devoted exclusively to
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them, and are sharply localized and superficially placed in the nerve (Fig. 7). Fasciculi are of two types as regards their branch fiber composition: (1) Simple fasciculi that are composed of fibers from the same source, and (2) compound fasciculi that are composed of fibers from several different sources in varying numbers, combinations, and proportions. Numbers of Nerve Fibers Representing Dlfferent Branches. Counting the number of fibers in ev-
ery branch of a major peripheral nerve would be a formidable task. It is possible to obtain some estimate of this feature, however, by measuring the cross-sectional area of the fasciculi devoted solely to individual branches. Admittedly, this method has its limitations because the relationship between area and numbers is affected by such factors as the size of individual nerve fibers and the amount of intra-fascicular endoneurial tissue. With this proviso, the cross-sectional area of the fasciculi devoted to individual branches may be accepted as a rough estimate of the number of fibers
L
in a nerve representing individual branches. Such data is available for the major peripheral nerves. As an example, the percentage values for the branches of the radial nerve, averaged from the examination of 11 specimens, are: Superficial radial 29 Brachialis 2 Brachioradialis 6 Extensor carpi radialis longus 9 Extensor carpi radialis brevis 7 Posterior interosseous 47 In expressing branch fiber numbers in this way, it should be noted that such estimates are also influenced by variations in the number of branches, the level of branching, and the distribution of those branches. The percentage cross-sectional area of fasciculi composed of fibers representing individual branches also depends on the level at which the measurement is made. This is illustrated by reference to the percentage cross-sectional fascicular areas of a median and an ulnar nerve trunk occupied by cutaneous and “muscle” nerve fibers from
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FIGURE 7. Transverse sections from a median nerve above the elbow and at the wrist to illustrate the sorting out of the different branch fiber systems that occur between these levels. (A) In the section above the elbow, the circles represent groups of fasciculi in which different branch fibers are represented. Al, anterior interosseous; FCR, flexor carpi radialis; FDS, flexor digitorum sublimis; PC, palmar cutaneous; PT, pronator teres; T, fibers of terminal branches in the hand. (B)In the section at the wrist, the circles represent individual fasciculi. A.B.C., digital cutaneous fibers from the third, second, and first interspaces; D, cutaneous fibers from the radial side of the thumb; M, fibers to thenar muscles; L, lumbrical fibers. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve injury
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the hand, measured at the wrist and above the elbow : Wrist / Elbow Median nerve Ulnar nerve
Muscle 614 44 I 28
Cutaneous 94 I 6 6 56 I 3 5
Above the elbow, the same nerve fibers from the hand are now combined with fibers of the remaining branches of the nerve so that the former now occupy a reduced percentage cross-sectional fascicular area of the nerve. T h e significance of this feature will emerge as we proceed. Regarding this feature of peripheral nerves, there is time only for a passing reference to points that call for special emphasis.
The Blood Supply of Nerves.
1. Nerves are well supplied by a longitudinally arranged anastomosing system of nutrient vessels and networks on the surface and within the nerve. This system is served by a succession of regional nutrient arteries that enter a nerve along its course. The arrangement is one that ensures a continuing supply of blood to the nerve should one or more entering nutrient arteries be blocked or destroyed. 2. The largest nutrient vessels are located on the surface of the nerve and in the epineurium. 3. The largest vessels inside a fasciculus are capillaries. 4. There is much experimental and clinical evidence to the effect that the blood supply to peripheral nerves plays a critical role in the survival and functional integrity of axons.
THE TENSILE STRENGTH AND ELASTICITY OF NERVE TRUNKS
A nerve trunk runs an undulating course in its bed, the fasciculi run an undulating course in the epineurium, and the nerve fibers run an undulating course inside the fasciculi. This means that the length of a nerve trunk, and its contained nerve fibers between any two fixed points on the limb, is greater than a straight line joining those points. When a nerve is gradually stretched, the undulations in the nerve and the fasciculi are first eIiminated but not those of the nerve fibers, which remain tension free inside the fasciculi (Fig. 8). In this way, the slack provided in the system absorbs and neutralizes traction forces generated during limb movements so that the contained nerve fibers
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4
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FIGURE 8. Changes occurring in the various components of a nerve trunk as it is stretched to structural failure. Only one fasciculus in the nerve is represented. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
are at all times protected from being overstretched. When the nerve and its contained fasciculi are finally straightened, the tensile properties of the nerve are recruited and the system commences to resist further elongation and to behave as an elastic material. With continued stretching, the nerve fibers are first straightened, then stretched, and finally ruptured. The nerve, however, continues to behave as an elastic structure despite the fact that nerve fibers have ruptured inside the fasciculi. Finally, the perineurial tissue ruptures, and with this structural failure the nerve loses its tensile strength and elasticity. Points of particular interest in this sequence of events include:
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~
Table 1. Percentage elongation of human nerve trunks under tensile loading rate of elongation 7.5 cmlrnin At the elastic limit Nerve
Range
At mechanical failure
Mean
Ranae
Mean -~
Ulnar Median Medial popliteal Lateral popliteal Anterior spinal roots Posterior spinal roots
8 to 21 6 to 22 7 to 21 9 to 22 9 to 15 8 to 16
1. The range of elongation over which a nerve retains its elasticity depends on such factors as the magnitude of the deforming force, the rate of its application and the time for which it operates, and its fascicular structure. Stretching the nerve at '7.5 cms/min gives a range of elasticity of 6% to 20% of the length of nerve being stretched (see Table 1). 2. The rupture of nerve fibers precedes structural failure of the fasciculi and occurs with elongations of about 4% after the slack in the nerve has been taken up and it commences to take load. 3. A nerve retains its elastic properties as long as the perineurium remains intact. 4. As the fasciculi are stretched, their crosssectional area is reduced, the intrafascicular pressure is increased, nerve fibers are compressed, and the intrafascicular microcirculation is compromised. 5. With tensile loading, the rate of deformation is as important as the magnitude of the deforming force. 6. Traction forces generated during normal limb movements are unlikely to reach limits that would compromise nerve fibers inside the fasciculi.
15 14 17 15 11 12
9 to 26 7 to 30 8 to 32 10 to 32 9 to 21 8 to 28
18 19 23 20 15 19
epineurial tissue, they are more vulnerable to mechanical injury than where the fasciculi are smaller and more widely separated by a greater amount of epineurial tissue. With the former arrangement, forces fall maximally on the main component of the nerve trunk which is fascicular tissue and, therefore, nerve fibers. In the latter, the damaging forces would be dissipated and cushioned by the epineurial tissue packing and the fasciculi would be more easily displaced within the nerve and so would tend to escape (Fig. 9). The significance of this feature is illustrated by reference to the well-established clinical finding that, in injuries of the sciatic nerve, the common peroneal division is known to be more frequently injured and more often suffers greater damage than the tibial. An investigation of the cross-sectional area of the sciatic nerve and its common peroneal and tibial divisions devoted to fasciculi and to epineurial tissue has revealed that the fascicular pattern of the common peroneal does present features that
i
THE CUSHlONlNa ROLE OF THE EPINEURIUM
1. A special feature of peripheral nerves is the often large amount of epineurial connective tissue that separates the fasciculi and holds them together. 2. When pressure is applied to a nerve, the epineurium functions as a shock-absorber which dissipates the stresses set up in the nerve, thereby cushioning the fasciculi and their contained nerve fibers and in this way protecting them from damage. 3. Where are Of large and closely packed fasciculi with little supporting
Anatomy and Physiology of Nerve Injury
FIGURE 9. Dispersion of compression stresses by the epineurial tissue. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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render this nerve more susceptible to injury than the associated tibial division. T h e peroneal division, particularly in the distal half of the thigh, is composed of fewer and larger fasciculi with less epineurial tissue than is the corresponding tibial division (Fig. 10). This morphologic difference is a significant factor contributing to the increased susceptibility of the common peroneal nerve to stretch and compression injury. In addition, the common peroneal division usually contains much less adipose tissue in the epineurium than does the tibial.
28 Sciatic notch Junction upper f
a of thigh
Mid thigh
THE STRUCTURE OF NERVE ROOTS
It is worth noting that nerve roots are more vulnerable to traction and compression injury than nerve trunks because (1) they lack both epineurial and perineurial tissue components (Fig. 1); (2) nerve root fibers are arranged in parallel nonplexiform bundles; and (3) the collagen fibers of the endoneurium are fewer and finer than elsewhere. A CLASSIFICATION OF NERVE INJURY
Currently, there are two classifications of nerve injury based not on the cause but on the nature of the lesion. In Seddon's classification, the terms neurapraxia, axonotmesis, and neurotmesis were introduced to cover conduction block, loss of continuity of axons, and loss of nerve trunk continuity. The second, which I naturally prefer since it is my own, is based on the histologic structure of a nerve trunk previously outlined. It recognizes five degrees or types of nerve damage of increasing severity from conduction block followed successively by loss of continuity of axons, then of nerve fibers, the fasciculi, and finally the entire nerve trunk (Fig. 11). Since my brief is to adhere strictly to the role of anatomy in these matters, reference to clinical detail is omitted. First Degree Injury (lo). This is the temporary conduction block lesion in which axonal continuity is preserved. The nerve conducts as far as and below the block, but not across it.
Continuity of the endoneurial sheath of nerve fibers is preserved. Wallerian degeneration occurs below the lesion, however, so that axonal continuity with the periphery is lost. Later the length of the axon that has perished as the result of the injury will be replaced by regeneration. Importantly, each regenerating axon as it grows is confined to the endoneurial tube that originally contained it. This ensures that
Second Degree Injury ( 2 O ) .
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Neck of the f~bula
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37
FIGURE 10. Diagrammatic representation of the fascicular structures of a sciatic nerve and its common peroneal and tibial divisions at the levels indicated. The figures give the cross-sectional fascicular areas measured at those levels. (From Sunderland S: NeNeS and Nerve injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
each axon is inevitably directed back to the end organ that it originally innervated. Consequently, the restored pattern of innervation is identical with the original and function is fully restored. This is the concealed intrafascicular lesion in which the fasciculi are left in continuity but continuity of nerve fibers is lost. The damage may be localized o r be irregularly distributed along a considerable length of the nerve. The internal structure of the fasciculi is disorganized with (1) the disintegration of axons and wallerian degeneration; (2) the loss of continuity of the endoneurial sheath and, therefore, the entire nerve fiber; and (3) hemorrhage, edema, an inflammatory reaction, and finally fibrosis. Axon regeneration is now complicated in two ways:
Third Degree Injury (3").
1. Intrafascicular fibrosis blocks some axons, delays others in their growth, diverts others from
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FIGURE 11. Diagrammatic representation of five degrees of nerve injury. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
their proper course and, later, by constricting those that are successful in negotiating the scar tissue between the nerve fiber ends, adversely affects their subsequent growth, development, and function. This disorderly axon growth may be so pronounced that the involved fasciculi develop a fusiform swelling at this site. 2. Loss of continuity of the nerve fibers means that regenerating axons, though still confined within the fasciculi, are no longer confined to the endoneurial tubes that originally contained them. Since there is no known mechanism directing axons into their original or functionally related endoneurial tubes, many fail to do so and instead are misdirected into foreign ones. The significance of the erroneous cross-shunting of axons occurring in this way depends on the fi-
Anatomy and Physiology of Nerve Injury
ber composition of the fasciculi (Fig. 6). Where the fibers have the same or a functionally related destination, the consequences are minimal. Where the fiber composition is one in which sensory and motor fibers and those representing functionally unrelated systems are intermingled, however, the consequences of the erroneous entry of axons into foreign tubes can be serious. Despite the fact that the nerve trunk is left in continuity, recovery following severe third degree damage is often negligible. Fourth Degree InJury (4'). In this type of injury, the fascicular structure of the nerve has been destroyed, nerve trunk continuity being preserved by a strand of disorganised tissue. Regenerating axons are now free to escape not only from endoneurial tubes but also from fasciculi. The trauma-
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tized, disorganized segment of the nerve trunk is replaced by a barrier of fibrous tissue in which axon growth is arrested. This is the type of injury that requires excision of the damaged segment and some form of nerve repair. Flfth Degree Injury (5'). This represents loss of continuity of the nerve trunk. Though the clinical details of this classification are not the concern of this presentation, one can say that the classification is one that (1) has a sound pathologic basis; (2) relates to the clinical events associated with a lesion; (3) has diagnostic, prognostic and therapeutic significance; (4)involves a terminology that is readily understood, and (5) has the added attractiveness of simplicity.
These are lesions in continuity in which all nerve fibers are damaged but to a varying degree.
30 154 mm FIGURE 13. The effect of the branch fiber composition of injured fasciculi in a partial nerve injury. The notations are given in Figure 6. (From Sunderland S : Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Mixed Nerve Injury.
These are lesions in which some nerve fibers escape while others sustain damage of varying degree. A common lesion in this category is partial severance of the nerve trunk. The consequences of such an injury depend on (1) the size and number of the fasciculi composing the nerve at that level; and (2) the branch fiber composition of the affected fasciculi.
Partial Nerve Injury.
Size and Number of the Farciculi (Figure 12).
Where the fasciculi are small, numerous, and well separated by epineurial tissue, such lesions tend to be self-limiting. When the fibers are contained in one or two large fasciculi, however, breaching these fasciculi has serious consequences. The Branch Fiber Composition of the Severed Fa$ciculi (Figure 13). Partial lesions produce variable
effects at the periphery depending on the branch fiber composition of the affected fasciculi that is, in turn, determined by the level of the injury. Where the severed fasciculi contain a few of the fibers of some or all branches, the resultant loss of function is minimal and widespread and might even escape detection clinically. On the other hand, where the severed fasciculi contain all or the majority of the fibers of a particular branch, the peripheral effects are sharply localized and clinically obvious. Thus, a partial injury at one level may either escape detection or give a widely distributed paresis, but a corresponding lesion at another level or involving a different sector of the nerve may produce a sharply localized paralysis or sensory loss. THE EFFECT OF A TRANSECTION INJURY ON THE NERVE BELOW THE LESION
Following a transection injury, changes occur in the axons and myelin, the endoneurial tubes, the fasciculi, and the nerve trunk. The Axon8 and Myelin. The final stage of wallerian degeneration is one in which the interior of the nerve fiber is occupied by axon and myelin debris which is removed by the phagocytic activity of macrophages and Schwann cells.
With the removal of the axon and myelin debris, tension is reduced in the endoneurial wall of the fiber which slowly contracts down on the remaining contents of the tube, which are Schwann cells, so that its caliber is gradually reduced. This reduction increases with the duration
The Endoneurial Tubes.
FIGURE 12. The effect of fascicular structure on the consequences of a partial nerve injury. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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of denervation, rapidly over the first 3 months beyond which there is little further change. The fibers are affected in proportion to their size, so that the largest are ultimately reduced to tubes 2 to 3 pm in diameter. At the end of 3 months, most tubes are less than 3 pm in diameter with only an occasional tube of 4 p,m (Fig. 14). The shrinkage of the endoneurial tubes is associated with a corresponding atrophy of the fasciculi. Thus, the cross-sectional fascicular area is reduced by about 50% to 60% at 2 months, and then by about another 10% over the next month, beyond which there is no further significant reduction (Table 2).
The Fasciculi.
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The epineurial tissue undergoes little change except for some edematous swelling at the nerve end. This tissue is excised at the time of the repair. Because the fasciculi and epineurial tissue react so differently to denervation, it follows that the extent of the shrinkage of the nerve trunk will be influenced, not only by the duration of denervation, but also by the percentage cross-sectional area of the nerve occupied by fascicular tissue. Thus, the reduction will be greater when the fasciculi are closely packed and occupy most of the cross-sectional area of the nerve than where the fasciculi are small and widely separated by a large amount of epineurial tissue.
The Nerve Trunk.
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Diameter of endoneuriol tubes (microns)
FIGURE 14. Histograms of endoneurial tube shrinkage with increasing periods of denervation (Australian marsupial, Trichosurus vulpecula). (From Sunderland S: Nerves and Nerve lnjuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve Injury
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Table 2. Nerve trunk and fascicular atrophy consequent on denervation.
Nerve Ulnar Median Ulnar Median Ulnar Ulnar Ulnar Median Ulnar Median Median Ulnar Ulnar Median Median Ulnar Median Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar
Duration of denervation in days
Percentage fascicular atrophy
Percentage nerve trunk atrophy
44 49 59 59 68 76 89 89 140 140 185 196 224 224 229 229 252 254 254 280 335 335 444 444 485 485
64 54 67 50 61 50 68 56 61 68 62 54 63 54 59 69 68 62 67 74 72 74 88 67 72 66
49 10 28 31 56 59 35 43 30 26 25 45 54 45 33 54 42 53 52 55 22 42 86 61 48 56 ~
Because of dffferencesin the cross-sectional areas of the distal nerve end devoted to fascicularand epfneurfaltissue, the degree of nerve trunk and fasocular atrophy do not necessanly correspond (Australfan marsupal. Trrchosurus vulpecula)
Consequently, the reduction in the crosssectional area of the nerve below the transection does not follow the fascicular atrophy. On the contrary it will, for a given period of denervation, vary irregularly depending on fascicularepineurial tissue ratios. This is illustrated in Table 2. THE MANNER IN WHICH ANATOMICAL FEATURES AT THE SUTURE LINE INFLUENCE THE OUTCOME OF AXON REGENERATION
The concluding section of this saga on the anatomy and physiology of nerve injury concerns axon regeneration and the inevitable loss of regenerating axons that occurs as they cross the suture line. Regarding axon regeneration, two points are worthy of special comment: (1) the distinction that should be drawn between axon regeneration and functional recovery; and (2) the role of neurotropism in axon regeneration.
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At the outset it is necessary to emphasise the importance of carefully distinguishing between axon regeneration and the functional outcome of that regeneration. The recovery of function requires far more than the regeneration of axons to replace the part lost below the injury. Of even more importance is the final destination of those axons because, for regeneration to be functionally effective, each axon must reach and reinnervate its old, or at least a functionally related, end organ. Failure to do this represents abortive and wasteful regeneration, which leaves recovery incomplete and impaired. Thus, axon regeneration per se does not necessarily guarantee functional recovery and, because it is possible to have good axon regeneration and yet little functional recovery, it is necessary at all times to keep in mind that axon regeneration and functionally effective axon regeneration are two very different events in the regenerative process.
Axon Regeneration and Functional Recovery.
Neurotropism. It is now well established that, when the nerve ends are well separated, regenerating axons are attracted to the distal nerve stump under the influence of neurotropic factors elaborated in and operating from that site. The source of the neurotropic factor appears to be widely distributed throughout the tissues of the distal stump and is not confined to Schwann cells as was originally believed. This influence, however, becomes irrelevant after nerve suture because when regenerating axons emerge from the proximal stump they are already at the distal nerve end. The question at issue now becomes one that asks, are there neurotropic influences operating at the suture line interface that impart a matching specificity to the process whereby each regenerating axon is inevitably attracted back to the endoneurial tube that it originally occupied or to which it is at least functionally related. It would be reassuring to know that such influences do exist but, unfortunately, there is some hard evidence against the concept.
1. Regenerating axons show no preference for fascicular tissue. They will grow just as readily outside the nerve or into the interfascicular tissues of the distal stump. 2. Nerve cross-union experiments show that regenerating motor axons will enter and grow down sensory endoneurial tubes, and sensory down motor.
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3. Regenerating motor axons will occupy the endoneurial tubes of a cutaneous nerve graft and grow rapidly and readily along them. 4. An analysis of the results of nerve repair are consistent with the random entry of regenerating axons into the endoneurial tubes of the distal nerve end. Neurotropism as a force converting order out of chaos at the suture line is a nonevent. Physical influences outlining paths of least resistance through the interface tissues are the principal determinants of the direction taken by regenerating axons after they leave the proximal nerve end. Under such circumstances, we may well ask what are the chances of regenerating axons reaching and reinnervating functionally related endoneurial tubes, particularly in view of the many hazards to be overcome enroute. Disregarding the well-established influence of suture line scarring, other less obvious hazards that are just as damaging include:
Discrepancies in the fascicular patterns at the nerve ends so that fasciculi are opposed to epineurial tissue and vice versa (Fig. 4). The absence of any branch fiber localization at the level of the repair particularly in mixed motor and sensory nerves (Fig. 16). The chances of useful regeneration are improved, however, at levels where some branch fiber localization is present. At levels where there is no branch fiber localization, the numbers of nerve fibers representing individual branches becomes a factor influencing the entry of axons into functionally related endoneurial tubes. Thus, in the median
1. Discrepancies that have developed in the crosssectional dimensions of the two nerve ends (Fig. 15).
36mm
132 m m FIGURE 15. Diagrammatic representationsof factors at the suture that are responsible for the loss of axons during axon regeneration. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve Injury
38mm
136mm
FIGURE 16. The effect of fascicular branch fiber localization on the outcome of axon regeneration. The notations are those given in Figure 6. The arrangement in the lower pair favors the misdirection of regenerating axons into foreign endoneurial tubes. (From Sunderland S: Nerves and Nerve lniuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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nerve in the mid-forearm, where the sensory fibers for the hand greatly outnumber motor fibers, the former will have a decided advantage in the competition for endoneurial tubes SO that the prospects for sensory recovery are much better than those for motor recovery. Clearly, large numbers of regenerating axons are inevitably lost at the suture line so that reinnervation is always incomplete and imperfect. A further minus is that, with delayed nerve repair, even those axons entering functionally related endoneurial tubes and reinnervating functionally related end organs fail to develop fully. This is be-
~~
~~~
~~
~~~
cause of irreversible changes in the wall of shrunken endoneurial tubes which prevent the maturation of fibers to their original calibre and degree of myelination. This could contribute to the permanent reduction in the conduction velocity of regenerated nerve fibers. The challenge is to correct or at least modify these adverse factors, but that is another story. I hope that sufficient has been said to convince the reader that the anatomy and physiology of nerve injury is a subject worthy of the most careful consideration; on that note I shall conclude this presentation.
~
REFERENCES 1 . Sunderland S: The blood supply of the nerves of the upper limb in man. Arch Neurol Psychiat~1945;53:91-115 2. Sunderland S: The blood supply of the sciatic nerve and its popliteal divisions in man. Arch Neurol Psychiatry 1945; 54:283-289. 3. Sunderland S: The blood supply of peripheral nerves: Some practical considerations. Arch Neurol Psychiatry 1945; 54:280-282. 4. Sunderland S: The intraneural topography of the radial, median and ulnar nerves. Brain 1945;68:243-299. 5. Sunderland S: Factors influencing the course of regeneration and the quality of the recovery after nerve suture. Brain 1952;75:19-54. 6. Sunderland S: The relative susceptibility to injury of the medial and lateral popliteal divisions of the sciatic nerve. Brit J Surg 1953;41 :300- 302. 7. Sunderland S: Funicular suture and funicular exclusion in the repair of severed nerves. B r J Surg 1953;40:580-587. 8. Sunderland S: The connective tissues of peripheral nerves. Brain 1965;88:841-853. 9. Sunderland S: Anatomical features of nerve trunks in relation to nerve injury and nerve repair. Clin Neurosurg 1970;17:38-62. 10. Sunderland S: Nerves and Nerve Injuries. 2nd Ed. Edinburgh, Churchill Livingstone, 1978. 1 1 . Sunderland S: The pros and cons of funicular nerve repair.J Hand Surg 1979;4(3):201-211 12. Sunderland S: The anatomical basis of nerve repair. In Jewett DL, McCarroll HR, eds. Nerve Repair and Regeneration: Its Clinical and Experimental Basis. St. Louis, CV Mosby 1980, pp 14-35.
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13. Sunderland S: The anatomic foundation of peripheral nerve repair techniques. Orthopedic Clinics of North America 198 1 ;12~245-266 14. Sunderland S, Bedbrook GM: The cross-sectional area of peripheral nerve trunks occupied by the fibers representing individual muscular and cutaneous branches. Brain 1949;72:613-624. 15. Sunderland S, Bradley KC: The cross-sectional area of peripheral nerve trunks devoted to nerve fibers. Brain 1949;72:428- 449. 16. Sunderland S, Bradley KC: Endoneurial tube shrinkage in the distal segment of a severed nerve. J Comp Neurol 1950;93:411-420. 17. Sunderland S, Bradley KC: Denervation atrophy of the distal stump of a severed nerve.] Comp Neurol 1950;93:401409. 18. Sunderland S, Bradley KC: The perineurium of peripheral nerves A m t Rec 1952;113:125-141. 19. Sunderland S, Bradley KC: Stress-strain phenomena in human peripheral nerve trunks. Brain 1961;84:102- 119. 20. Sunderland S, Bradley KC: Stress-strain phenomena in human spinal nerve roots. Brain 1961;84:120- 124. 21. Sunderland S, Bradley KC: Stress-strain phenomena in denervated peripheral nerve trunks. Brain 1961;84:125127. 22. Sunderland S, Marshall RD, Swaney WE: The intraneural topography of the circumflex musculocutaneous and obturator nerves. Brain 1959;82:116- 129. 23. Sunderland S, Ray LJ: The intraneural topography of the sciatic nerve and its popliteal divisions in man. Brain 1948;71:242-273.
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THE ANATOMY AND PHYSIOLOGY OF NERVE INJURY SIR SYDNEY SUNDERLAND, MD, DSc, FRACS, FRACP
Although it is true that many of the problems of nerve injury and nerve repair must wait on the molecular biologist for their solution, it is equally clear that, for the time being, we cannot afford to overlook the use of somewhat old fashioned but well-tried methods and techniques that still have much to offer. It is such an approach that forms the substance of this article. THE MICROSTRUCTURE OF NERVE TRUNKS
A convenient starting point for our purposes is a transverse section of a peripheral nerve trunk. This reveals those structural features that have special relevance to nerve injury (Fig 1). Such a section shows that nerve fibers are collected into fasciculi, each fasciculus being (1) surrounded by a thin but distinctive lamellated sheath of perineurial cells interspersed with fine collagen fibers, and (2) occupied by a framework of endoneurial tissue
From the Department of Anatomy, University of Melbourne, Australia. Dr. Sunderland is Professor Emeritus of Experimental Neurology. Second Annual Reiner Memorial Lecture presented at AAEE (now AAEM) Annual Meeting, International Symposium on Peripheral Nerve Regeneration, Washington, DC, September 17, 1989. Address reprint requests to Dr. Sunderland at the Department of Anatomy, University of Melbourne, Parkville, Victoria, 3052, Australia. Accepted for publication December 13, 1989 CCC 0148-639W90/090771-014 $04.00 Q 1990 John Wiley & Sons,Inc.
Anatomy and Physiology of Nerve Injury
that is organized around each nerve fiber to form its outer endoneurial sheath. T h e endoneurial tissue has some tensile strength. T h e main component giving tensile strength and elasticity to the nerve, however, is the perineurium. This sheath also constitutes a diffusion barrier and resists and maintains an intrafascicular pressure. The term perineural is often used incorrectly to apply to the perineurium. Perineural means around the nerve trunk and perineurial means around a fasciculus; the two terms are not interchangeable. The fasciculi are, in turn, set in an areolar connective tissue packing, the epineurium, which protects them from compression. The superficial epineurium forms an external sheath for the nerve, which gives it a cord-like appearance and consistency and which permits it to be easily separated from the surrounding tissues. The deep fascia1 or paraneural tissue refers to the unnamed, nonspecialized loose meshwork of areolar connective tissue that fills the space between specialized structures, such as muscles, nerves, and vessels, connecting them loosely together and permitting the movement of one on the other. Though this tissue is associated in this way with nerve trunks, it is not regarded as a component of the nerve trunk whose outer limits are clearly outlined by a definitive sheath of epineurial tissue. T o inspection and palpation, the nerve is a
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FIGURE 1. Diagrammatic representation of a transverse section of a nerve trunk. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
cord-like structure; the light microscope examination of a single transverse section reveals the structural features just outlined, while the electron microscope reveals details of only a fragment of the nerve at very high magnifications. All miss the significant point that the structure of a nerve is constantly changing along its entire length because the fasciculi are repeatedly dividing and uniting to form complex fascicular plexuses (Fig. 2). No fasciculus runs an independent unaltered course along the entire length of a nerve. The examination of successive transverse sections reveals that these plexus formations are responsible for bringing about:
FIGURE 2. Fascicular plexus formations in a 3 cm length of the musculocutaneous nerve reconstructed from a serially sectioned specimen. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
1. Repeated changes in the size, number, and ar-
rangement of the fasciculi so that sections taken more than a few millimetres apart fail to present fascicular patterns that are identical in every respect (Figs. 3 and 4). 2. The fascicular redistribution, dispersal, and intermingling of different branch fiber systems as they are traced along the nerve (Fig. 5). Features of this fascicular behavior are: a. The number of fasciculi varies from 1 to more than 100 depending on the nerve and the level. The following give some idea of the range of variation of fascicular numbers in 4 specimens of each nerve: Median: 3-22, 5- 16, 4- 13, 15-36. Ulnar: 1-8, 1-18, 3-8, 12-36.
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Radial: 1-20, 2- 13, 2-36, 8-29. Sciatic nerve: medial popliteal: 11-27, 16-33, 28-93, 32-83.
b.
c. d.
e.
lateral popliteal: 1-15, 1-21, 5-20, 824. Generalizing, the fasciculi in the median and ulnar nerves are larger and fewer in number above the elbow compared with the forearm. T h e size and number of fasciculi are inversely related at any level. T h e fasciculi are smaller and more numerous where a nerve crosses a joint. For a given total fascicular area, the tensile
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E picondyle
Supracondylar
FIGURE 3. Variations in the size and number of fasciculi in a specimen of the radial nerve. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
strength of a nerve increases with the number of fasciculi. Cables of the same size are stronger and more flexible if composed of many strands. The Cross-Sectional Areas of Nerves Devoted to Fascicular and Epineurial Tissue. The relative
amounts of fascicular and epineurial tissue con-
@@ A
f-
2mm+
B
tributing to the cross-sectional area of the nerve varies from level to level along the same nerve. In general, the fascicular contribution varies from about 30% to 70%. The sciatic nerve in the gluteal region is an exception in that the fascicular tissue in most of these nerves occupies only 20% to 30% of the nerve; in one specimen examined, this area was as low as 12%. As we shall see, the connective tissue component of a nerve trunk and features of the fascicular anatomy of nerves provide an important line of defense against compression injury. The Fascicular Redistribution, Dispersal, and Mixing of the Different Branch Fiber Systems. Fascicular
A on 6
FIGURE 4. The fascicular patterns present in transverse sections from a radial nerve taken 2 mm apart. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve Injury
FIGURE 5. Diagrammatic representation of the fascicular redistribution of nerve fibers brought about by the fascicular plexus. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
plexuses bring about the fascicular redistribution, dispersal, and intermingling of different branch fiber systems as they are traced along the nerve (Fig. 6). Thus the arrangement, considered from distal to proximal, is one-in which the localization of any particular branch system is at first discrete, then discrete in combination with other branch fiber% and finally a predominant one only until fiber scattering ultimately reaches a degree at the
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13 mm
63mm
85mm
127mm
i8omm
FIGURE 6. The fascicular redistribution of branch fiber systems in a radial nerve affected by fascicular plexus formations. The figures give the level of the section in mm above the lateral humeral epicondyle. APL and M indicate anterior, posterior, lateral, and medial aspects of the nerve. o superficial radial; 0 combined posterior interosseous fibers, S, supinator; + extensor carpi radialis brevis; x extensor carpi radialis longus; * combined radial extensor fibers; A brachioradialis; A brachialis. (From Sunderland S: Nerves and Nerve lnjuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
root of the limb where there is no segregation or localization of the branch fiber system. Expressed in another way, this means that, at the root, the nerve fibers representing the distal branches are intermingled and widely distributed through the fasciculi of the nerve. On the other hand, the fibers of proximal branches are concentrated in that sector of the nerve from which branching is about to occur, though the fibers will be mixed with those for distally destined branches. As the nerve proceeds distally, the fascicular plexuses effect a sorting out of the different branch fiber systems until, finally, the fibers for a particular branch are collected into their own fasciculus, or group of fasciculi, which then leaves the nerve as a definitive branch. The fascicular composition of the fibers representing any particular branch can be expressed in terms of three levels:
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1. At the root of the limb, the fibers of branches at and below the elbow and knee are widely distributed over many, if not all, of the fasciculi. They are mixed with the fibers of other more distal branches in varying combinations and proportions, though each fasciculus does not necessarily contain fibers from every branch. T h e fibers of high branches, though mixed with those from distal sources, are relatively localized and superficially placed because they are shortly to leave the nerve. 2 An intermediate zone where the fibers of a particular branch are contained in fasciculi that, though not devoted exclusively to them, occupy a relatively localized position in the nerve. 3. A distal zone where,-for a variable, but usually short, distance above the site of branching, the fibers of a branch are contained in a fasciculus or group of fasciculi devoted exclusively to
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them, and are sharply localized and superficially placed in the nerve (Fig. 7). Fasciculi are of two types as regards their branch fiber composition: (1) Simple fasciculi that are composed of fibers from the same source, and (2) compound fasciculi that are composed of fibers from several different sources in varying numbers, combinations, and proportions. Numbers of Nerve Fibers Representing Dlfferent Branches. Counting the number of fibers in ev-
ery branch of a major peripheral nerve would be a formidable task. It is possible to obtain some estimate of this feature, however, by measuring the cross-sectional area of the fasciculi devoted solely to individual branches. Admittedly, this method has its limitations because the relationship between area and numbers is affected by such factors as the size of individual nerve fibers and the amount of intra-fascicular endoneurial tissue. With this proviso, the cross-sectional area of the fasciculi devoted to individual branches may be accepted as a rough estimate of the number of fibers
L
in a nerve representing individual branches. Such data is available for the major peripheral nerves. As an example, the percentage values for the branches of the radial nerve, averaged from the examination of 11 specimens, are: Superficial radial 29 Brachialis 2 Brachioradialis 6 Extensor carpi radialis longus 9 Extensor carpi radialis brevis 7 Posterior interosseous 47 In expressing branch fiber numbers in this way, it should be noted that such estimates are also influenced by variations in the number of branches, the level of branching, and the distribution of those branches. The percentage cross-sectional area of fasciculi composed of fibers representing individual branches also depends on the level at which the measurement is made. This is illustrated by reference to the percentage cross-sectional fascicular areas of a median and an ulnar nerve trunk occupied by cutaneous and “muscle” nerve fibers from
v
FIGURE 7. Transverse sections from a median nerve above the elbow and at the wrist to illustrate the sorting out of the different branch fiber systems that occur between these levels. (A) In the section above the elbow, the circles represent groups of fasciculi in which different branch fibers are represented. Al, anterior interosseous; FCR, flexor carpi radialis; FDS, flexor digitorum sublimis; PC, palmar cutaneous; PT, pronator teres; T, fibers of terminal branches in the hand. (B)In the section at the wrist, the circles represent individual fasciculi. A.B.C., digital cutaneous fibers from the third, second, and first interspaces; D, cutaneous fibers from the radial side of the thumb; M, fibers to thenar muscles; L, lumbrical fibers. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve injury
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the hand, measured at the wrist and above the elbow : Wrist / Elbow Median nerve Ulnar nerve
Muscle 614 44 I 28
Cutaneous 94 I 6 6 56 I 3 5
Above the elbow, the same nerve fibers from the hand are now combined with fibers of the remaining branches of the nerve so that the former now occupy a reduced percentage cross-sectional fascicular area of the nerve. T h e significance of this feature will emerge as we proceed. Regarding this feature of peripheral nerves, there is time only for a passing reference to points that call for special emphasis.
The Blood Supply of Nerves.
1. Nerves are well supplied by a longitudinally arranged anastomosing system of nutrient vessels and networks on the surface and within the nerve. This system is served by a succession of regional nutrient arteries that enter a nerve along its course. The arrangement is one that ensures a continuing supply of blood to the nerve should one or more entering nutrient arteries be blocked or destroyed. 2. The largest nutrient vessels are located on the surface of the nerve and in the epineurium. 3. The largest vessels inside a fasciculus are capillaries. 4. There is much experimental and clinical evidence to the effect that the blood supply to peripheral nerves plays a critical role in the survival and functional integrity of axons.
THE TENSILE STRENGTH AND ELASTICITY OF NERVE TRUNKS
A nerve trunk runs an undulating course in its bed, the fasciculi run an undulating course in the epineurium, and the nerve fibers run an undulating course inside the fasciculi. This means that the length of a nerve trunk, and its contained nerve fibers between any two fixed points on the limb, is greater than a straight line joining those points. When a nerve is gradually stretched, the undulations in the nerve and the fasciculi are first eIiminated but not those of the nerve fibers, which remain tension free inside the fasciculi (Fig. 8). In this way, the slack provided in the system absorbs and neutralizes traction forces generated during limb movements so that the contained nerve fibers
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J
J
J
4
4
J
FIGURE 8. Changes occurring in the various components of a nerve trunk as it is stretched to structural failure. Only one fasciculus in the nerve is represented. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
are at all times protected from being overstretched. When the nerve and its contained fasciculi are finally straightened, the tensile properties of the nerve are recruited and the system commences to resist further elongation and to behave as an elastic material. With continued stretching, the nerve fibers are first straightened, then stretched, and finally ruptured. The nerve, however, continues to behave as an elastic structure despite the fact that nerve fibers have ruptured inside the fasciculi. Finally, the perineurial tissue ruptures, and with this structural failure the nerve loses its tensile strength and elasticity. Points of particular interest in this sequence of events include:
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~
Table 1. Percentage elongation of human nerve trunks under tensile loading rate of elongation 7.5 cmlrnin At the elastic limit Nerve
Range
At mechanical failure
Mean
Ranae
Mean -~
Ulnar Median Medial popliteal Lateral popliteal Anterior spinal roots Posterior spinal roots
8 to 21 6 to 22 7 to 21 9 to 22 9 to 15 8 to 16
1. The range of elongation over which a nerve retains its elasticity depends on such factors as the magnitude of the deforming force, the rate of its application and the time for which it operates, and its fascicular structure. Stretching the nerve at '7.5 cms/min gives a range of elasticity of 6% to 20% of the length of nerve being stretched (see Table 1). 2. The rupture of nerve fibers precedes structural failure of the fasciculi and occurs with elongations of about 4% after the slack in the nerve has been taken up and it commences to take load. 3. A nerve retains its elastic properties as long as the perineurium remains intact. 4. As the fasciculi are stretched, their crosssectional area is reduced, the intrafascicular pressure is increased, nerve fibers are compressed, and the intrafascicular microcirculation is compromised. 5. With tensile loading, the rate of deformation is as important as the magnitude of the deforming force. 6. Traction forces generated during normal limb movements are unlikely to reach limits that would compromise nerve fibers inside the fasciculi.
15 14 17 15 11 12
9 to 26 7 to 30 8 to 32 10 to 32 9 to 21 8 to 28
18 19 23 20 15 19
epineurial tissue, they are more vulnerable to mechanical injury than where the fasciculi are smaller and more widely separated by a greater amount of epineurial tissue. With the former arrangement, forces fall maximally on the main component of the nerve trunk which is fascicular tissue and, therefore, nerve fibers. In the latter, the damaging forces would be dissipated and cushioned by the epineurial tissue packing and the fasciculi would be more easily displaced within the nerve and so would tend to escape (Fig. 9). The significance of this feature is illustrated by reference to the well-established clinical finding that, in injuries of the sciatic nerve, the common peroneal division is known to be more frequently injured and more often suffers greater damage than the tibial. An investigation of the cross-sectional area of the sciatic nerve and its common peroneal and tibial divisions devoted to fasciculi and to epineurial tissue has revealed that the fascicular pattern of the common peroneal does present features that
i
THE CUSHlONlNa ROLE OF THE EPINEURIUM
1. A special feature of peripheral nerves is the often large amount of epineurial connective tissue that separates the fasciculi and holds them together. 2. When pressure is applied to a nerve, the epineurium functions as a shock-absorber which dissipates the stresses set up in the nerve, thereby cushioning the fasciculi and their contained nerve fibers and in this way protecting them from damage. 3. Where are Of large and closely packed fasciculi with little supporting
Anatomy and Physiology of Nerve Injury
FIGURE 9. Dispersion of compression stresses by the epineurial tissue. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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render this nerve more susceptible to injury than the associated tibial division. T h e peroneal division, particularly in the distal half of the thigh, is composed of fewer and larger fasciculi with less epineurial tissue than is the corresponding tibial division (Fig. 10). This morphologic difference is a significant factor contributing to the increased susceptibility of the common peroneal nerve to stretch and compression injury. In addition, the common peroneal division usually contains much less adipose tissue in the epineurium than does the tibial.
28 Sciatic notch Junction upper f
a of thigh
Mid thigh
THE STRUCTURE OF NERVE ROOTS
It is worth noting that nerve roots are more vulnerable to traction and compression injury than nerve trunks because (1) they lack both epineurial and perineurial tissue components (Fig. 1); (2) nerve root fibers are arranged in parallel nonplexiform bundles; and (3) the collagen fibers of the endoneurium are fewer and finer than elsewhere. A CLASSIFICATION OF NERVE INJURY
Currently, there are two classifications of nerve injury based not on the cause but on the nature of the lesion. In Seddon's classification, the terms neurapraxia, axonotmesis, and neurotmesis were introduced to cover conduction block, loss of continuity of axons, and loss of nerve trunk continuity. The second, which I naturally prefer since it is my own, is based on the histologic structure of a nerve trunk previously outlined. It recognizes five degrees or types of nerve damage of increasing severity from conduction block followed successively by loss of continuity of axons, then of nerve fibers, the fasciculi, and finally the entire nerve trunk (Fig. 11). Since my brief is to adhere strictly to the role of anatomy in these matters, reference to clinical detail is omitted. First Degree Injury (lo). This is the temporary conduction block lesion in which axonal continuity is preserved. The nerve conducts as far as and below the block, but not across it.
Continuity of the endoneurial sheath of nerve fibers is preserved. Wallerian degeneration occurs below the lesion, however, so that axonal continuity with the periphery is lost. Later the length of the axon that has perished as the result of the injury will be replaced by regeneration. Importantly, each regenerating axon as it grows is confined to the endoneurial tube that originally contained it. This ensures that
Second Degree Injury ( 2 O ) .
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Joint lml
a&O&~c$)o
Neck of the f~bula
@
37
FIGURE 10. Diagrammatic representation of the fascicular structures of a sciatic nerve and its common peroneal and tibial divisions at the levels indicated. The figures give the cross-sectional fascicular areas measured at those levels. (From Sunderland S: NeNeS and Nerve injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
each axon is inevitably directed back to the end organ that it originally innervated. Consequently, the restored pattern of innervation is identical with the original and function is fully restored. This is the concealed intrafascicular lesion in which the fasciculi are left in continuity but continuity of nerve fibers is lost. The damage may be localized o r be irregularly distributed along a considerable length of the nerve. The internal structure of the fasciculi is disorganized with (1) the disintegration of axons and wallerian degeneration; (2) the loss of continuity of the endoneurial sheath and, therefore, the entire nerve fiber; and (3) hemorrhage, edema, an inflammatory reaction, and finally fibrosis. Axon regeneration is now complicated in two ways:
Third Degree Injury (3").
1. Intrafascicular fibrosis blocks some axons, delays others in their growth, diverts others from
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FIGURE 11. Diagrammatic representation of five degrees of nerve injury. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
their proper course and, later, by constricting those that are successful in negotiating the scar tissue between the nerve fiber ends, adversely affects their subsequent growth, development, and function. This disorderly axon growth may be so pronounced that the involved fasciculi develop a fusiform swelling at this site. 2. Loss of continuity of the nerve fibers means that regenerating axons, though still confined within the fasciculi, are no longer confined to the endoneurial tubes that originally contained them. Since there is no known mechanism directing axons into their original or functionally related endoneurial tubes, many fail to do so and instead are misdirected into foreign ones. The significance of the erroneous cross-shunting of axons occurring in this way depends on the fi-
Anatomy and Physiology of Nerve Injury
ber composition of the fasciculi (Fig. 6). Where the fibers have the same or a functionally related destination, the consequences are minimal. Where the fiber composition is one in which sensory and motor fibers and those representing functionally unrelated systems are intermingled, however, the consequences of the erroneous entry of axons into foreign tubes can be serious. Despite the fact that the nerve trunk is left in continuity, recovery following severe third degree damage is often negligible. Fourth Degree InJury (4'). In this type of injury, the fascicular structure of the nerve has been destroyed, nerve trunk continuity being preserved by a strand of disorganised tissue. Regenerating axons are now free to escape not only from endoneurial tubes but also from fasciculi. The trauma-
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tized, disorganized segment of the nerve trunk is replaced by a barrier of fibrous tissue in which axon growth is arrested. This is the type of injury that requires excision of the damaged segment and some form of nerve repair. Flfth Degree Injury (5'). This represents loss of continuity of the nerve trunk. Though the clinical details of this classification are not the concern of this presentation, one can say that the classification is one that (1) has a sound pathologic basis; (2) relates to the clinical events associated with a lesion; (3) has diagnostic, prognostic and therapeutic significance; (4)involves a terminology that is readily understood, and (5) has the added attractiveness of simplicity.
These are lesions in continuity in which all nerve fibers are damaged but to a varying degree.
30 154 mm FIGURE 13. The effect of the branch fiber composition of injured fasciculi in a partial nerve injury. The notations are given in Figure 6. (From Sunderland S : Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Mixed Nerve Injury.
These are lesions in which some nerve fibers escape while others sustain damage of varying degree. A common lesion in this category is partial severance of the nerve trunk. The consequences of such an injury depend on (1) the size and number of the fasciculi composing the nerve at that level; and (2) the branch fiber composition of the affected fasciculi.
Partial Nerve Injury.
Size and Number of the Farciculi (Figure 12).
Where the fasciculi are small, numerous, and well separated by epineurial tissue, such lesions tend to be self-limiting. When the fibers are contained in one or two large fasciculi, however, breaching these fasciculi has serious consequences. The Branch Fiber Composition of the Severed Fa$ciculi (Figure 13). Partial lesions produce variable
effects at the periphery depending on the branch fiber composition of the affected fasciculi that is, in turn, determined by the level of the injury. Where the severed fasciculi contain a few of the fibers of some or all branches, the resultant loss of function is minimal and widespread and might even escape detection clinically. On the other hand, where the severed fasciculi contain all or the majority of the fibers of a particular branch, the peripheral effects are sharply localized and clinically obvious. Thus, a partial injury at one level may either escape detection or give a widely distributed paresis, but a corresponding lesion at another level or involving a different sector of the nerve may produce a sharply localized paralysis or sensory loss. THE EFFECT OF A TRANSECTION INJURY ON THE NERVE BELOW THE LESION
Following a transection injury, changes occur in the axons and myelin, the endoneurial tubes, the fasciculi, and the nerve trunk. The Axon8 and Myelin. The final stage of wallerian degeneration is one in which the interior of the nerve fiber is occupied by axon and myelin debris which is removed by the phagocytic activity of macrophages and Schwann cells.
With the removal of the axon and myelin debris, tension is reduced in the endoneurial wall of the fiber which slowly contracts down on the remaining contents of the tube, which are Schwann cells, so that its caliber is gradually reduced. This reduction increases with the duration
The Endoneurial Tubes.
FIGURE 12. The effect of fascicular structure on the consequences of a partial nerve injury. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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Anatomy and Physiology of Nerve Injury
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of denervation, rapidly over the first 3 months beyond which there is little further change. The fibers are affected in proportion to their size, so that the largest are ultimately reduced to tubes 2 to 3 pm in diameter. At the end of 3 months, most tubes are less than 3 pm in diameter with only an occasional tube of 4 p,m (Fig. 14). The shrinkage of the endoneurial tubes is associated with a corresponding atrophy of the fasciculi. Thus, the cross-sectional fascicular area is reduced by about 50% to 60% at 2 months, and then by about another 10% over the next month, beyond which there is no further significant reduction (Table 2).
The Fasciculi.
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The epineurial tissue undergoes little change except for some edematous swelling at the nerve end. This tissue is excised at the time of the repair. Because the fasciculi and epineurial tissue react so differently to denervation, it follows that the extent of the shrinkage of the nerve trunk will be influenced, not only by the duration of denervation, but also by the percentage cross-sectional area of the nerve occupied by fascicular tissue. Thus, the reduction will be greater when the fasciculi are closely packed and occupy most of the cross-sectional area of the nerve than where the fasciculi are small and widely separated by a large amount of epineurial tissue.
The Nerve Trunk.
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Diameter of endoneuriol tubes (microns)
FIGURE 14. Histograms of endoneurial tube shrinkage with increasing periods of denervation (Australian marsupial, Trichosurus vulpecula). (From Sunderland S: Nerves and Nerve lnjuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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Table 2. Nerve trunk and fascicular atrophy consequent on denervation.
Nerve Ulnar Median Ulnar Median Ulnar Ulnar Ulnar Median Ulnar Median Median Ulnar Ulnar Median Median Ulnar Median Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar Ulnar
Duration of denervation in days
Percentage fascicular atrophy
Percentage nerve trunk atrophy
44 49 59 59 68 76 89 89 140 140 185 196 224 224 229 229 252 254 254 280 335 335 444 444 485 485
64 54 67 50 61 50 68 56 61 68 62 54 63 54 59 69 68 62 67 74 72 74 88 67 72 66
49 10 28 31 56 59 35 43 30 26 25 45 54 45 33 54 42 53 52 55 22 42 86 61 48 56 ~
Because of dffferencesin the cross-sectional areas of the distal nerve end devoted to fascicularand epfneurfaltissue, the degree of nerve trunk and fasocular atrophy do not necessanly correspond (Australfan marsupal. Trrchosurus vulpecula)
Consequently, the reduction in the crosssectional area of the nerve below the transection does not follow the fascicular atrophy. On the contrary it will, for a given period of denervation, vary irregularly depending on fascicularepineurial tissue ratios. This is illustrated in Table 2. THE MANNER IN WHICH ANATOMICAL FEATURES AT THE SUTURE LINE INFLUENCE THE OUTCOME OF AXON REGENERATION
The concluding section of this saga on the anatomy and physiology of nerve injury concerns axon regeneration and the inevitable loss of regenerating axons that occurs as they cross the suture line. Regarding axon regeneration, two points are worthy of special comment: (1) the distinction that should be drawn between axon regeneration and functional recovery; and (2) the role of neurotropism in axon regeneration.
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At the outset it is necessary to emphasise the importance of carefully distinguishing between axon regeneration and the functional outcome of that regeneration. The recovery of function requires far more than the regeneration of axons to replace the part lost below the injury. Of even more importance is the final destination of those axons because, for regeneration to be functionally effective, each axon must reach and reinnervate its old, or at least a functionally related, end organ. Failure to do this represents abortive and wasteful regeneration, which leaves recovery incomplete and impaired. Thus, axon regeneration per se does not necessarily guarantee functional recovery and, because it is possible to have good axon regeneration and yet little functional recovery, it is necessary at all times to keep in mind that axon regeneration and functionally effective axon regeneration are two very different events in the regenerative process.
Axon Regeneration and Functional Recovery.
Neurotropism. It is now well established that, when the nerve ends are well separated, regenerating axons are attracted to the distal nerve stump under the influence of neurotropic factors elaborated in and operating from that site. The source of the neurotropic factor appears to be widely distributed throughout the tissues of the distal stump and is not confined to Schwann cells as was originally believed. This influence, however, becomes irrelevant after nerve suture because when regenerating axons emerge from the proximal stump they are already at the distal nerve end. The question at issue now becomes one that asks, are there neurotropic influences operating at the suture line interface that impart a matching specificity to the process whereby each regenerating axon is inevitably attracted back to the endoneurial tube that it originally occupied or to which it is at least functionally related. It would be reassuring to know that such influences do exist but, unfortunately, there is some hard evidence against the concept.
1. Regenerating axons show no preference for fascicular tissue. They will grow just as readily outside the nerve or into the interfascicular tissues of the distal stump. 2. Nerve cross-union experiments show that regenerating motor axons will enter and grow down sensory endoneurial tubes, and sensory down motor.
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3. Regenerating motor axons will occupy the endoneurial tubes of a cutaneous nerve graft and grow rapidly and readily along them. 4. An analysis of the results of nerve repair are consistent with the random entry of regenerating axons into the endoneurial tubes of the distal nerve end. Neurotropism as a force converting order out of chaos at the suture line is a nonevent. Physical influences outlining paths of least resistance through the interface tissues are the principal determinants of the direction taken by regenerating axons after they leave the proximal nerve end. Under such circumstances, we may well ask what are the chances of regenerating axons reaching and reinnervating functionally related endoneurial tubes, particularly in view of the many hazards to be overcome enroute. Disregarding the well-established influence of suture line scarring, other less obvious hazards that are just as damaging include:
Discrepancies in the fascicular patterns at the nerve ends so that fasciculi are opposed to epineurial tissue and vice versa (Fig. 4). The absence of any branch fiber localization at the level of the repair particularly in mixed motor and sensory nerves (Fig. 16). The chances of useful regeneration are improved, however, at levels where some branch fiber localization is present. At levels where there is no branch fiber localization, the numbers of nerve fibers representing individual branches becomes a factor influencing the entry of axons into functionally related endoneurial tubes. Thus, in the median
1. Discrepancies that have developed in the crosssectional dimensions of the two nerve ends (Fig. 15).
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132 m m FIGURE 15. Diagrammatic representationsof factors at the suture that are responsible for the loss of axons during axon regeneration. (From Sunderland S: Nerves and Nerve Injuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
Anatomy and Physiology of Nerve Injury
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FIGURE 16. The effect of fascicular branch fiber localization on the outcome of axon regeneration. The notations are those given in Figure 6. The arrangement in the lower pair favors the misdirection of regenerating axons into foreign endoneurial tubes. (From Sunderland S: Nerves and Nerve lniuries. Edinburgh, Churchill Livingston, 1979. Used with permission.)
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nerve in the mid-forearm, where the sensory fibers for the hand greatly outnumber motor fibers, the former will have a decided advantage in the competition for endoneurial tubes SO that the prospects for sensory recovery are much better than those for motor recovery. Clearly, large numbers of regenerating axons are inevitably lost at the suture line so that reinnervation is always incomplete and imperfect. A further minus is that, with delayed nerve repair, even those axons entering functionally related endoneurial tubes and reinnervating functionally related end organs fail to develop fully. This is be-
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cause of irreversible changes in the wall of shrunken endoneurial tubes which prevent the maturation of fibers to their original calibre and degree of myelination. This could contribute to the permanent reduction in the conduction velocity of regenerated nerve fibers. The challenge is to correct or at least modify these adverse factors, but that is another story. I hope that sufficient has been said to convince the reader that the anatomy and physiology of nerve injury is a subject worthy of the most careful consideration; on that note I shall conclude this presentation.
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REFERENCES 1 . Sunderland S: The blood supply of the nerves of the upper limb in man. Arch Neurol Psychiat~1945;53:91-115 2. Sunderland S: The blood supply of the sciatic nerve and its popliteal divisions in man. Arch Neurol Psychiatry 1945; 54:283-289. 3. Sunderland S: The blood supply of peripheral nerves: Some practical considerations. Arch Neurol Psychiatry 1945; 54:280-282. 4. Sunderland S: The intraneural topography of the radial, median and ulnar nerves. Brain 1945;68:243-299. 5. Sunderland S: Factors influencing the course of regeneration and the quality of the recovery after nerve suture. Brain 1952;75:19-54. 6. Sunderland S: The relative susceptibility to injury of the medial and lateral popliteal divisions of the sciatic nerve. Brit J Surg 1953;41 :300- 302. 7. Sunderland S: Funicular suture and funicular exclusion in the repair of severed nerves. B r J Surg 1953;40:580-587. 8. Sunderland S: The connective tissues of peripheral nerves. Brain 1965;88:841-853. 9. Sunderland S: Anatomical features of nerve trunks in relation to nerve injury and nerve repair. Clin Neurosurg 1970;17:38-62. 10. Sunderland S: Nerves and Nerve Injuries. 2nd Ed. Edinburgh, Churchill Livingstone, 1978. 1 1 . Sunderland S: The pros and cons of funicular nerve repair.J Hand Surg 1979;4(3):201-211 12. Sunderland S: The anatomical basis of nerve repair. In Jewett DL, McCarroll HR, eds. Nerve Repair and Regeneration: Its Clinical and Experimental Basis. St. Louis, CV Mosby 1980, pp 14-35.
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13. Sunderland S: The anatomic foundation of peripheral nerve repair techniques. Orthopedic Clinics of North America 198 1 ;12~245-266 14. Sunderland S, Bedbrook GM: The cross-sectional area of peripheral nerve trunks occupied by the fibers representing individual muscular and cutaneous branches. Brain 1949;72:613-624. 15. Sunderland S, Bradley KC: The cross-sectional area of peripheral nerve trunks devoted to nerve fibers. Brain 1949;72:428- 449. 16. Sunderland S, Bradley KC: Endoneurial tube shrinkage in the distal segment of a severed nerve. J Comp Neurol 1950;93:411-420. 17. Sunderland S, Bradley KC: Denervation atrophy of the distal stump of a severed nerve.] Comp Neurol 1950;93:401409. 18. Sunderland S, Bradley KC: The perineurium of peripheral nerves A m t Rec 1952;113:125-141. 19. Sunderland S, Bradley KC: Stress-strain phenomena in human peripheral nerve trunks. Brain 1961;84:102- 119. 20. Sunderland S, Bradley KC: Stress-strain phenomena in human spinal nerve roots. Brain 1961;84:120- 124. 21. Sunderland S, Bradley KC: Stress-strain phenomena in denervated peripheral nerve trunks. Brain 1961;84:125127. 22. Sunderland S, Marshall RD, Swaney WE: The intraneural topography of the circumflex musculocutaneous and obturator nerves. Brain 1959;82:116- 129. 23. Sunderland S, Ray LJ: The intraneural topography of the sciatic nerve and its popliteal divisions in man. Brain 1948;71:242-273.
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