Overview

The purpose of this chapter is twofold. The first purpose is to develop the concept that the entire nervous system forms a continuous tissue tract. This concept is central to the idea that movements of the trunk and/or limbs can have a profound biomechanical and physiological impact on the peripheral nervous system (PNS) and central nervous system (CNS). Mobility of the nervous system and some of the responses of the system to movement in normal and sensitized states are discussed.

The second purpose of this chapter is to develop in the reader an understanding of neurovascular entrapment syndrome. This is an underrecognized impairment present in some patients with a wide variety of diagnoses—for example, nonspecific arm pain, repetitive strain injury, carpal tunnel syndrome, and thoracic outlet syndrome. Standard medical care frequently fails with these patients. A theoretical model for the development and perpetuation of neurovascular entrapment syndrome is presented. Background information regarding the syndrome is provided, and the appropriate screening tools for assessment of the impairment are discussed. Treatment suggestions and a case study are presented at the end of the chapter.

Peripheral neuroanatomy

The PNS is generally regarded as the portion of the nervous system that lies outside the CNS (i.e., the brain and spinal cord).^1,2 The major components of the PNS include motor, sensory, and autonomic neurons found in spinal, peripheral, and cranial nerves. Although this partitioning is valid from an anatomical perspective, it often leads to a lack of appreciation as to the truly continuous nature and integrative function of the nervous system as a whole. The concept that the entire nervous system is a continuous tissue tract reinforces the idea that limb and trunk movements can have a mechanical effect on the PNS and the CNS that is local and global.

The nervous system is composed of two functional tissue types. One type of tissue is concerned with impulse conduction. This functional category includes nerve cells and Schwann cells. The second functional tissue type provides support and protection of the conduction tissues—that is, the connective tissues.

Three levels in the organization of a peripheral nerve have been described^2,3 (Figure 18-1). At the innermost level the nerve fiber is the conducting component of a neuron (nerve cell). A connective tissue layer called the endoneurium surrounds each nerve fiber. The endoneurium surrounds the basement membrane of the neuron and plays an important role in maintaining fluid pressure within the endoneurial space. There are no lymphatic channels within the endoneurial space. The pressure within the endoneurial space increases with compression of the neuron.⁴

The second level of organization consists of a collection of many nerve fibers (a fascicle) surrounded by a layer of connective tissue called the perineurium.^2,3 The perineurium acts as a selective barrier to diffusion and as such exerts significant control over the local movement of fluid and ions. This connective tissue layer acts like a pressurized container—that is, extrusion of the contents occurs if the membrane is cut. The compartment enclosed by the perineurium does not contain lymphatic channels.⁴ This may be a problem during inflammatory states when edema is present deep to the perineurium. The perineurium is the last connective tissue layer to rupture in tensile testing of peripheral nerves.⁵ The outermost connective tissue layer of a peripheral nerve is called the epineurium. The epineurium surrounds, protects, and enhances gliding between the fascicles. Lymphatic channels are found within the epineurial compartment.

All three connective tissue layers are interconnected—they are not separate and distinct, but continuous tissue layers.^2,3 Each of the connective tissue layers contains free nerve endings from the nervi nervorum. As a result, all three connective tissue layers are a potential source of pain. In addition, all three layers are continuous with the homologous connective tissue layers of the CNS—for example, the dura mater and the epineurium.

The vascular supply for peripheral nerves is designed to provide uninterrupted blood flow regardless of the position of the trunk and limbs. Extrinsic vessels provide blood flow to segmental vessels that in turn supply an extensive intrinsic (intraneural) vasculature within the PNS. These segmental vessels branch off of the extrinsic vessels and enter peripheral nerves in areas of low nerve mobility relative to the surrounding tissue. The intrinsic vasculature supplies all three connective tissue layers within the PNS. Arterioles and venules are found in the epineurial and perineurial spaces, but only capillaries are found in the endoneurial compartment.

Peripheral nerves are regularly subjected to compression and elongation (stretching), which have been shown to increase intraneural pressure. An increase in intraneural pressure decreases the diameter of the intrinsic blood vessels and results in a reduction in blood flow within the nerve. Compressive forces of 20 to 30 mm Hg have been shown to adversely affect intraneural blood flow,⁶ and compressive forces of 50 to 70 mm Hg have been shown to result in complete arrest of blood flow⁷ and cause damage to myelin and axons.⁶ A strain (elongation) of 6% to 8% has been shown to decrease intraneural blood flow by 50% to 70% in the sciatic nerve of rats.^4,8,9 A strain of 15% in the sciatic nerve of a rabbit has been shown to result in complete arrest of blood flow,⁷ and the same strain produces an 80% reduction in blood flow in the rat sciatic nerve.⁹ Strains of 11% or greater are produced by some of the positions used in neurodynamic tests of the upper limb.⁶ Significant increases in intraneural pressure and concomitant decreases in intraneural blood flow have been shown to adversely affect neuronal conduction.^7,10,11

The cytoplasm in cells moves and has thixotropic properties—that is, the viscosity of cytoplasm is lower when it is continuously moving.⁴ In neurons the movement of the cytoplasm from the cell body through the axons (anterograde movement) occurs at two speeds. Fast axoplasmic flow occurs at a rate of about 100 to 400 mm/day and is used to carry ion channels and neurotransmitters (i.e., materials required for normal impulse conduction) to the nerve terminals. Slow axoplasmic flow occurs at a rate of about 6 mm/day and is used to transport cytoskeleton proteins, neurofilaments, and other materials used to maintain the physical health of the cell. A third flow occurs in the opposite direction (retrograde) at a rate of about 200 mm/day. Retrograde transport carries unused substances and exogenous materials taken up at the terminus—for example, neurotrophic factors. The material carried back to the cell body by retrograde transport has been shown to influence activity in the cell nucleus.⁴

Compression raises intraneural pressure, which has a negative impact on the flow of cytoplasm.⁴ Anterograde and retrograde flow of axoplasm is impaired with 30 mm Hg compression on the nerve, hypoxia, or a strain of 11% or greater.^12–14 Prolonged or intense exposure to compression can result in conduction abnormalities, endoneurial edema, fibrin deposition, demyelination, and axonal sprouting. Each of these events increases the likelihood of developing adhesions and abnormal impulse-generating sites (AIGSs).⁴ (The negative impact of AIGSs is discussed in the section on adaptive responses to pain.)

Mobility of the peripheral nervous system

Several types of tissues (e.g., bone, fascia, and muscle) surround peripheral nerves as they “travel” to target tissues. Peripheral nerves can be thought of as passing through a series of tissue tunnels composed of various biological materials. The composition of the tissue tunnel changes with the passage of the nerve from the vertebral column (an osseous tunnel) to the target tissue—for example, from an osseous tunnel to a soft tissue and/or fibro-osseous tunnel. A “mechanical interface” exists at the junction between the nerve and the material adjacent to the nerve that forms the tissue tunnel. Movement of the trunk and/or limbs can cause three types of movement to occur in the peripheral nerves: unfolding, sliding, and elongation.¹⁵

When there is little or no tension in a peripheral nerve, the axon typically contains undulations (folds). As tension is applied the axon will “unfold” so that the undulations disappear. “Sliding” can be defined as movement between the nerve and the surrounding tissues at the mechanical interface (extraneural movement). Sliding by itself does not cause significant elongation or tension to develop within the nerve, so intraneural pressure remains relatively unchanged. Ultrasound studies have shown that the median, ulnar, sciatic, and tibial nerves undergo extraneural movement (sliding) with movement of the upper and lower limbs, respectively.16–19

“Elongation” of the nerve occurs when tension is applied to a nerve and there is little or no unfolding and sliding at the mechanical interface. Elongation causes movement to occur between the neural elements and connective tissue layers (intraneural movement). Elongation decreases the diameter of the nerve, resulting in an increase in the intraneural tension and pressure.¹⁵ An increase in intraneural pressure has been shown to decrease the flow of blood and axoplasm, resulting in altered neural function (see previous section). Elongation within the median and ulnar nerves has been shown to occur with movements of the upper limb.⁶

Both extraneural and intraneural movements may occur simultaneously within a nerve, but they may not be uniformly distributed. When a body moves, some parts of the PNS will undergo primarily extraneural movement (sliding) with little or no development of tension while other areas undergo intraneural movement (elongation) that results in an increase in intraneural tension and pressure. As a consequence, some areas within a nerve slide, developing little or no tension, whereas other areas of the same nerve elongate significantly, increasing the amount of intraneural tension.⁶ In areas repeatedly exposed to high amounts of tension, for example, the median nerve at the wrist, the nerves are found to contain a higher-than-average amount of connective tissue.¹⁵

If one considers the entire nervous system as a continuous tissue tract, then the idea that movement and/or tension developed in one region of the nervous system can be distributed and dissipated throughout the entire nervous system becomes apparent.^20,21 The inability of a component within the nervous system to dissipate and/or distribute movement and tension can lead to abnormal force development and lesions elsewhere in the continuous tissue tract.²²

Peripheral nerve entrapment

Seddon’s classification of nerve injury is based upon mechanical trauma.²³ Schaumberg² modified this paradigm into an anatomically based scheme containing three classes of injury (Table 18-1). Injuries in class II and III are caused by macrotrauma that results in some disruption to the integrity of the nerve fiber. The following discussion of entrapment is focused on microtrauma in which there is no breach in the anatomical integrity of the nerve fiber (class I). Mechanical microtrauma resulting in nerve entrapment can occur with excessive or abnormal friction, compression, and/or tension (elongation).²

Tissue tunnels, peripheral nerves, and the mechanical interfaces between them are all vulnerable to mechanical microtrauma—that is, abnormal friction, compression, and/or tension.^2,15 Some peripheral nerves are exposed to bony hard interfaces, for example, the lower cords of the brachial plexus at the first rib, which are potential sources of abnormal friction. Inflammation and swelling within a tissue tunnel can produce compression of a nerve, for example, the median nerve within the carpal tunnel. The point at which a nerve branches limits the amount of gliding (extraneural movement) available at that location and increases the amount of local intraneural tension developed with movement, for example, the tibial nerve in the popliteal fossa.^2,15

Microtrauma can produce an intraneural lesion that causes a decrease in intraneural flow of blood and axoplasm, demyelination, and/or conduction defects.^2,15 If the lesion occurs in the connective tissues of the nerve, there may be pain, inflammation, proliferation of fibroblasts, and scar formation (fibrosis). Ultrasound studies have shown that the median nerve in patients with carpal tunnel syndrome is enlarged approximately 30%.²⁴ An intraneural scar decreases the compliance of the nerve and increases the amount of intraneural pressure and tension generated with elongation.²¹ Intraneural lesions can impair or completely block the ability of the nerve to conduct action potentials.^2,15,25 Partial or complete conduction blocks can result in abnormal sensation, loss of motor function, autonomic dysfunction, and atrophy of target tissue, for example, muscle and/or skin.

Microtrauma can produce an extraneural lesion.^2,15,21,25 The damage in an extraneural lesion occurs in the tissue surrounding the nerve or at the mechanical interface. Swelling within the tissue tunnel can produce compression of the nerve. Fibrosis can produce adhesions at the mechanical interface leading to a decrease in sliding of the nerve. A decrease in the ability of a nerve to slide within a tissue tunnel will result in an abnormal increase in intraneural tension and pressure as movement is imposed on the nerve. The increase in local intraneural tension can produce abnormal changes in the conduction of action potentials, and the tension will be distributed in an aberrant pattern throughout the continuous tract of the nervous system. The resultant abnormal distribution of tension predisposes the nervous system to the development of lesions at other sites.¹⁵

Friction, compression, and tension can produce microtrauma that results in intraneural and extraneural pathology.^2,15 For example, fibrosis can produce a combined pathological state that results in a substantial reduction in the ability of a nerve to slide within the tissue tunnel and a substantial increase in intraneural tension during nerve elongation as the compliance of the nerve is decreased. Movement of the median nerve at the carpal tunnel has been shown to occur with movements of the upper limb.^16–19 Longitudinal and transverse movements of the median nerve at the carpal tunnel have been shown to be reduced in the presence of microtrauma, that is, carpal tunnel syndrome,^24,26 nonspecific arm pain,^27,28 and whiplash injury.²⁸

Intraneural and extraneural lesions result in an abnormal distribution of sliding and tension throughout the nervous system with movement of the trunk and/or limbs. The abnormal distribution of tension within a nerve increases the probability of a second lesion or abnormality developing within the nerve. This situation led Upton and McComas²⁹ in 1973 to first use the term “double crush injury.” (This term should be considered a misnomer because a “crush” does not necessarily occur.) For example, entrapment of the median nerve at the carpal tunnel can cause the development of abnormal tension in cervical spinal nerves, resulting in a lesion at that site. Upton and McComas²⁹ have shown that a lesion at the carpal tunnel increases the risk of having a second neural lesion in the cervical region.

Pathogenesis of neurovascular entrapment

Neurovascular entrapment can occur at any point along the continuous tract of the nervous system. The carpal tunnel, a common site of entrapment, has been studied and provides a framework of information regarding the pathogenesis of neurovascular entrapments. Sunderland³⁰ has reasoned that a change in the normal pressure gradients within the carpal tunnel can lead to compression of the median nerve. In order to maintain homeostasis in the carpal tunnel and the median nerve, blood must flow into the tunnel, then into the nerve and back out of the tunnel. For normal blood flow to occur in the median nerve the blood pressure must be highest within the epineurial arterioles and becomes progressively lower in the capillaries and epineurial venules and lowest within the extraneural space of the carpal tunnel. Any increase in the pressure of a single compartment has the potential to disrupt the normal pressure gradients and impair the flow of blood within the compartments of the carpal tunnel and median nerve. Impaired intraneural blood flow can lead to localized hypoxia, edema, inflammation, and fibrosis.³⁰

An increase in pressure within the carpal tunnel can occur for a variety of reasons, for example, synovial hyperplasia, thickening of tendons, venous congestion, inflammation, and/or edema. Venous blood flow within a nerve will be impaired and venous stasis will develop if pressure within the extraneural space of the carpal tunnel becomes greater than the pressure within the epineurial venules. Because blood pressure within venules is relatively low, partial occlusion of blood flow can begin to occur with pressures as low as 20 to 30 mm Hg.^15,31

The pressure within the carpal tunnel is normally about 3 mm Hg with the wrist in a neutral position.⁴ The pressure can rise to over 30 mm Hg when the wrist is placed in 90 degrees of extension³² or with the functional task of using a computer mouse to drag or point at an object.³³ Studies have shown that the pressure within the carpal tunnel in someone with carpal tunnel syndrome can be 30 mm Hg, or more, with the wrist in neutral and can increase to about 100 mm Hg when the wrist is in 90 degrees of flexion^4,12,13 or extension.¹² Compressive forces of 20 to 30 mm Hg have been shown to adversely affect intraneural blood flow,⁶ whereas compressive forces of 50 to 70 mm Hg have been shown to result in complete arrest of blood flow⁷ and cause demonstrable damage to myelin and axons.⁶ Motor and sensory abnormalities begin to manifest at about 40 mm Hg, and complete blockade of the median nerve has been shown to occur at 50 mm Hg.³⁴ The pressure found in the carpal tunnel of people with carpal tunnel syndrome is clearly adequate to disrupt the normal flow of blood, axoplasm, and action potentials within the median nerve, causing severe impairment to normal nerve functions.

Sunderland³⁰ proposed that venous congestion or stasis within the carpal tunnel will lead to localized hypoxia, edema, and fibrosis. Hypoxia causes capillary endothelial cells to deteriorate and local C fibers to secrete substance P and calcitonin gene–related peptide,⁴ which in turn cause mast cells to release histamine and serotonin.^35,36 Together these chemical mediators augment the inflammatory state and cause the endothelial cells of capillaries to further deteriorate by becoming flatter, larger, and leakier, enhancing exudation and edema.

Deterioration of the capillary endothelium results in exudation and the formation of a protein-rich edema in the interstitial space. Protein-rich edema stimulates proliferation of fibroblasts, resulting in fibrosis, and intensifies the abnormal pressure gradients, resulting in more tissue hypoxia—that is, a positive feedback or self-perpetuating cycle of pathology is initiated. Intraneural fibrosis decreases compliance of the nerve, and extraneural fibrosis results in the formation of adhesions at the mechanical interface between the nerve and tissue tunnel. Fibrosis causes a nerve to become stiffer and less mobile, resulting in an abnormal increase in tension when movement is imposed on the nerve.

The set of circumstances described earlier may be referred to as a neurovascular entrapment syndrome, and it has the potential to cause the development of problems elsewhere in the system—that is, a double crush injury (see previous section). Upton and McComas²⁹ studied 115 subjects with carpal tunnel syndrome or ulnar impingement at the elbow. They found that 81 of the 115 subjects also had evidence of a neural lesion at the neck. Because all nerves essentially travel within tissue tunnels, the potential exists for this scenario to occur elsewhere in the continuous tissue tract of the nervous system, for example, the capsule of the dorsal root ganglion and the thoracic outlet.^5,15,37

Adaptive responses to pain

A thorough discussion of the pain associated with neurovascular entrapment is beyond the scope and intent of this chapter. The topic of pain management is discussed in Chapter 32 of this book. However, we would like to describe the development of hyperexcitable states and AIGSs in neurons as well as their role in the development of pain associated with neurovascular entrapment.

“Normal” or physiological pain occurs when peripheral nociceptors are subjected to a stimulus that is at or above the threshold for firing. “Abnormal” or pathological pain can occur when there is a change in the sensitivity (threshold) of the somatosensory system.³⁸ Devor³⁹ wrote that “the crucial pathophysiological process triggered by nerve injury is an increase in neuronal excitability.”

Neurons that become inflamed, hypoxic, and/or demyelinated can enter a hyperexcitable state.²,^39–47 A neuron in a hyperexcitable state can begin to discharge spontaneously and/or develop a sustained rhythmic discharge after stimulation. In addition, hyperexcitable neurons can develop mechanosensitivity,⁴¹ chemosensitivity,⁴ and/or thermal sensitivity,⁴⁵ all of which can result in the production of allodynia, a form of pathological pain.* These changes in the behavior of a nerve can occur in the absence of detectable degeneration.^40–42 The changes in impulse generation and neuronal sensitivity are characteristics of an AIGS.⁴ A hyperexcitable state and an AIGS can develop with the mechanical microtrauma and inflammation often associated with peripheral nerve pathology, for example, compression, tension, and friction.^2,39,48,49 A variety of chemical mediators have been implicated in the development of a hyperexcitable state in a neuron—for example, neurotrophins,^50,51 histamine,⁵² and other inflammatory mediators,⁵³ which are thought to act through changes in gene expression,^45,50,51 changes in voltage gated sodium channel expression,⁴⁵ and a reduction in anterograde axoplasmic transport.^44,52

The dorsal root ganglion appears to play a significant role in the pain associated with peripheral nerve pathology.^38,41 Mechanical microtrauma to and inflammation of peripheral nerves can cause the dorsal root ganglion to become hyperexcitable (sensitized).⁴¹ The change in sensitivity allows what were weak, subthreshold stimuli to evoke pain and suprathreshold stimuli to evoke exaggerated pain (hyperalgesia). In addition, the dorsal root ganglion can develop mechanosensitivity, chemosensitivity, and thermal sensitivity, resulting in allodynia.⁴⁵ This change in sensitivity reflects a change in the physiology of the nerve and may be a component in the development of enhanced central sensitivity to pain and development of a chronic pain state.³⁸

As noted previously, the PNS and CNS represent a continuous tissue tract. The pain and symptoms associated with musculoskeletal injury and/or peripheral nerve pathology can include changes that are the result of an alteration in the autonomic nervous system, which is considered part of the continuous tissue tract of the nervous system.^2,54 For example, catecholamines do not normally elicit pain. However, if a nerve is injured or if there is local inflammation, the catecholamines can induce pain (chemosensitivity) and they can maintain or enhance pain in inflamed tissues.⁴

Some patients who are treated for musculoskeletal injuries have signs that may be related to autonomic dysreflexia.³⁷ Wyke⁵⁵ demonstrated that stimulation of nociceptors in spinal joints resulted in reflex changes in the cardiovascular, respiratory, and endocrine systems. Dysregulated breathing has been documented in patients with chronic pain.⁵⁶ Patients with nonspecific arm pain have a reduced sympathetic vasoconstrictor response in the hand of the affected limb.⁵⁷ Thermal asymmetry has been documented in the hands of patients with neurogenic thoracic outlet syndrome.⁵⁸ Feinstein^59,60 has shown that injecting saline solution into the thoracic paraspinal muscles caused pallor, diaphoresis, bradycardia, and a drop in the blood pressure. These cardiovascular and respiratory changes are often associated with an alteration in the output from the autonomic nervous system.^37,54,61

In patients with cumulative trauma disorder (CTD), signs of abnormal autonomic nervous system output can include (1) vasomotor reflexes leading to cool, pale skin,⁵⁷ (2) changes in the pattern of sweating (hypohidrosis and/or hyperhidrosis), (3) trophic changes in the skin, (4) hyperactive flexor withdrawal reflexes, and/or (5) paradoxical breathing patterns.³⁷ Edgelow has described paradoxical breathing as the predominant use of the scalene muscles for ventilation during quiet breathing versus normal ventilation, which is predominantly a function of the diaphragm.³⁷