Biological Response of Peripheral Nerves to Loading: Pathophysiology of Nerve Compression Syndromes and Vibration Induced Neuropathy

David Rempel, MD, MPH

Department of Medicine, Division of Occupational and Environmental Medicine, University of California, San Francisco

and

Lars Dahlin, MD, Ph.D. and Göran Lundborg, MD, Ph.D. Department of Hand Surgery, Malmö University Hospital, Malmö, Sweden

Introduction

Nerve compression syndromes involve peripheral nerve dysfunction due to localized microvascular interference and structural changes in the nerve or adjacent tissues. Although a well known example is compression of the median nerve at the wrist (e.g., carpal tunnel syndrome) other nerves are vulnerable (e.g., ulnar nerve at the wrist or elbow, spinal nerve roots at the vertebral foramen, etc.).

When tissues are subjected to pressure, they deform and create pressure gradients, redistributing compressed tissue toward areas of lower pressure. Nerve compression syndromes usually occur at sites where the nerve passes through a tight tunnel formed by stiff tissue boundaries. The resultant 'confined space' limits tissue movement and can lead to sustained tissue pressure gradients. Based on case reports, space occupying lesions (e.g., lumbricle muscles, tumors, cysts, etc.) can cause nerve compression injury, as can conditions associated with the accumulation of fluid (edema) or extracellular matrix in soft tissues (e.g., pregnancy, congestive heart failure, acromegally, myxedema hypothyroidism, muscle compartment syndromes, etc.). Although nerve injuries related to vibration occur near the region of vibration exposure, they may be manifested at constriction sites. Other conditions, such as diabetes mellitus may increase the susceptibility of the nerve to compression. In addition, an inflammatory reaction may occur which may impair the normal gliding of the nerve. Basic knowledge of the microanatomy of the peripheral nerve and the neuron and their complex reactions to compression are essential to understanding, preventing, and treating nerve compression injuries.

Structure and Function of Peripheral Nerves

Microanatomy

The neuron consists of the nerve cell body which is located in the anterior horn of the spinal cord (motor neuron) or in the dorsal root ganglia (sensory neuron), and of a process extending into the periphery—the axon—which is surrounded by Schwann cells arranged in a longitudinal continuous chain forming myelinated nerve fibers (Figure 1 (from Lundborg G and



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--> Biological Response of Peripheral Nerves to Loading: Pathophysiology of Nerve Compression Syndromes and Vibration Induced Neuropathy David Rempel, MD, MPH Department of Medicine, Division of Occupational and Environmental Medicine, University of California, San Francisco and Lars Dahlin, MD, Ph.D. and Göran Lundborg, MD, Ph.D. Department of Hand Surgery, Malmö University Hospital, Malmö, Sweden Introduction Nerve compression syndromes involve peripheral nerve dysfunction due to localized microvascular interference and structural changes in the nerve or adjacent tissues. Although a well known example is compression of the median nerve at the wrist (e.g., carpal tunnel syndrome) other nerves are vulnerable (e.g., ulnar nerve at the wrist or elbow, spinal nerve roots at the vertebral foramen, etc.). When tissues are subjected to pressure, they deform and create pressure gradients, redistributing compressed tissue toward areas of lower pressure. Nerve compression syndromes usually occur at sites where the nerve passes through a tight tunnel formed by stiff tissue boundaries. The resultant 'confined space' limits tissue movement and can lead to sustained tissue pressure gradients. Based on case reports, space occupying lesions (e.g., lumbricle muscles, tumors, cysts, etc.) can cause nerve compression injury, as can conditions associated with the accumulation of fluid (edema) or extracellular matrix in soft tissues (e.g., pregnancy, congestive heart failure, acromegally, myxedema hypothyroidism, muscle compartment syndromes, etc.). Although nerve injuries related to vibration occur near the region of vibration exposure, they may be manifested at constriction sites. Other conditions, such as diabetes mellitus may increase the susceptibility of the nerve to compression. In addition, an inflammatory reaction may occur which may impair the normal gliding of the nerve. Basic knowledge of the microanatomy of the peripheral nerve and the neuron and their complex reactions to compression are essential to understanding, preventing, and treating nerve compression injuries. Structure and Function of Peripheral Nerves Microanatomy The neuron consists of the nerve cell body which is located in the anterior horn of the spinal cord (motor neuron) or in the dorsal root ganglia (sensory neuron), and of a process extending into the periphery—the axon—which is surrounded by Schwann cells arranged in a longitudinal continuous chain forming myelinated nerve fibers (Figure 1 (from Lundborg G and

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--> Dahlin L 1996)). Between the Schwann cells, non-myelinated nerve fibers are located in a large number. Myelinated and non-myelinated nerve fibers are organized in bundles, called fascicles, and surrounded by a mechanical strong membrane consisting of laminas of flattened cells, the perineurial membrane. The bundles are usually organized in groups, held together by a loose connective tissue called the epineurium. In between the nerve fibers and their basal membrane is located an intrafascicular connective tissue—the endoneurium. The amount of the connective tissue components may vary between various nerves and also between various levels along the same nerve. For example, nerves located superficially in the limb or parts of the peripheral nerve that cross a joint contain an increased quantity of connective tissue, possibly as a response to repeated loading (Sunderland 1978). The normal propagation of impulses in the nerve fibers as well as the communication and nutritional transport system in the neuron—axonal transport—require a sufficient energy supply. The peripheral nerve therefore contains a well developed microvascular system with vascular plexa in all connective tissue layers of the nerve (Lundborg 1970, 1975). The vessels approach the nerve trunk segmentally and these vessels have a coiled appearance so that the vascular supply is not impaired during the normal gliding or excursion of the nerve trunk. When the vessels reach the nerve trunk they divide into branches running longitudinally in various layers of the epineurium and also form numerous collaterals to vessels in the perineurial sheath. When the vessels pass through the perineurium into the endoneurium, which primarily contains capillaries, they often go through the perineurium obliquely thereby constituting a possible ''valve mechanism" (Lundborg 1970, 1975). The perineurial layer and the endoneurial vessels play an important role in protecting the nerve fibers in the fascicles. The endoneurial milieu is preserved by a blood-nerve barrier, and the tissue pressure in the fascicle—endoneurial fluid pressure—is slightly positive (Myers et al. 1978). This is obvious when there is injury to the perineurium; following a transaction a "mushrooming" effect is observed. There are no lymphatic vessels in the epineurial space, therefore problems occur when an edema is formed in the endoneurial space. Following such an edema the pressure in the fascicle may increase and rapidly interfere with the endoneurial microcirculation (Lundborg and Dahlin 1996). The epineurial vessels are more vulnerable than the endoneurial vessels to trauma and even to surgical handling of the nerve. The neuron itself is, as mentioned above, a unique cell with the cell body and the extending process (axon). The length of the axon may be 10 to 15,000 times the diameter of cell body. Therefore, there is a need for an intraneuronal transport system—axonal transport—where essential products are produced and constantly transported from the nerve cell body down the axon (anterograde transport), and disposal materials and trophic factors are also transported in the opposite direction (retrograde transport) (Grafstein and Forman 1980). The axonal transport consists of various components where fast axonal transport (up to around 410 mm per day) involves various enzymes, transmitter substance vesicles and glycoproteins and the various slow components (up to 30 mm per day) involve mainly cytoskeletal elements such as subunits of microtubules and neurofilaments. It should be noted that axonal transport is energy depend and disturbances in axonal transport may be involved not only in the development of diabetic neuropathy but also in nerve compression injuries (Dahlin et al. 1986).

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--> Normal Gliding of Nerve Trunks Outside the peripheral nerve trunk there is a conjunctive like "adventitia" that permits an excursion of the nerve trunk which is a feature of normal nerve functioning during, for example, joint movements. Such an extraneural gliding surface together with the normally occurring sliding of fascicles against each other in deeper layers—intraneural gliding surfaces—make the normal gliding of the nerve possible. The median and ulnar nerve may glide 7.3 and 9.8 mm respectively during full elbow flexion and extension, and the extent of excursion of the nerve just proximal to the wrist is even more pronounced (14.5 and 13.8 mm respectively) (Wilgis and Murphy 1986). In relation to the flexor retinaculum the median nerve may move up to 9.6 mm during wrist flexion and to a slight degree in wrist extension but the nerve also moves during finger moments (Millesi et al. 1990). Purpose of this Report—Database Search The epidemiologic evidence linking repetitive loading to nerve injuries will be reviewed elsewhere. The purpose of this report is to review human and animal studies which examine the physiologic, pathophysiologic, biochemical and histologic effects of loading on the peripheral nerve. The database PubMed was searched on August 3, 1998 for peer-reviewed articles from scientific journals from 1965 to 1998 using the following query: (english [Language] AND (((("nerve compression syndromes/etiology" [MeSH Major Topic] OR "nerve compression syndromes/pathology" [MeSH Major Topic] ) OR "nerve compression syndromes/physiopathology" [MeSH Major Topic] ) OR Nerve Compression Syndromes/prevention and control [MeSH Terms] )) OR ("hand arm vibration syndrome" AND nerve)) The search produced 3025 citations. On a case by case review, the following citations were eliminated: case reports, reviews, surgical techniques or complications, nerve crush studies, and nerve conduction techniques. All citations with titles suggesting study of physical exposures, loading, vibration, etiology, mechanisms of injury, biological response, and histology were retained. Total citations identified: 190. In addition, the files of the authors were searched and a request was made to the seven discussants of this topic to provide 5 to 10 key citations. One discussant responded and provided 5 citations. These citations had been captured by the PubMed query, providing some confidence in the database search. Experimental devices for nerve compression in animals Various methods have been used to induce an acute or chronic compression of a peripheral nerve in animal models. There are advantages and disadvantages with all used methods. For acute compression, tourniquets can be used to apply compression around, for example, the hind limb of

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--> rabbits where it is possible to induce compression/ischemia of a limb (Lundborg et al. 1970). By this method, as well as the later presented invasive methods to induce acute graded compression of rat and rabbit nerves, the magnitude as well as the duration of the pressure can be varied (Dahlin 1986; Rydevik and Lundborg 1977; Lundborg 1970). Tourniquets have also used to induce and to evaluate structural changes in peripheral nerves in baboons (Ochoa et al. 1972; Fowler & Ochoa 1975). However, in the latter report very high pressures of 67 to 133 kPa were used. A small compression chamber, used by Rydevik and Dahlin (Rydevik and Lundborg 1977; Dahlin 1986) to induce acute, graded compression, consisted of two Plexiglas halves onto which thin rubber membranes were glued. It was applied around a mobilized nerve segment to apply low magnitude pressures for two to eight hours (for results see below). Similar methods have been used by others (Dyck et al. 1990). Chronic nerve compression models have involved compression of mobilized nerve segments by using tightly fitting arteries (Weiss and Davis 1943), metal spring clips (Denny Brown and Brenner 1944), compression clamps, where it is possible to grade the applied pressure (Nemoto et al. 1983; Horiutchi et al. 1983) and tubes of various materials such as polyethylene (Weisl and Osborn 1964) and silicone (Dahlin and Kanje 1992; Kanje et al. 1995; MacKinnon et al. 1985). By using tubes of varying inner diameters it is possible to obtain a graded compression but it is not possible to relate the compression to a specific pressure level as can be done in acute compression models. Furthermore, the implantation of foreign materials may generate an inflammatory response induced by the material (Kanje et al. 1995, Kajander et al. 1996). A normal developing chronic entrapment of the median nerve at the wrist in guinea pigs has also been used to study the structural changes of myelinated fibers (Ochoa and Marrot 1973), but as with the other chronic models neither the external load nor extraneural pressure has been measured. Table 1. Pressures are frequently reported in units of mmHg. The units used in this paper are SI units (kPa). Conversions between the two units are listed. mmHg kPa 20 2.7 30 4.0 40 5.3 50 6.7 80 10.7 150 20.0 500 66.7 1000 133.3 Nerve Compression—Acute Effects (Hours) Low-magnitude extraneural compression can decrease intraneural microvascular flow, impair axonal transport, and alter nerve structure and function in animal experiments. Miniature inflatable cuffs are used to apply controlled local compression around a nerve in vivo. Pressures of 2.7 can reduce epineurial venule blood flow (Rydevik et al. 1981). At pressures of 10.7 kPa all intraneural blood flow ceases. Likewise, pressures of 4.0 kPa inhibit both fast and slow

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--> anterograde as well as retrograde axonal transport (Dahlin et al. 1986). Therefore, cell nutrition and the intraneuronal communication system will be compromised at elevated extraneural pressures. Extraneural compression to 6.7 kPa applied for 2 minutes alters the shape of myelin sheaths and at higher pressures the myelin is severely split and distorted (Dyck et al. 1990). The role of pressure applied cyclically on nerve function has been evaluated in a rat tibial nerve model (Szabo et al. 1993). Static extraneural pressures of 4.0 kPa caused a decline in nerve function. The mean value of a pressure applied cyclically (e.g., mean 4.7 kPa; 2.7 to 6.7 kPa peak to peak) at 1 Hz for 20,000 cycles had a similar effect as the continuous pressure on nerve function. In healthy human volunteers, the extraneural pressure within the carpal tunnel was experimentally controlled by applying an external pressure over the palm (Gelberman et al. 1983a, 1983b, Szabo et al. 1983). Nerve function was followed for up to 4 hours. Some nerve function loss occurred at 5.3 kPa and complete nerve function was blocked at 6.7 kPa. In subjects with different blood pressures, the critical pressure threshold occurred at 4 kPa below the diastolic pressure, supporting an ischemic mechanism for acute nerve dysfunction. In addition, carpal tunnel syndrome may manifest with the treatment of hypertension (Emara and Saadah 1988). Nerve Compression—Short-Term Effects (Days) A persistent edema due to the increased vascular permeability of the epineurial and endoneurial vessels has been observed following compression at low pressures (Rydevik and Lundborg 1977). Using a pressure cuff the extraneural pressure around the rat sciatic nerve was elevated to 4 or 10.7 kPa for periods of 2, 4, 6, and 8 hours (Lundborg et al. 1983). The endoneurial fluid pressure was measured with a micropipette one hour and 24 hours after removal of the cuff, then the nerve underwent histologic analysis. A sham intervention was performed for 2 to 8 hours without inflating the cuff. A compression of 4 kPa led to elevated endoneurial pressures at 1 hour which increased with increasing duration of compression. A greater effect was observed with 10.7 kPa compression. The endoneurial pressures were similarly elevated at 24 hours. Nerve histology demonstrated endoneurial edema after 8 hours compression at 4 kPa but not with shorter durations. Greater edema and degenerating nerve fibers were observed at 10.7 kPa of compression. The endoneurial pressures measured after 8 hours of extraneural compression at 4 kPa can reduce intraneural blood flow (Myers et al. 1982). Limitations of the study were: (1) the short duration of follow-up, (2) small number of animals, (3) lack of quantitative histologic technique, and (4) no statistical testing. The study demonstrated that endoneurial fluid pressures can increase rapidly following extraneural compression and persist for at least 24 hours. A dose response effect of both compression magnitude and duration was demonstrated. Other studies have demonstrated that ischemia alters endothelial and basement membrane structure over a similar time course (Benstead et al. 1990) Nerve Compression—Long-Term Effects (Weeks) The same model was used to study the long-term biological effects of brief, graded nerve compression (Powell et al. 1986). Extraneural pressure of 10.7 kPa was applied for 2 hours to the sciatic nerve of the rat. At intervals of 4 hours, 1, 2, 5, 6, 7, 10, 14, and 28 days the nerves

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--> were excised for histologic analysis. In a smaller number of animals pressures of 1.3 and 4 kPa were applied for 2 hours with follow-up intervals of 5 to 7 days. Sham intervention in the contralateral limb of the low pressure animals was performed by inserting the uninflated chamber. Sham surgery without insertion of the chamber was also performed. Edema within the subperineurial space was visible within 4 hours in all compression groups and persisted for the entire time of the study. Inflammation and fibrin deposits occurred within hours of compression followed by a proliferation of endoneurial fibroblasts and capillary endothelial cells. Within days, vigorous proliferation of fibrous tissue was noted with marked fibrosis at day 28 and sheets of fibrous tissue extending to adjacent structures. Endoneurial invasion of mast cells and macrophages were noted, especially at day 28. Axonal degeneration was notable at days 10 to 18 at 10.7 kPa compression and to a lesser extent at 4 kPa with rare observations at 1.3 kPa. Axonal degeneration was correlated with degree of endoneurial edema. Demyelination was increased, especially on days 7 to 10 with remyelination observed on days 14 and 28. Demyelination was associated with Schwann cell necrosis. Demyelination was prominent with 4 kPa compression and to a lesser extent at 1.3 kPa. The sham intervention also demonstrated demyelination in regions close to the cuff surface, thought by the authors due to the tense but uninflated rubber cuff pressing the nerve. The sham surgery demonstrated no lesions. Limitations: (1) primarily a descriptive study, (2) unequal numbers of animals per group, (3) lack of follow-up of low pressure groups beyond 7 days, (4) Table II missing, (5) no quantification of fibrosis or edema, (6) pressure likely applied to nerve for the first sham intervention, and (7) statistical methods no clear. In a similar model using the peroneal nerve of rats, pressures of 6.7 and 20 kPa applied for 2 minutes led 10 days later to demyelination under the cuff and degeneration distal to the cuff (Dyck et al. 1990). The effect was greater at the higher pressure and for pressures applied for 30 minutes. Structural changes in myelin were also observed immediately at the end of compression leading the authors to conclude that the long term effects of brief compression are due to mechanical shear forces disrupting the myelin. Limitations: single nerve per exposure group, therefore, no statistical comparisons and no very low pressure compression as control. Effects on the nerve cell bodies have also been observed in ganglion cells of rabbits 7 days following compression at 4.0 kPa for two hours. The changes consisted of decrease in nuclear volume density, an eccentric position of the nucleus in the cell and frequent dispersion of the Nissl substance (Dahlin et al. 1987). Such changes may be followed by a change in the tubulin transport in the neurons (Dahlin et al 1993) as well as functional changes in the neuron and in the nerve trunk itself (conditioning lesion effect; Dahlin and Kanje 1992; Dahlin and Thambert 1993). Such changes may be involved in conditions where one part of the nerve trunk is compressed and thereby making other parts of the same nerve more susceptible to compression at another level (double crush and reverse double crush syndrome; Dahlin and Lundborg 1990). To model chronic nerve compression other investigators have placed short silicon tubes of varying internal diameters or loose ligatures around the rat sciatic or sural nerve (Mackinnon et al. 1984, Mosconi et al. 1996). The tube inner diameters or ligature tensions are generally selected so that blood flow is not restricted. At regular intervals, up to a year later, the animal behavior, nerve electrophysiology and histology are evaluated. Although these are primarily observational studies, they provide some insight into the biological response of the nerve to continuous low-grade compression.

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--> The response of nerve to compression in these studies is similar to the cuff experiments. For example, Sommer et al. (93) used loose ligatures around the sciatic nerve in one limb and very loose ligatures as a sham intervention on the contralateral side. In the sham ligatures there were no changes in the endoneurium at 1 and 4 weeks but fibrous tissue was increased in the epineurium near the ligatures but did not compress the nerve fascicles. In the exposed nerve perineurial edema was observed in the first days with proliferating endothelial cells and demyelination. Within a week increased proliferation of endothelial cells, fibroblasts and macrophages, continued demyelination and distal nerve fiber degeneration and the beginning of nerve sprouts. At 2 weeks, invasion by fibrous tissue and remyelination. At 4 weeks, less edema, thickened endothelium, remyelination. At 6 weeks regenerated nerve fibers, thickened perineurium and vessel walls. At 12 weeks remyelination of distal nerve segments. This model has been used to study pain related behavior (Mosconi et al. 1996). The limitations of this model are (1) the effects of the tissue inflammatory reaction to the device (e.g., foreign body reaction) are not usually considered but do occur (Kanje et al. 1995) and (2) it is not possible to measure the applied pressure in these chronic compression models. Similar biological responses to compression are observed after chronic, low grade compression of the cauda equine and spinal nerve roots (Toh & Mochida 1997; Yoshizawa et al. 1995; Cornefjord et al. 1997). It should also be noted that, especially at the nerve root, increasing age is associated with increasing presence of fiber degeneration and regeneration but not with changes in number of myelinated fibers per nerve or fascicle (Knox et al. 1989). Fiber degeneration is more common in compressed nerve roots from older rabbits than younger ones (Toh & Mochida 1997). Histology of Human Nerve Compression A biopsy of the nerve is likely to lead to permanent nerve dysfunction, therefore there are few human histologic studies of nerves at common sites of compression. In a few case reports (surgical resection of nerve, autopsy with known disease) the nerve at the site of injury was compared to a site proximal or distal to the injury (Thomas 1963; Mackinnon et al. 1986; Neary et al. 1975a). In each case, the site of injury demonstrated thickening of the walls of the microvessels in the endoneurium and perineurium along with epineurial and perineurial edema, thickening and fibrosis. Myelin thinning was also noted along with evidence of fiber degeneration and regeneration. These reports are from patients with advanced stage of compression. In earlier disease a segment of the medium nerve is usually compressed with disturbed microcirculation which is immediately restored after the transection of the flexor retinaculum. There is usually both an immediate and delayed return of nerve function indicating the importance of ischemia in the early stages of the compression syndrome (Lundborg et al. 1982). Increased connective tissue density has also been observed along the median nerve from six elderly cadavers wrists, without knowledge of medical history (Armstrong et al. 1984). The greatest density of connective tissue was observed at the level of the wrist crease with a fall in density 40 mm proximal and distal to the crease. Similar findings are observed in the ulnar nerve at the elbow (Neary et al. 1975b). These findings suggest that extracellular matrix is deposited within the nerve at sites of bending.

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--> The tissues which lie next to a nerve, within a confined space, are more easily harvested and can provide information on the response of adjacent tissues to compression. For example, synovial tissue has been harvested from within the carpal tunnel next to the median nerve for histologic and biochemical analyses (Yamaguchi et al. 1965, Phalen 1972, Neal et al. 1987, Faithful et al. 1986, Sclesi et al. 1989, Schuind et al. 1990, Fuchs et al. 1991, Kerr et al. 1992). In the Fuchs study, one of the few to include a control group, synovium from 147 patients was harvested at time of carpal tunnel release and compared to synovium from 19 controls. The significant findings were greater edema and vascular sclerosis (endothelial thickening) in patient samples. Inflammatory cell infiltrates (lymphocytes, histiocytes) were observed in only 10% of samples. Surprisingly, the observed incidence of 3% with fibrosis was much less than the 36% to 100% reported in other studies. The authors conclude that tenosynovitis is uncommon in patients undergoing surgery for idiopathic carpal tunnel syndrome. Limitations: case definitions did not include nerve conduction findings, only ten controls were age appropriate and four of these were cadavers without history, no definition of primary endpoints (e.g., edema, fibrosis. .), and the histology was semi-quantitative. The lack of definition of histologic endpoints in this and the other studies and differences in subject selection may account for differences in observed incidence of inflammation and fibrosis. The most consistent histologic features of synovium from the carpal tunnel of patients with CTS are edema and thickening of the vascular walls. To a limited degree these findings correspond to biological responses to nerve compression observed in the later stages of the animal models. Vibration and Nerve—Short-Term Effects (Days) Work with handheld vibrating tools can lead to a complex of symptoms known as the hand-arm vibration syndrome in which sensori-neural disturbances are prominent (Strömberg et al. 1996). The pathophysiological process associated with a vibration induced neuropathy remains still to be clarified but there is evidence that the injury may be located along the whole length of the neuron. Animal models have been developed to evaluate the events taking place in peripheral nerves following vibration exposure. Acute vibration (82 Hz, peak-to-peak magnitude of 0.21 mm) with an exposure time of five hours per day up to five days induces an intraneural edema as well as transient structural changes in thin non-myelinated fibers in the nerve trunks close to the vibration exciter (Lundborg et al. 1990; Lundborg et al. 1987). Other studies indicate that demyelination is an early event in the process and later a loss of axons may occur (Ho and Yu, 1989; Chang et al. 1994). Functional changes of both nerve fibers and non-neural cells such as Schwann cells may also occur following vibration exposure and are noted as an increased regenerative capacity following a nerve injury (Bergman et al. 1995; Dahlin et al. 1992). Histology of Human Vibration Induced Neuropathy Biopsies from fingertips of patients who have been exposed to vibrating handheld tools demonstrate nerve demyelination, loss of axons and fibrosis in small nerve trunks (Takeuchi et al. 1986, 1988). Recently, biopsies were taken from the dorsal interosseus nerve just proximal to the wrist from 10 men exposed to hand vibration at work and from 12 male age matched necropsy controls (Strömberg et al. 1997). In all 10 exposed and 1 control, pathological changes

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--> such as breakdown of myelin and presence of interstitial and perineurial fibrosis were observed. The histology results suggest that demyelination may be a primary lesion in the neuropathy which is followed by fibrosis associated with incomplete regeneration or with organization of an edema. Limitations: (1) detailed exposure information not available, (2) use of necropsy controls, (3) semi-quantitative endpoints, and (4) no statistical analyses. This study demonstrates that vibration exposure at work can induce structural changes in a peripheral nerve trunk at the wrist. Such changes may occur to the median nerve in the carpal tunnel among people exposed to vibration. Nerve Excursion in Nerve Compression Syndromes Longitudinal gliding of the nerve trunk occurs normally during joint motions and has been measured using ultrasound in humans or with markers placed in the nerve in cadavers. In patients with CTS, nerve excursion during wrist flexion/extension or finger flexion is restricted in comparison to healthy controls (Nakamichi et al. 1995; Valls-Solé et al. 1995). The basis for this limited motion is unknown. If the limited motion is due to adhesions to adjacent tissues, local regions of limited microvascular flow may occur due to nerve strain. A strain of 6 to 8% can limit blood flow or alter nerve function in a nerve (Clark et al. 1992; Ogata et al. 1986, Lundborg et al. 1973). Based on a cadaver study it may be that elevated pressures in the carpal tunnel do not restrict median nerve excursion (Bay et al. 1997). Extraneural Pressure in Nerve Compression Syndromes The hydrostatic pressures in the tissue next to a nerve can be measured with a small diameter wick or saline filled catheter. A number of studies have measured extraneural pressure in patients with carpal tunnel syndrome in comparison to controls (Table 2). The extraneural pressure is almost always higher in patients with CTS than in normal subjects. However, in one study, the mean pressure in patients with very severe or 'end-stage' CTS was low (Szabo et al. 1989). Differences in selection criteria and measurement techniques (e.g., catheter type, catheter location, use of patients with paraplegia, anesthesia, forearm postures, etc.) may explain differences in pressure measured. Taken together, these studies demonstrate that the extraneural pressure is elevated in patients with carpal tunnel syndrome in comparison to controls. Effects of Joint Posture and Hand Loading on Extraneural Pressure in Normal Subjects In many of the same studies, the wrist was moved either passively or actively to full flexion and extension and the pressures were measured. In patients with CTS the pressures increased by a factor of two to ten with flexion or extension. Although in normal subjects the pressures were of lower magnitude a similar response to extension and flexion has been consistently observed (Table 1). A similar pattern of increasing extraneural pressure with increasing joint deviation from neutral has been reported for other nerves. For example, in 10 cadavers the extraneural pressure adjacent to the ulnar nerve at the elbow, with the elbow extended, was 1.0 ± 0.3 kPa and rose to 6.3 ± 2.5 kPa when the elbow was flexed to 150 degrees (Macnicol et al. 1982). In normal

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--> humans the extraneural pressure response to joint posture appears to be independent of gender and age (Kumar et al. 1988). In normal subjects the simultaneous recording of posture and extraneural pressure in the carpal tunnel has been performed to investigate the dose-response effects of finger posture (Keir et al. 1998a, Werner et al. 1997), wrist extension/flexion (Werner et al. 1997, Weiss et al. 1995, Keir et al. 1998a), and forearm rotation (Werner et al. 1997, Rempel et al. 1998) to pressure. For example, extraneural pressure was measured in 17 normal volunteers while they slowly repeated forearm rotations of supination to pronation (Rempel et al. 1998). Hand and finger postures were held constant and the pressure was recorded at specific angles of pronation/supination as measured with a manual goniometer. The sweeps were repeated with different finger metacarpophalangeal flexion angles. The lowest pressures were recorded between 0 degrees and full pronation, while pressures up to 7.3 kPa were recorded in full supination. The limitations of this and the other studies are (1) due to the invasiveness of the procedure sample sizes are small for controls, leading to difficulty evaluating the effects of gender, age and other demographic factors, (2) selection biases are not addressed, (3) source of high inter-subject variability is unknown, (4) the tasks studied are difficult to generalize to working populations. Significant findings: increasing wrist extension and to a lesser degree wrist flexion, increasing forearm supination, and increasing metacarpophalangeal deviation from 45 degrees flexion increase extraneural pressure in the carpal tunnel. Finger loading also increases carpal tunnel pressure in normal subjects and in cadavers. In cadavers, the extraneural pressures rise in the carpal tunnel when the flexor tendons are loaded (Smith et al. 1977; Cobb et al. 1996). Similarly, in normal volunteers the pressures rise during simulated holding and gripping tasks. In the Serage et al. (95) study the pressure rose to 10.1 ± 8.7 kPa when subjects held a 10.5 cm cylinder and rose further to 31.2 ± 1.32 kPa when an active fist was made. Similar findings have been observed by others (Okutsu et al. 1989; Hamanaka et al. 1995; Werner et al. 1997). During a task of loading and unloading 1 lb cans from a box at a rate of 20 cans per minute, the carpal tunnel pressure was measured in 19 subjects (Rempel et al. 1994). The pressures fluctuated, with peak pressures occurring during can gripping. The mean pressure rose significantly from 1.1 ± 0.8 kPa at rest to 2.4 ± 1.7 during the task. In two subjects the mean pressure was greater than 4.0 kPa. In two studies, fingertip load and extraneural pressure in the carpal tunnel were quantified simultaneously in normal volunteers to investigate the dose-response relationships (Rempel et al. 1997, Keir et al. 1998b). Fingertip loads increased extraneural pressure independent of wrist posture (Rempel et al. 1997). In the other study (Keir et al. 1998b), 20 subjects (10 male, 10 female, mean age 30 yrs) pressed with the index finger on a load cell then pinched the load cell between the index finger and the thumb. Increasing fingertip load led to increasing extraneural pressure, in a dose-response manner, with the mean highest pressure of 6.6 kPa, occurring during the pinching task at 15 N force. The pinch task led to extraneural pressures that were twice those of the pressing task. Limitations: (1) incomplete knowledge of catheter tip location may have contributed to inter-subject variability and (2) no simultaneous evaluation of effects of hand postures. Conclusions: in healthy subjects relatively low fingertip loads during pinching (e.g., 5, 10, 15 N) elevate mean extraneural pressures in the carpal tunnel to 4.0, 5.6, and 6.6 kPa, respectively.

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--> Conclusions Elevated extraneural pressures can, within minutes or hours, inhibit intraneural microvascular blood flow, axonal transport, nerve function, and cause endoneurial edema with increased intrafascicular pressure and displacement of myelin, in a dose-response manner. Pressures of 2.7 kPa can limit epineurial blood flow, pressures of 4.0 kPa can limit axonal transport and cause nerve dysfunction and endoneurial edema, and pressures of 6.7 kPa can alter the structure of myelin sheaths. In several animal models, low magnitude, chronic nerve compression causes a biological response of: endoneurial edema, demyelination, inflammation, distal axon degeneration, extensive fibrosis, new axon growth, remyelination, and thickening of the perineurium and endothelium. Axonal degeneration was correlated with degree of endoneurial edema. In a animal model, extraneural pressures of 4 kPa applied for 2 hours can initiate a process of nerve injury and repair and can cause structural tissue changes that persist for at least one month. While a dose-response relationship with pressure occurs, the critical pressure/duration values for nerve injury are unknown. No animal model has been developed to evaluate the effects of repetitive hand-finger loading on nerve structure and function in order to study mechanisms of injury and dose-response relationships. In healthy humans, non-neutral finger, wrist and forearm postures and fingertip loading can elevate extraneural pressure in the carpal tunnel in a dose-response manner. For example, fingertip pinch forces of 5, 10, 15 N can elevate pressures to 4.0, 5.6, and 6.6 kPa, respectively. Extraneural pressures in healthy humans performing repetitive tasks at the workplace are unknown. In a rat model, exposure of the hind limb to vibration for 4 to 5 hours per day for 5 days can cause intraneural edema, structural changes in myelinated and unmyelinated fibers in the sciatic nerve, as well as functional changes of both nerve fibers and non-neuronal cells. Exposure to vibrating hand tools at work can lead to permanent nerve injury with structural neuronal changes in finger nerves as well as the nerve trunks just proximal to the wrist. The relationships between duration of exposure, vibration magnitude and nerve structural changes are still unknown. References Armstrong TJ, Castelli WA, Evans FG, Diaz-Perez R. Some Histological Changes in Carpal Tunnel Contents and Their Biomechanical Implications. J Occup Med 1984; 26(3):197-201. Bay BK, Sharkey NA, Szabo RM. Displacement and strain of the median nerve at the wrist. J Hand Surg 1997; 22A:621-627. Benstead TJ, Sangalang VE, Dyck PJ. Acute endothelial swelling is induced in endoneurial microvessels by ischemia. J Neurol Sci 1990; 99:37-49. Bergman S, Widerberg A, Danielsen N. Lundborg G, Dahlin LB. Nerve regeneration in nerve grats conditioned by vibration exposure. Restorative Neurol and Neurosci 1995; 7:165-169.

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--> Biological response of Nerves to Loading Table 2. Mean (S.D.) extraneural pressure within the carpal tunnel in patients and control subjects with the wrist moved passively to three postures. Pressures are reported in kPa.   Patients with Carpal Tunnel Syndrome Control Subjects   No. of wrists (subjects) Neutral Flexion Extension No. of wrists (subjects) Neutral Flexion Extension Gelberman et al. 198124,1 15 4.3 (0.5) 12.5 (4.5) 14.7 (2.9) 12 (12) 2.5 — — Werner et al. 1983 92,2 16 4.1 10.0 14.0 — — — — Szabo et al. 198981,3 22 ( 22) 1.3 4.3 (na) 6.8 (na)  6 ( 6) 0.7 (na) 2.1 (na) 3.6 (na) Okutsu et al. 198962,4 62 ( 46)1 5.7 (2.3) 25.6 (8.5) 29.6 (5.9) 162(16) 1.9 (1.3) 19.2 (8.8) 21.1 (8.7) Luchetti et al. 198936,5 30 ( 26) 5.9 (2.7) — —  4( 4) 2.0 (2.4) — — Rojviroj et al. 199068,6 61 ( 33) 1.6 (1.6) 3.6 (2.6) 4.4 (3.3) 16(32) 0.5 (0.3) 1.2 (0.8) 1.7 (0.9) Seradge et al. 199573,7,9 81 ( 72) 5.8 (4.3) 10.6 (5.3) 13.5 (6.8) 21 (21) 3.2 (2.1) 13.1 (9.2) 15.9 (10.0) Hamanaka et al. 199526,8 957 (647) 8.0 (4.2) — — 31 (31) 2.0 (1.4) — — 1 carpal tunnel syndrome: 11 male, 4 female, mean age 56 years; control: information not available 2 carpal tunnel syndrome: 1 male, 15 female, mean age 46 years 3 carpal tunnel syndrome: 6 male, 16 female, mean age 51 years; control: 6 male, mean age 32 years 4 carpal tunnel syndrome: 16 male, 30 female, mean age 51 years; control: 10 male, 6 female, mean age 36 years 5 carpal tunnel syndrome: 1 male, 25 female, mean age 51 years; control: 1 male, 3 female, mean age 48 years 6 carpal tunnel syndrome: 8 male, 25 female, mean age 46 years; control: 12 male, 4 female 7 carpal tunnel syndrome: 18 male, 54 female, mean age 46 years; control: 10 male, 11 female, age range 20 to 74 years 8 carpal tunnel syndrome: 253 male, 394 female, mean age 54 years; control: 19 male, 12 female, mean age 38 years 9 active wrist flexion and extension during pressure measurements