Normal pressure in the Carpal tunnel ranges from 2 to 10 mmHg [23]. Changes in the wrist position or application of external forces can lead to increased pressure resulting in nerve entrapment and injury. It is not completely clear how the carpal tunnel pressure rises over time and as a result of wrist position. Within the carpal tunnel, pressure can be exerted on the median nerve both as a result of the hydrostatic pressure of the carpal tunnel interstitial fluid and as a result of direct contact between the median nerve and adjacent tissues [5]. The hydrostatic pressure may become elevated over time due to a combination of synovial tissue hypertrophy and the space constraint of the carpal tunnel [12]. Cadaver studies have shown that the most significant hypertrophy of the synovial tissue occurs at the entrance and exit of the carpal canal, where the tendons slide over the flexor retinaculum, using it as a pivot [24]. As wrist position changes, the hydrostatic pressure in the carpal tunnel is altered significantly; wrist extension causes a tenfold rise in the pressure, while wrist flexion results in an eightfold rise in the pressure [11, 12].

Extension of the wrist causes the compression of the extensor retinaculum on the dorsal side and an increase in spacing of the volar carpal ligament on the volar side. This increase in spacing causes the volar carpal ligament to squeeze against the volar surface of the carpal bones causing an increase in the pressure in the carpal tunnel. In wrist flexion, the flexor retinaculum presses the flexor tendons and the bursa against the head of the radius. This results in an increase in fluid pressure. In addition to the fluid pressure, the movement of flexor tendons causes friction affecting the median nerve [5].

The musculature surrounding the carpal tunnel is also known to play a role in increasing the pressure and causing entrapment of the median nerve. The lumbrical muscles, which are four small intrinsic muscles, are involved in intricate movements of the fingers. The lumbricals originate proximally from the flexor digitorum profundus and attach distally to the extensor expansions . Several reports have shown that the proximal attachments of the lumbrical muscles can be varied. Thus, if the lumbrical muscles originate closer to the transverse carpal ligament, their hypertrophy due to repetitive movement of the fingers can result in increased pressure in the carpal tunnel [25].

The palmaris longus is a weak wrist flexor muscle that is not present in a large minority of the human population. It has been hypothesized that the presence of a palmaris longus tendon may be an independent risk factor for the development of carpal tunnel syndrome [26]. Jafari et al. [27]found a statistically significant association between the development of carpal tunnel syndrome and the presence of a palmaris longus tendon. The shape and volume of the carpal tunnel might be affected by the presence of the palmaris longus, most notably when the wrist is extended under load [28]. It has been shown by a biomechanical study that the carpal canal fluid pressure is elevated by palmaris longus loading more than by any other tendon that passes through the carpal tunnel, provided that the palmaris longus is loaded beyond 20° of extension. When extended, the palmaris longus vector pulls the transverse carpal ligament in the direction of the median nerve (Fig. 3.2). The insertion of the palmaris longus into the palmar fascia that overlies the carpal tunnel likely exerts a pressure effect on the carpal tunnel, resulting in a predisposition to carpal tunnel syndrome [29].

Compression of the median nerve , due to mechanical forces, results in its demyelination ([30]; Fig. 3.3). In order for a focal demyelination to occur, pressure more than the systolic is required [23]. The demyelination not only occurs at the particular spot but also spreads to entire internodal segment. This results in a block of nerve transmission called neuropraxia.

Persistent compression can lead to a decrease in blood flow to the surrounding endoneurial capillary system and changes in the blood-nerve barrier and endoneurial edema ([30]; Fig. 3.3). Decreased blood flow causes local ischemia and metabolite changes, whereas breach in the blood-nerve barrier can cause infiltration of inflammatory cells and proteins that can result in endoneurial edema. These factors can ultimately cause neuritis and result in axonal degeneration [23].

The median nerve moves up to 9.6 mm during wrist flexion and slightly less during extension [31]. Nerve movement is crucial for normal physical activity; if nerve gliding is impaired, pain or discomfort may result [13]. Nerve gliding prevents nerves from sustaining injury due to excessive stretch during joint movement and is dependent upon the extensibility of the layers of connective tissue that surround the nerve fibers, namely, the endoneurium, mesoneurium, perineurium, and epineurium [32]. When the median nerve is chronically compressed, fibrosis occurs, resulting in the inhibition of nerve gliding. This causes injury to the mesoneurium and subsequent formation of scar tissue. Mesoneural scarring results in the median nerve adhering to surrounding tissue and leading to traction of the median nerve during wrist motion as the median nerve attempts to glide from this immobilized position [33]. The tethered median nerve stress test (TMNST) is based on this and may be useful for the diagnosis of chronic low-grade carpal tunnel syndrome [34].

Arendt-Neisen et al. [35] attempted to measure the involvement of thin afferent nerves (which transmit pain signals) in carpal tunnel syndrome patients. They showed that the threshold of pain was increased in the third digit (innervated by the median nerve) as compared to the threshold of pain in the fifth digit (innervated by the ulnar nerve) in patients with carpal tunnel syndrome but not in controls, suggesting that small fibers are injured in carpal tunnel syndrome [5].

Small unmyelinated C fibers are also shown to be responsible for the various symptoms of the carpal tunnel syndrome. The transmission of pain signals through the unmyelinated C fibers is modulated via voltage-gated sodium channels (VGSC). Damaged C fibers cause an abnormal expression of VGSC that result in exaggerated ectopic responses to stimuli. These spontaneous firings result in a sensation of pain [36].

In the CNS , there is a highly selective semipermeable barrier formed by capillary endothelial cells connected to each other by tight junctions. It effectively separates the blood in the capillaries of the CNS from the CNS interstitial fluid. It allows certain substances, such as water, gases, and hydrophobic molecules to enter the interstitial fluid, along with other compounds essential for neuron survival such as glucose and amino acids. However, it prevents most other substances (including most pharmacological therapeutic agents) from entering the interstitial fluid of the CNS, thus providing a protective function preventing potentially toxic substances from entering and damaging the vital CNS .

Similarly, there is a “blood-nerve barrier ,” formed by the inner cells of the perineurium and the tight junctions of the endothelial cells of the endoneurial microvessels that branch off the radial and ulnar arteries proximal to the flexor retinaculum, regulating the intraneural environment and providing immunologic protection for the median nerve as it passes through the carpal tunnel. When nerve injury occurs, the blood-nerve barrier can break down at the level of the microvessels, resulting in an elevation of the intrafascicular pressure. Since there is no lymphatic circulation in the endoneurial space, edema can result subsequently, interfering with the microcirculation in the nerve fascicles [37]. Leaking capillaries in the endoneurium eventually allow proteins and fluid to enter the area and accumulate. This may cause a “mini compartment syndrome ” of sorts as the pressure increases in the endoneurial space; eventually local ischemic damage to the nerve may occur [13]. The risk of blood-nerve barrier injury is especially high in patients with pre-existing vascular conditions or prolonged exposure to static loading [23].

Gelberman et al. [10] demonstrated that the symptoms of carpal tunnel syndrome improve quickly following surgical carpal tunnel release, thereby implicating ischemic injury as an important component in carpal tunnel syndrome. Ischemic injury combined with an increase in mechanical contact pressure over time effects changes in the nerve fiber myelin sheath and causes axonal injury, which may be detected using neurophysiologic testing like standard nerve conduction studies (NCS) [5]. However, in the absence of focal contact pressure, ischemia injures the axons but does not injure the myelin [14, 38]. In the early stages of focal ischemia, physiological impairment of nerves occurs in the absence of histological changes [38]. In the early stages of compression, venous outflow is obstructed. Therefore, the nerve becomes hyperemic and edematous; this might have particular importance in carpal tunnel syndrome pathogenesis. Sunderland [39] hypothesized that external pressure leads to a decrease in venous return. This would lead to the pressure rising in the area of entrapment as blood accumulates, ultimately leading to a blockage of flow in the vasa nervorum and leading to ischemia. Ischemic damage in compression neuropathies begins with elevated intrafunicular pressure, followed by capillary injury resulting in leakage and therefore edema, and finally results in blockage of arterial flow [5]. Lundborg et al. [40] showed that externally compressing the carpal canal causes the pressure inside the carpal canal to be elevated. When external pressure was applied to the carpal canal, subjects reported paresthesia-like symptoms followed by neurophysiologic changes; these symptoms and neurophysiologic abnormalities (attributed to conduction block) disappeared as soon as the external pressure was removed. However, if a blood pressure cuff on the upper arm was inflated to or above arterial pressure, the symptoms and neurophysiologic changes remained even after release of the compressive force on the carpal tunnel. Therefore, Lundborg et al. showed that ischemia, as opposed to mechanical deformation , was the primary cause of nerve fiber functional deterioration under pressure [5, 40].

When carpal tunnel syndrome was first described, tenosynovitis was considered to be an important cause [5]. Repetitive motion of the hand may result in inflammation or hypertrophy of the synovial lining of the tendons that run through the carpal tunnel with the median nerve [12, 24]. This may contribute to median nerve compression [3, 41]. Hirata, H et al. showed that levels of interleukin-6 (IL-6), prostaglandin E-2 (PGE₂), and vascular endothelial growth factor (VEGF) were increased in CTS patients (2004). IL-6, PGE2, and VEGF are known to stimulate fibrogenesis (Meager 1986). Therefore, upregulation of these factors causes an increase in fibroblast density, type III collagen, and vascular proliferation [42]. These changes cause the total tissue volume in the carpal canal to increase thereby causing an increase in the baseline and mechanical pressures in the carpal tunnel [5].

Altinok and Karakas [43] found a very strong correlation between age and bowing of the flexor retinaculum, the connective tissue sheath covering the carpal tunnel. Since Sarria et al. [44] suggested that bowing of the flexor retinaculum could be used as a diagnostic criterion for carpal tunnel syndrome, it is possible that age-related changes in the flexor retinaculum may be involved in the etiology of carpal tunnel syndrome. The mechanism behind age-related changes in the flexor retinaculum is unclear. They might be explained by an increase in the volume of the carpal tunnel in older people, although the mechanism of this is also unclear [45]. The presence of the carpal bones on the dorsal side of the carpal tunnel might prevent the contents of the carpal tunnel from extending dorsally, causing the flexor retinaculum to be pushed out by the enlargement of the tunnel contents. Another possibility is age-related laxity of the flexor retinaculum, which, if true, may itself cause an increase in the tunnel’s volume [43]. It is possible that age-related collagen changes in the flexor retinaculum might cause the elasticity thereof to be decreased as individuals age. As a result, flexor retinaculum in older patients would be less likely to accommodate volume changes without increasing the pressure. This would therefore mean that any increase in the volume of the carpal tunnel contents in older patients would be more likely to cause the pressure in the carpal tunnel to increase than in younger patients, thereby making older patients more susceptible to carpal tunnel syndrome.

Women have a two- to threefold higher risk of developing carpal tunnel syndrome than men [46]; their risk is especially elevated around menopause. Therefore, it is suspected that female hormones may play a role in the high incidence of carpal tunnel syndrome in women [47]. This is further supported by the fact that the development of carpal tunnel syndrome has been reported to be linked to a large number of pregnancies [48], early menopause [49], bilateral oophorectomy [50], use of oral contraceptives [51], aromatase inhibitors [52], and hormone replacement therapy [51]. Additionally, it has been reported that estrogen receptor alpha is present in the transverse carpal ligament and in the flexor tenosynovium [53], and it has been demonstrated that the upregulation of estrogen receptors in tenosynovial tissue is associated with carpal tunnel syndrome in postmenopausal women [54]. It is known that estrogen regulates collagen synthesis and fibroblast proliferation [55]. When the collagen composition of tenosynovial tissue is altered, tissue compliance changes. This elevates the risk of shear injury of the tenosynovial tissue by the flexor tendons during finger motion [56]. It has been reported that estrogen receptors alpha and beta in the fibroblasts and synovial lining cells of the tenosynovium have higher immunoreactivities in patients with carpal tunnel syndrome than in controls. This could explain the relationship between female hormones and carpal tunnel syndrome pathogenesis. On the other hand, no correlation was seen between symptom severity and estrogen receptor expression in tenosynovial tissue [54].

A strong association exists between carpal tunnel syndrome and female gender; this has been proposed to be due to their smaller wrist and hand size [57]. Chiotis et al. [58] found that patients with carpal tunnel syndrome had larger carpal tunnel cross-sectional areas than those without carpal tunnel syndrome. They showed that a more circular carpal canal was linked to the development of carpal tunnel syndrome and suggested that a more circular carpal canal may somehow change the effect of elevated carpal canal pressure on the median nerve. It was found that in carpal tunnel syndrome patients, the contents of the tunnel took up a greater percentage of the tunnel’s cross-sectional area than in those who do not have carpal tunnel syndrome, implying that carpal tunnel syndrome patients have “more” contents in the carpal tunnel than patients without carpal tunnel syndrome; this would fit with a higher pressure [59]. Sassi and Giddins [60] found that the relative cross-sectional area of the carpal tunnel in women is significantly smaller than in men. This means that while women have smaller carpal tunnels than men just because they have smaller hands, their carpal tunnels are actually disproportionately smaller than men’s even taking into account their smaller hands [60]. This suggests that carpal canal size may have importance in the development of carpal tunnel syndrome.

Multiple studies have shown that genetic factors play a major role in the development and risk of carpal tunnel syndrome [61–63]. It has been hypothesized that pathology of the flexor tendons and the subsynovial connective tissue play a role in the development of carpal tunnel syndrome [64, 65]. This is supported by the fact that sequence variants in the gene that codes for the alpha-1 chain of type V collagen, a part of the collagen fibril, the basic structural unit of tendons, have been demonstrated to affect risk of developing carpal tunnel syndrome [66]. Sequence variants in other collagen genes have also been shown to increase the risk of developing carpal tunnel syndrome [67]. A certain allele has been shown to be associated both with carpal tunnel syndrome [67] and with increased degradation of mRNA’s encoding the alpha-1 chain of type XI collagen [68]. This suggests that decreased alpha-1 chain production, and therefore decreased type XI collagen synthesis, may be involved in the development of carpal tunnel syndrome [69]. Since types V and XI collagen both regulate the assembly and diameter of collagen fibrils, variation in the genes that encode them might change the mechanical properties of tendons and other extracellular structures in the carpal tunnel, which may be implicated in the development of carpal tunnel syndrome. Another allele variant was found to be significantly associated with increased risk of carpal tunnel syndrome in females [67].

Additionally, a certain genotype of an interleukin-6 receptor gene was found to be independently associated with reduced risk of carpal tunnel syndrome, while other genotypes of the same gene were found to be associated with elevated risk of developing carpal tunnel syndrome. Certain variants of interleukin-1-beta and interleukin-6 genes were found to interact with the aforementioned interleukin-6 receptor gene to modulate the risk of developing carpal tunnel syndrome. This therefore suggests that the risk of developing carpal tunnel syndrome is associated partly by gene-gene interactions in cytokine signaling cascade. A certain allele of a regulatory interleukin-6 DNA sequence variant was found to be associated with elevated risk of developing carpal tunnel syndrome ([61]; Fig. 3.4). This allele is associated with decreased interleukin-6 expression , leading to low plasma interleukin-6 levels, and is hypothesized to lead to decreased tenocyte apoptosis ([70]; Fig. 3.5).

Numerous studies have indicated that carpal tunnel syndrome tends to run within families [71–77]. This trend is associated with a variety of defects, ranging from systemic biochemical anomalies to heritable structural aberrations of the carpal tunnel itself [78]. Biochemical alterations associated with familial carpal tunnel syndrome include various point mutations that yield transthyretin variants, resulting in familial amyloidosis polyneuropathy [76, 77]. Systemic disorders associated with the development of carpal tunnel syndrome include inheritable myopathies [71] and familial hypercholesterolemia [74]. One often reported structural aberration associated with familial carpal tunnel syndrome is a thickening of the transverse carpal ligament [72]; this includes one report of a median nerve aplasia distal but not proximal to a thickened transverse carpal ligament in a child with three immediate family members having the same abnormality [75]. Congenitally small carpal tunnel, distal prolongation of the superficial flexor muscle bellies, anomalous muscles, and anomalous paths of the medial artery and median nerve branches are some structural alterations associated with familial carpal tunnel syndrome [73]. There is quite a bit of disagreement over whether or not carpal tunnel syndrome is inheritable [78]. Tanzer [79] described carpal tunnel as a “familial trait” in 18% of surgical patients. Phalen [3] concluded that “there is probably some familial predisposition to carpal tunnel syndrome.” Danta [72] reported that children with carpal tunnel syndrome often had a family member with the same symptoms as the child (Table 3.1). While Stevens et al. [48] failed to find a familial trend in carpal tunnel syndrome, Radecki [80] demonstrated an increased incidence of family occurrence in carpal tunnel syndrome patients. Alford et al. [78] found a high incidence of familial carpal tunnel syndrome in patients with bilateral carpal tunnel syndrome, which may suggest either a systemic biochemical anomaly or a heritable anatomical variation in the size of the carpal tunnel or the size of its contents. However, they were unable to rule out environmental factors as a cause of familial carpal tunnel syndrome [78].

Obesity , as measured by increased BMI (body mass index), has been associated with increased risk and increased severity of carpal tunnel syndrome ([81]; Table 3.2). Kouyoumdjian et al. [85] found that higher BMI increases the risk of developing carpal tunnel syndrome, but is not correlated with the severity thereof. Werner et al. [83] showed that patients with BMI greater than 29 had a risk of carpal tunnel syndrome that was 2.5 times higher than the risk for slender individuals (BMI < 20). Dieck and Kelsey [82] identified recent weight gain as a possible risk factor for carpal tunnel syndrome; this supports the idea that fluid retention in the soft tissues of the carpal tunnel somehow contributes to the development of carpal tunnel syndrome. It has been suggested that individual characteristics such as BMI, age, wrist dimensions, and hand dominance are more important in determining one’s risk of developing carpal tunnel syndrome than work-related factors. In fact, it was found that BMI can be used to accurately predict which industrial workers would develop median nerve slowing [86]. Radecki [87] demonstrated that prolongation of median latencies was associated with increased BMI regardless of whether or not the symptoms were considered work related. The exact pathophysiology behind this result is still not well understood. It has been suggested that the cause-effect relationship between increased BMI and the development of carpal tunnel syndrome could be due to an increase in the amount of fatty tissue present inside the carpal canal or due to elevated fluid pressure in the carpal canal in obese individuals [83]. Radecki [87] stated that individuals with increased BMI have increased translocated blood volume from the legs after lying down. This extra volume must go somewhere other than the thorax; if it goes into the arms, an elevated blood volume in the arms while lying down would cause the veins of the flexor synovial tissue and cause tissue pressure in the carpal tunnel to become elevated. Such synovial engorgement explains both the noninflammatory edema and elevated mean tissue pressures above critical pressure in the carpal tunnels of patients who have carpal tunnel surgery. Sustained increase in the carpal tunnel hydrostatic pressure can result in impaired blood circulation resulting in ischemia, local demyelination, and axonal loss. In addition, the sustained pressure can result in fibrosis and thickening of the subsynovial connective tissue and canal [88]. Furthermore, obesity is one of the components of metabolic syndromes that can result in peripheral neuropathy. Mechanisms by which obesity and metabolic syndrome can cause nerve injury include fatty deposits in the nerves, oxidative stress, mitochondrial dysfunction, and glycation of extracellular proteins. Neuropathy causes the median nerve to be more vulnerable to compression within the carpal tunnel [89].