Carpal tunnel syndrome: Pathophysiology and risk factors

INTRODUCTION — Carpal tunnel syndrome (CTS) refers to the complex of symptoms and signs brought on by compression of the median nerve as it travels through the carpal tunnel. Patients commonly experience pain, paresthesia, and, less commonly, weakness in the median nerve distribution. CTS is the most frequent compressive focal mononeuropathy seen in clinical practice.

This topic will review the anatomy, pathophysiology, epidemiology, and risk factors associated with CTS. Other aspects of CTS are discussed separately.

●(See "Carpal tunnel syndrome: Clinical manifestations and diagnosis".)

●(See "Carpal tunnel syndrome: Treatment and prognosis".)

●(See "Surgery for carpal tunnel syndrome".)

ANATOMY — The peripheral nerve pathway that leads to the median nerve in the carpal tunnel begins at the cervical spine. Understanding the nerve contributions leading to the median nerve is important to help discriminate symptoms attributed to the carpal tunnel from more proximal symptoms.

Median nerve

●Cervical nerve root origins – The nerve fibers that are destined to comprise the median nerve exit the spine at the C6, C7, C8, and T1 nerve roots (figure 1). Roots C6 and C7 supply the median fibers that provide sensation to the thenar eminence and the first three and a half digits of the hand. Roots C8 and T1 supply the motor fibers to the muscles of the forearm and hand that are innervated by the median nerve.

●Brachial plexus contributions – The nerve fibers that are destined to comprise the median nerve travel in the upper, middle, and lower trunks of the brachial plexus (figure 1). These fibers will then pass through the lateral and medial cords of the brachial plexus and combine to form the median nerve.

●Median nerve in the arm – The median nerve emerges from the brachial plexus in the upper arm. As the median nerve passes through the antecubital fossa region, it lies adjacent to the brachial artery on the medial side before passing more deeply within the forearm.

In the upper portion of the forearm, the median nerve innervates four muscles (the pronator teres, flexor carpi radialis, palmaris longus, and the flexor digitorum superficialis).

The anterior interosseous nerve arises in the forearm as a peripheral nerve branch of the median nerve. The anterior interosseous nerve innervates pronator quadratus, flexor pollicis longus, and the lateral aspects of the flexor digitorum profundus I and II muscles.

The median nerve proper runs parallel to the anterior interosseous nerve in the forearm. In the region proximal to the wrist, the palmar cutaneous sensory branch of the median nerve provides sensation to the lateral half of the palm.

●Traversing the carpal tunnel – As the median nerve crosses the wrist, it passes through the carpal tunnel along with nine flexor muscle tendons (figure 2 and figure 3). Inflammation and compression of the median nerve most commonly occurs within the carpal tunnel. Rarely, median entrapment can also occur more proximally in the region of the elbow or just distal to the elbow. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis", section on 'Differential diagnosis'.)

●Innervation of the hand – Upon exiting the carpal tunnel, the median nerve provides motor and sensory innervation to the hand. The muscles of the hand that are innervated by the median nerve are the abductor pollicis brevis, the flexor pollicis brevis (superficial head), the opponens pollicis, and the first and second lumbricals. Weakness of these muscles may occur in patients with severe or longstanding CTS, but the lumbricals are sometimes spared.

Sensory change (pain or numbness) involving the thenar eminence is typically not reported in CTS because the palmar cutaneous branch of the median nerve passes over, rather than through, the carpal tunnel. The pattern of sensory innervation of the median nerve is demonstrated in the figure (figure 4).

●Variations – Variations in the peripheral pathway of the median nerve can result in anomalous innervations in the arm and hand. These variations can make the diagnosis of CTS more challenging [1]. Anomalous innervations are relatively common and may require detailed neurodiagnostic testing to identify. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis", section on 'Electrodiagnostic testing'.)

•Connections between the median nerve fibers in the forearm with the ulnar nerve (Martin–Gruber anastomosis) may result in ulnar innervation of hand muscles typically supplied by the median nerve. This may be found in up to approximately 40 percent of patients in anatomic studies [2,3].

•The connection between the recurrent branch of the median nerve in the hand with the deep branch of the ulnar nerve (Riche–Cannieu anastomosis) can result in ulnar innervation of thenar hand muscles typically supplied by median nerve [4,5]. It has been reported in more than 50 percent of patients [6].

•Connection between sensory branches of the median and ulnar nerves in the hand (Berrettini anastomosis) may result in sensory abnormalities from the median nerve extending to hypothenar regions typically supplied by ulnar branches [4,7].

•Other less common variations, including anastomoses resulting from aberrant reinnervation after injury, have also been described [4,8].

Carpal tunnel — The carpal tunnel is formed by the transverse carpal ligament (flexor retinaculum) superiorly with the carpal bones inferiorly (figure 2) [9]. The median nerve, accompanied by the nine flexor tendons of the forearm musculature, must pass through this anatomic tunnel (figure 3) [9-11]. Compression of the median nerve leads to ischemia and mechanical disruption.

PATHOPHYSIOLOGY — The pathophysiology of CTS is multifactorial. Increased pressure in the intracarpal canal plays a key role in the development of clinical CTS [12]. While the precise etiology of increased carpal tunnel pressure in CTS is uncertain, experimental evidence suggests that anatomic compression and inflammation are contributing mechanisms.

●Anatomic compression – Increased pressure in the carpal tunnel can injure the nerve directly, impair axonal transport, or compress vessels in the perineurium and cause median nerve ischemia [13].

Anatomic compression of the median nerve may result from increased volume of other components of the carpal tunnel. This includes any of the nine flexor tendons, which pass through the carpal tunnel alongside the median nerve. Fibrosis of the subsynovial connective tissue that surrounds the flexor tendons may also be a source of compression [12]. Other possible causes include congenitally small anatomic space, mass lesions (such as a cyst, neoplasm, or persistent median artery), and edema or inflammatory conditions that result from systemic illness such as rheumatoid arthritis. (See 'Medical conditions and medications' below.)

Upper extremity posture also influences carpal tunnel pressure. The lowest carpal tunnel pressure is seen when the wrist is in a neutral or slightly flexed position, and it increases proportionately with deviation from this posture [10,14-17].

●Inflammation – Compression at the carpal tunnel may lead to endoneurial edema from venous congestion and inflammation following injury to the endoneurial capillary system [18]. Pathologic analysis of nerve compression has revealed edema and thickening of vessel walls within the endoneurium and perineurium, synovial fibrosis and vascular proliferation, myelin thinning, and subsequent nerve fiber degeneration followed by regeneration [10,19,20]. These factors may also account for surgical reports of an "hour glass"–shaped deformity of the median nerve in the region of the carpal tunnel [12]. This deformity may reflect relative thinning of the nerve beneath the transverse carpal tunnel ligament and swelling of the nerve in more distal and proximal segments [12].

There is some evidence that vascular proliferation and fibrosis are associated with increased expression of prostaglandin E2 and vascular endothelial growth factor [12]. However, the precise role of these factors in CTS is uncertain.

EPIDEMIOLOGY — CTS is a common disorder among adults. The estimated annual incidence of CTS per 1000 person-years ranges from 2.2 to 5.4 for females and 1.1 to 3 for males [21-23]. Among children, CTS is rare [24,25], though its incidence is unknown.

Depending on diagnostic criteria used, the estimated prevalence of CTS in the general population is 1 to 5 percent [23,26,27]. CTS is more frequent in females (0.7 to 9.2 percent) than in males (0.4 to 2.1 percent) [23,26,28-30]. The female-to-male ratio for CTS prevalence is approximately 3:1 [23,26,29,31]. The prevalence of CTS appears to be higher for older patients and those with higher a body mass index (BMI) [26,32].

The prevalence of CTS appears to be highest for females with a BMI >29 and lowest in males with a BMI <25 [33].

For unclear reasons, studies of American workers consistently report higher risk estimates of CTS than studies published elsewhere [34].

RISK FACTORS — Genetic susceptibilities, several medical conditions, and environmental risk factors have been associated with CTS.

Sex and genetic factors

Female sex — Most studies have reported a female predominance in the frequency of CTS. (See 'Epidemiology' above.)

One possible explanation for the female predominance is anatomic. The cross-sectional area of the proximal carpal tunnel is generally smaller in females than in males. In addition, females with CTS have been found to have smaller cross-sectional areas than female subjects without CTS [10].

Genetic predisposition — Limited data suggest that some patients may have a genetic susceptibility to CTS. A twin study found that up to one half of the liability for CTS in female patients was genetic [35]. In addition, patients with bilateral CTS are more likely to have a family history of CTS than patients with unilateral or no disease [36]. This may reflect an inherited liability for nerve injury or may be due to an inherited anatomic variability in the size of the carpal tunnel. Alternatively, this observation may reflect a shared familial predisposition to other medical conditions (ie, diabetes) or some undefined predisposing factor.

Hereditary neuropathy with liability to pressure palsy (HNPP) is a recurrent, episodic demyelinating neuropathy. Affected patients with HNPP typically present with isolated nerve palsies, including CTS. The most frequently affected nerves are those at common sites of trauma or entrapment and include the axillary, median, radial, ulnar, peroneal, or brachial plexus nerves. Single nerve palsies typically appear sequentially, resolving in days to months. (See "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Hereditary neuropathy with liability to pressure palsy'.)

Medical conditions and medications

Diabetes mellitus — The frequency of CTS in patients with diabetes is higher than the general population [37-39]. In a meta-analysis of 18 observational studies, both type 1 and type 2 diabetes mellitus were associated with CTS (pooled odds ratio 1.69, 95% CI 1.45-1.96) [40].

Patients with diabetic polyneuropathy (DPN) may have a higher risk of CTS than patients without DPN. In a cohort of nearly 70,000 patients from Korea with diabetes mellitus, DPN was associated with increased risk of CTS (hazard ratio 1.33, 95% CI 1.12-1.58) [41]. However, other studies have failed to find this association [42].

Arthritis — Osteoarthritis and rheumatoid arthritis (RA) may lead to anatomic compression of the carpal tunnel and are risk factors for CTS [39,43-45]. In a Finnish study of more than 6000 patients, those with osteoarthritis of the hand were more than twice as likely to have CTS as those without [23]. Similarly, in a small study of 100 patients with RA, the frequency of CTS was more than three times higher than matched controls but was not related to the severity of disease activity [46].

Obesity — Obesity, usually defined as body mass index >30, is a probable risk factor for median neuropathy at the wrist and for symptomatic CTS [27,32,33,47-51]. However, not all studies support the relationship [35].

Thyroid disease — Hypothyroidism contributes to the development of CTS by increasing peripheral tissue edema [39]. In a 2014 meta-analysis of five studies that controlled for potential confounders, hypothyroidism was associated with CTS (effect size 1.44, 95% CI 1.27-1.63) [52].

Pregnancy — Pregnancy has been established as a risk factor for CTS [53]. Patients may frequently report symptoms in the third trimester, but a retrospective study of 91 pregnant patients found that more than 90 percent were diagnosed with CTS in the first or second trimester [54]. In most cases, they gradually resolve over a period of weeks to months after delivery; however, symptoms can be prolonged for several months in patients who are breastfeeding [55]. In one series of 37 patients followed prospectively from near term to approximately 12 months after delivery, symptoms remained in 46 percent and were more common in patients with early onset of disease [56].

The true prevalence is unknown because symptoms may be underreported or diagnosed on clinical grounds alone [57]. In one large series, pregnancy accounted for 7 percent of cases of CTS in females between the ages of 15 and 44 [58]. In a systemic review, the incidence of CTS associated with pregnancy ranged from 7 to 43 percent and persisted after three years in 30 percent of patients [59]. Weight gain and comorbid conditions such as diabetes mellitus have been associated with the risk of CTS in pregnancy [60]. Accumulation of fluid is the likely etiology of CTS in pregnant patients [53]. This was demonstrated by a study of 76 pregnant patients with symptoms suggestive of CTS: 43 percent had abnormal nerve conduction studies of their carpal tunnel, and these patients were more likely to have edema than patients with normal studies [53].

Trauma — The median nerve may be injured with trauma at the wrist, including crush injury of the hand, and radius or carpal bone fractures [61,62]. CTS in the setting of trauma may occur acutely or in a delayed fashion, after repair of the fracture [63].

Aromatase inhibitors — Aromatase inhibitors, used to suppress plasma estrogen levels for cancer treatment and prevention, appear to be associated with an increased risk of arthralgias and CTS [64-66]. As an example, a trial that evaluated over 6000 females with breast cancer found that CTS developed more frequently in patients assigned to the aromatase inhibitor anastrozole than in those assigned to tamoxifen (2.6 versus 0.7 percent) [65]. Most of the CTS cases were mild to moderate in severity and did not require treatment.

In addition, a prospective case-control study found increased tendon thickness by ultrasound in patients taking aromatase inhibitors compared with those not taking these medications [67]. These results suggest that the mechanism of aromatase inhibitor-associated CTS is tendon thickening.

Others — Other medical conditions that may be associated with CTS due to compression at the carpal tunnel from bony or soft tissue enlargement include prior fracture of the distal radius, acromegaly, metabolic syndrome, and systemic amyloidosis [63,68-70].

Individuals with a preexisting median mononeuropathy, defined using commonly accepted electrodiagnostic parameters, are more likely to develop symptomatic CTS [47,71,72]. In addition, CTS can occur in rare patients who have HNPP. (See 'Genetic predisposition' above.)

There are limited and conflicting data with regard to the potential association between CTS and estrogen-progestin oral contraceptive use [27,50,73-75] and tobacco use [75-77].

Environmental factors — The role of repetitive hand/wrist use and workplace factors in the development of CTS is controversial [78,79]. The attribution of an occupation to the subsequent development of CTS may be confounded by the presence of other risk factors for CTS or individual ergonomic factors. Occupational factors that have been proposed to cause or aggravate CTS include the following:

●Repetitive hand and wrist use

●Forceful hand and wrist use

●Work with vibrating tools

●Sustained wrist or palm pressure

●Prolonged wrist extension and flexion

●Use of hands in cold temperatures

There is evidence suggesting that several of these occupational and biomechanical factors are associated with CTS. One large study analyzed data from 10 systematic reviews (covering 143 original studies) that were published from 1998 to 2014 and also performed a meta-analysis of seven primary studies published from 2011 to 2014 [80]. For all included studies, the population was employed adults, and CTS was a primary outcome. High-quality evidence found repetitive movements, forceful exertion, and combined exposure (repetition and force) to be risk factors for CTS. In addition, there was a dose-response effect between cumulative exposure to force and repetition and increased risk. Vibration as a risk factor for CTS was supported by moderate-quality evidence and low-quality evidence suggested non-neutral wrist postures were risk factors. However, moderate-quality evidence suggested that computer use was not associated with CTS.

Occupational categories with particularly high risk of CTS include production and manufacturing, office and administrative support, and food processing and preparation [23].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Carpal tunnel syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Carpal tunnel syndrome (The Basics)")

SUMMARY

●Anatomy – The carpal tunnel is formed by the transverse carpal ligament (flexor retinaculum) superiorly and the carpal bones inferiorly (figure 2). The median nerve, accompanied by the nine flexor tendons of the forearm musculature, must pass through this anatomic tunnel (figure 3). (See 'Anatomy' above.)

●Pathophysiology – The pathophysiology of carpal tunnel syndrome (CTS) is multifactorial. Increased pressure in the intracarpal canal is thought to play a key role in the development of clinical CTS. Anatomic compression and inflammation are contributing mechanisms. (See 'Pathophysiology' above.)

●Epidemiology – CTS is a common disorder. The estimated prevalence of CTS in the general population is 1 to 5 percent. CTS is more frequent in females, with a female-to-male ratio of approximately 3:1. (See 'Epidemiology' above.)

●Risk factors – Risk factors for CTS include the following:

•Genetic predisposition

•Diabetes mellitus

•Osteoarthritis and rheumatoid arthritis

•Obesity

•Thyroid disease

•Pregnancy

•Trauma to the wrist

•Aromatase inhibitor use

•Occupational biomechanical factors involving the hand and wrist, particularly repetition, forceful exertion, and vibration

The role of repetitive hand/wrist use and workplace factors in the development of CTS is controversial. (See 'Environmental factors' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Kevin Scott, MD, and Robert Sheon, MD, who contributed to earlier versions of this topic review.