Carpal tunnel syndrome: pathophysiology and clinical neurophysiology

Clinical Neurophysiology 113 (2002) 1373–1381 www.elsevier.com/locate/clinph

Review

Carpal tunnel syndrome: pathophysiology and clinical neurophysiology Robert A. Werner a,b,c,*, Michael Andary d a

Physical Medicine and Rehabilitation Service, Veterans Affairs Medical Center, Ann Arbor, MI 48105, USA Department of Physical Medicine and Rehabilitation, University of Michigan Medical Center, Ann Arbor, MI, USA c Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA d Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine, East Lansing, MI, USA b

Accepted 21 May 2002

Abstract Carpal tunnel syndrome (CTS) is a constellation of symptoms associated with compression of the median nerve at the wrist. The pathophysiology of CTS is not fully understood but mechanical aspects of injury within the carpal tunnel are most likely. The issues of ischemia, mechanical trauma, ectopic impulse generation, demyelination, tendonitis, elevated carpal tunnel pressure, mechanical factors, small and large fiber involvement and the variability of symptoms are presented. Documentation of neurophysiologic abnormalities in the median nerve is helpful to establish the diagnosis for CTS. There are several types of clinical neurophysiologic evaluations of the median nerve across the wrist. Sensory and motor nerve conduction studies (NCS) of the median nerve segment across the wrist compared to another nerve segment that does not go through the carpal tunnel (i.e. median, radial, or ulnar) are the most sensitive and accurate techniques. Other neurophysiologic techniques used to document CTS include vibrometry threshold testing, current perception testing, Semmes–Weinstein monofilament testing and two-point discrimination. These techniques have considerable subjective components and have not been found to be as sensitive as traditional NCS. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Median nerve; Nerve injury; Carpal tunnel syndrome; Electromyography; Vibrometry

1. Introduction Carpal tunnel syndrome (CTS) is a constellation of symptoms associated with localized compression of the median nerve at the wrist. It is the most commonly reported nerve compression syndrome. The impairment of the median nerve within the carpal canal is secondary to compression of the median nerve within the carpal tunnel resulting in mechanical compression and local ischemia. CTS is considered as a clinical entity and diagnosis is still based upon symptoms of numbness, tingling and/or burning in the distribution of the median nerve in the hand. However, the symptoms are frequently documented outside the distribution of the median nerve as well. Repetitive hand activity may cause thickening of the synovial lining of the tendons that share the carpal tunnel with the median nerve (Armstrong et al., 1984; Werner and Armstrong, 1997) This increases the volume of tissue within the canal and leads to an increase in the baseline and the mechanical pressure within the carpal tunnel. The combination of * Corresponding author. Tel.: 143-1-734-761-7176. E-mail address: [email protected] (R.A. Werner).

ischemic changes and mechanical contact pressure over time lead to changes in the myelin sheath and occasionally result in injury to the axon that can be detected on neurophysiologic testing such as standard nerve conduction studies (NCS). These studies access only the large myelinated fibers but not the small ones that mediate pain. The exact symptoms or criteria for the diagnosis of CTS remain poorly defined. A consensus conference was organized that identified a combination of symptoms (numbness, tingling, burning and pain in combination with nocturnal symptoms) plus abnormal median nerve function based upon NCS as the best ‘gold standard’ for diagnosis of CTS (Rempel et al., 1998) This definition is accepted for epidemiological studies but there is still some confusion regarding the clinical diagnosis.

2. Pathophysiology of CTS CTS is the classic example of a chronic compression neuropathy. Most of our understanding regarding the pathophysiology of compression neuropathies has come from animal studies but there have been a few pressure related

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studies of the carpal tunnel in humans (Gelberman et al., 1988; Werner et al., 1983; Werner and Armstrong, 1997). The challenge in interpreting the data is understanding the relationship of acute vs. chronic nerve injury. In acute compression neuropathies, there is a sudden increase in pressure that results in local ischemia; i.e. the capillaries in the vasa nervorum collapse, the nerve is deprived of oxygen and the physiologic response is conduction block. This is a rapidly reversible condition and when the pressure is released there is a quick return to normal nerve conduction (Lundborg et al., 1982; Gelberman et al., 1988). Animal studies demonstrate mechanical damage at the edges of the compression with invagination of the myelin sheath and shortening of the inter-node distances with resultant slowing of the conduction velocity (Ochoa et al., 1972; Fowler and Ochoa, 1975; Rudge et al., 1974). These studies were conducted by placing a tourniquet around a limb and studying the pathophysiologic and histologic changes in the nerve related to the amount of compression force and course of application of the compressive forces. Short intervals of high compression produced focal slowing or conduction block. The longer the compression interval was, the longer was the latency period needed before recovery after release of compressive force. Myelin deformity was most severe at the edge of the cuff where there was a steep compression pressure gradient. There are several factors in compression neuropathies that are related to the nature of external force application. The external compression can be applied in several ways including: (a) a low force present for a long time period; (b) an acute focal application of a large external force (e.g. Saturday night palsy) or (c) repetitive application of brief large forces. The compression may also be associated with some combination of stretching, shearing and/or compressive force application. The physiologic response of peripheral nerve fibers to injury include conduction block and slowing of conduction but can also include ectopic impulse production involving efferent fiber effects (i.e. fasciculation, myokymia, etc.) as well as afferent fiber effects (i.e. paraesthesias, pain, etc). The typical classification of nerve injury (neurapraxia, axonotmesis and neurotmesis) is inadequate to describe the majority of pathophysiologic changes seen in CTS. Chronic models are more relevant to human entrapment neuropathies, which often have a slow, insidious course. The lack of human studies on this topic requires us to rely on animal studies. Unfortunately, there are no animal models that accurately and completely simulate CTS. Observations at the time of surgery in human entrapments indicate thinned nerve in the zone of entrapment with a swelling of the nerve at the proximal edge of the zone of entrapment. This could be related to an accumulation of axoplasm, nerve swelling (edema) or fibrosis following chronic inflammatory changes. One report of nerve histology from a patient with CTS who died of a brain tumor (Thomas and Fullerton, 1963) demonstrated extensive

demyelination and remyelination in the region of entrapment of the nerve. They noted significant loss of large myelinated axons. Proximal to the lesion, the nerve was swollen and this correlated with increased perineurial and endoneurial fibrosis. The animal studies suggest that mechanical factors predominate in terms of producing histological distortion of myelin in the carpal tunnel. Pressures much higher than systolic were necessary to produce the focal demyelination and if vascular block (proximal to the area of compression) was added to the external compression, the lesion was no different. The effects of ischemia, without focal contact pressure, are to damage the axons without damaging myelin (Dahlin et al., 1989, Rydevik et al., 1981). Muscle tissue is more susceptible to the effects of limb ischemia than the peripheral nerve. Most studies on compression and nerve function focus on the large myelinated nerves. However, the involvement of small fibers is very relevant to this discussion and helps to understand the diversity of symptoms. Arendt-Neisen et al. (1991) performed a study trying to assess the involvement of thin afferent nerves in patients with CTS. An argon laser, heating the hand, can induce brain potentials that are related to the pain. They demonstrated that the thresholds were elevated (abnormal) in finger 3, compared to finger 5, in CTS subjects when compared to controls. This strongly suggests that the small fibers in humans are affected in CTS and is consistent with the fact that small fibers are affected in chronic, low-pressure nerve compression such as CTS. Since the thresholds on digit 5 (ulnar nerve) were normal, it suggests that the abnormalities on digit 3 were not due to central nervous system processing issues. This does not clarify in which nerve type (small or large) the dysfunction occurs first, since the subjects in this study already had large fiber involvement as determined by slowed NCS. In clinical CTS, the rapid resolution of symptoms which frequently occurs after carpal tunnel release surgery suggests an ischemic component in what is considered a chronic compression neuropathy (Gelberman et al., 1988). With early focal ischemia, nerves are physiologically impaired but histologic examination shows no abnormality (Dahlin et al., 1989). Prolonged limb ischemia can result in nerve infarction. In early compression, the effect is to block venous outflow causing the nerve to become hyperemic and edematous. This factor may be particularly important in the pathogenesis of CTS. As Sunderland (1976) hypothesized, the obstruction of venous return due to external pressure will cause increased pressure in the region of entrapment due to accumulation of blood and this will result in ischemia due to obstruction of flow in the vasa nervorum. The three stages of ischemic injury in compression neuropathy include: (1) increased intrafunicular pressure; (2) capillary damage with leakage and edema, and (3) obstruction of arterial flow. It has been demonstrated that limb ischemia significantly increases paraesthesias in carpal tunnel patients. Lundborg

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et al. (1982) demonstrated that a fixed external compression over the carpal canal could be regulated to create an increased intra-carpal canal pressure. Repeated neurophysiologic measures were also recorded. The subjects reported symptoms of paraesthesias prior to neurophysiologic changes noted by nerve conduction, vibrometry or Semmes–Weinstein monofilaments. The last neurophysiologic measure to change was two-point discrimination. Symptoms resolved within seconds with the release of the external pressure at the carpal tunnel, as did the neurophysiologic abnormalities, which were associated primarily with conduction block. If an upper arm blood pressure cuff was applied at or above arterial pressure, the symptoms and neurophysiologic changes persisted even after the direct compression over the carpal tunnel was removed (Gelberman et al., 1988). The Phalen’s maneuver and the carpal compression test are based upon the direct response of the median nerve to increased carpal tunnel pressures where an injured median nerve responds quickly to the increased pressure with focal conduction block and reproduction of symptoms. The exact pathophysiology of how the pressure in the carpal tunnel increases over time and in response to wrist postures is unclear. Two types of pressure can be exerted: interstitial fluid pressure within the carpal canal and direct contact pressure on the median nerve from adjacent tissues. The increase of the fluid pressure over time is thought to reflect synovial thickening in a limited space (Werner and Armstrong, 1997). Cadaver studies have demonstrated synovial thickening in the region of the carpal canal with the most profound thickening at the entrance and exit regions of the canal where the tendons slide over a fulcrum of the flexor retinaculum (Armstrong et al., 1984). There are dramatic changes of fluid pressure in the carpal tunnel with wrist position; extension increases the pressure 10-fold and wrist flexion increases it 8-fold (Werner, 1983; Werner and Armstrong, 1997). The carpal tunnel is formed by a U-shaped trough consisting of carpal bones and the flexor retinaculum forms the roof of the canal. In addition, there is an annular group of ligaments that form the extensor retinaculum on the dorsal side of the wrist and the volar carpal ligament on the volar side. These ligaments can be characterized as an annular set of bands that are separated by longitudinal elastic elements (see Fig. 1). Extension of the wrist causes the rings to spread apart and stretch the longitudinal elements on the volar side of the wrist and move closer together and compress the elements on the dorsal side (see Fig. 1). The longitudinal stiffness of soft tissue is very low, so these elements easily buckle and form wrinkles. This analogy also applies to the skin, which is why it can be seen to stretch on one side of the joint and wrinkle on the other when the wrist is bent. Thus wrist extension causes the volar carpal ligament to press down on the carpal contents. Interestingly, the flexor retinaculum protects the carpal contents from this pressure. Wrist extension also causes the proximal margin of the carpal bones to glide in

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Fig. 1. The tissues around the wrist can be characterized as series of elastic bands separated by a series of elastic longitudinal elements (a). Extension (dorsiflexion) causes the bands to spread apart stretching the longitudinal elements on the palmar side of the wrist and to be pressed together on the dorsal side compressing the longitudinal elements (b). Extension of the wrist also causes the proximal edge of the carpal bones to press against the volar aspect of the joint capsule and reduce the amount of available space (c). Flexion of the wrist causes the proximal edge of the carpal tunnel to press against the volar aspect of the joint capsule (d). [Reproduced with permission from W.B. Saunders Company].

the opposite direction across the concave surface of the radial head and creates a bulge in the volar aspect of the joint capsule. Thus, wrist extension will cause the carpal contents to be squeezed between the volar carpal ligament and the volar aspects of the carpal bones. In addition, extension causes the proximal portion of the finger flexor tendons (which are thicker than the distal portion) to be drawn into the area of the volar carpal ligament and the carpal tunnel. This increases the volume of the carpal contents and at the same time the available space is reduced. Similar pressure effects would occur in volar, radial and ulnar deviations; however, they would not be as great as for extension. The range of joint motion is smaller for radial and ulnar deviations than for flexion and extension and the lateral dimensions of the compartment are established by the radius and the carpal bones. Increased fluid pressure in wrist flexion may be attributed to pressure from the proximal margin of the flexor retinaculum pressing the flexor tendons and bursa against the head of the radius. This effect would be more localized than that of extension and may contribute to thickening of the median nerve often observed proximal to the carpal tunnel. In addition to fluid pressure, the tendons and nerves are also subjected to compression against adjacent anatomical structures resulting in stretching as forces are transmitted from

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the finger flexor muscles and subjected to friction forces as the tendons slide back and forth through the carpal tunnel. The distribution of parasthesias and pain associated with CTS is extremely variable. Classically, symptoms are considered to be located primarily in the median distribution. However, systematic study suggests that this is not the case. Stevens et al. (1999) reported on symptoms in 159 hands of patients with electrodiagnostically confirmed CTS, using a hand symptom questionnaire. Symptoms were most commonly reported in both the median and ulnar digits more frequently than the median digits alone. They also report location of symptoms in areas other than the digits. Twenty-one percent of patients had forearm paraesthesias and pain; 13.8% reported elbow pain; 7.5% reported arm pain; 6.3% reported shoulder pain; and 0.6% reported neck pain. This diversity in symptoms and their pathophysiology has been very difficult to understand fully. Although there are statistical correlations between symptoms and NCS, this relationship is variable and inconsistent. You et al. (1999) prospectively evaluated patients with CTS (defined by NCS) and attempted to correlate and identify significant relationships between symptoms and NCS. Their criteria for electrodiagnostic abnormality was: delay in distal latency sensory of greater than 3.7 ms, a distal latency motor of greater than 4.4 ms, or a sensory conduction velocity across the carpal tunnel of less than 49 m/s. They identified significant correlations (P , 0:001) for what they labeled as ‘primary symptoms’ (numbness, tingling, nocturnal symptoms). There was also a weaker statistical correlation at P , 0:01 for ‘secondary symptoms’ (pain, weakness, clumsiness). This study suggests that these persistent ‘secondary symptoms’ (pain, weakness, clumsiness) may not be directly related to nerve impingement and dysfunction per se but could be related to other factors. In some of the original descriptions of CTS, tenosynovitis was frequently implicated as a major causative factor for CTS. Inflammation in the synovium of the flexor tendons can cause increased pressure in the carpal tunnel and contribute to median nerve compression (Hybbinette and Mannerfelt, 1975; Phalen, 1966). Other studies confirm that the most common synovial histological changes are related more to fibrosis and edema and not to inflammation (Rosenbaum and Ochoa. 1993; Neal et al., 1987; Fuch et al., 1991).

3. Clinical neurophysiology, testing the health of the median nerve The available techniques for evaluating the median nerve across the carpal tunnel include: nerve conduction testing; vibrometry threshold testing; current perception testing; symptom questionnaire (hand diagrams), and other quantitative sensory testing (i.e. Semmes–Weinstein monofilaments, two-point discrimination and tactile sensation).

3.1. Nerve conduction studies These studies are considered by some to be a gold standard for defining CTS. It is an objective test that demonstrates the physiologic health of the median nerve across the carpal tunnel. The diagnostic standard is a comparison of focal median nerve function across the wrist compared to another section of nerve, usually in the same hand. The nerve is stimulated by a transcutaneous pulse of electricity, inducing an action potential in the nerve and a recording electrode (either distally or proximally) detects the wave of depolarization as it passes by the surface electrode. The latency and amplitude of the signal are recorded. The ability to confirm the diagnosis of CTS using electrodiagnostic techniques lies with testing the median nerve fiber across the wrist and comparing the latency (and sometimes amplitude) to normal conduction or comparison of the median nerve segment to some other nerve segment in the same hand that does not travel through the carpal tunnel (either median, ulnar or radial). Numerous studies report that comparison of sensory nerve responses is more sensitive than absolute median latency in documenting the electrodiagnostic abnormalities consistent with CTS (Jablecki et al., 1993). 3.2. Defining diagnostic criteria The diagnosis of a median mononeuropathy should not be based solely on a median motor or sensory evoked response using an absolute cutoff value. There are many influences on the amplitude and latency of an individual nerve, which could give a false positive result. Age, gender, obesity, finger diameter, concurrent systemic disease, and temperature have all been demonstrated to have impact on the absolute amplitude or latency of an evoked response in the hand (Salerno et al., 1998; Stetson et al., 1993; Sunderland, 1976). The normative upper limits of normal for an individual nerve absolute latency response can range over 1.4 ms depending on age, gender and obesity (Salerno et al., 1998). These factors along with the influence of systemic disease are well controlled when the median nerve response is compared to another nerve segment that does not travel through the carpal tunnel. (Salerno et al., 1998). For example, a 20-year-old female who is thin would have a latency of 3.3 ms as the upper limit of normal (well below the reported cutoff of 3.7 ms used by many electromyographic (EMG) laboratories) whereas a 50-year-old female who is overweight would have a latency of 4.7 ms as the upper limit of normal (see Table 1). By using a relative comparison of two nerve segments, these factors are controlled. Whenever possible, we should be using normative data to establish the appropriate cutoffs. There are many published comparisons and associated cutoffs for CTS (see Table 2) but the reference group must be appropriate for the person being tested. Several studies have suggested a 0.5 ms cutoff for the comparison of the median (digit 2) and ulnar (digit 5)

R.A. Werner, M. Andary / Clinical Neurophysiology 113 (2002) 1373–1381 Table 1 Predicted nerve conduction values – dominant hand (Salerno et al., 1998) Median sensory peak latency Age/sex

Weight (kg)

Mean (ms)

95% upper limit (ms)

20/F 20/F 20/F 20/F 50/F 50/F 50/F 50/F

50 80 110 140 50 80 110 140

2.9 3.0 3.1 3.2 3.2 3.3 3.4 3.5

3.3 3.4 3.6 3.8 3.8 4.0 4.3 4.7

sensory evoked responses but this does not agree with several recent studies of unique sub-populations. The published normative data usually represents a sample of convenience, not a true random sample of the population. It is expensive and time consuming to collect normative data

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for the general population. A large sample of industrial and clerical workers, who were chosen based upon their job, from 5 different locations were tested using the same protocol (Salerno et al., 1998). Results obtained from studies in these populations showed that when the criteria for abnormality was set at the mean ^ 2 SD, the upper limit of normal for the comparison of median and ulnar sensory evoked response was 0.8 ms and not 0.4 or 0.5 ms that was commonly used. When studying an active worker, the 0.8 ms cutoff is the most appropriate reference group (assuming the same techniques are used). To define a median mononeuropathy in a large population of mild diabetics, a cutoff of 1.0 ms was found to represent the upper limit of normal (using 2 SD as the 95% confidence interval) (Albers et al., 1996). Another method to minimize errors and improve accuracy was described by Robinson et al. (1998). They described a combination of 3 sensory comparison techniques: (a) median and ulnar mid-palmar; (b) median and

Table 2 Summary of comparison studies used to define CTS Comparison

Technique

Sensory nerve responses Median–median Short segment, 1 cm antidromic (inching) Median–median Median–median Median–median Median–ulnar Median–ulnar

Side to side Trans carpal, 7 cm vs. palmar, 7 cm orthodromic Digit 1, 10 cm orthodromic, palmar cutaneous branch, 10 cm orthodromic Digit 4, 14 cm antidromic Digit 2 or digit 3–5, 14 cm antidromic

Median–ulnar

Digit 4, 14 cm antidromic

Median–ulnar

Median–radial

Motor responses Median–ulnar Median–ulnar Median–ulnar

Mid palmar, 8 cm orthodromic

Digit 1, 10 cm antidromic or orthodromic

Median to thenar eminence Ulnar to hypothenar eminence Median and ulnar to intrinsics Median and ulnar to thenar

Investigator

Kimura (1979) Nathan et al. (1988) Kimura (1983) Chang and Lien (1991)

Felsenthal and Spindler (1979) Kuntzer (1994) Salerno et al. (1998) Albers et al. (1996) (diabetics) Johnson et al. (1981) Jackson and Clifford (1989) Robinson et al. (1998) Uncini et al. (1989) (onset) (13 cm) Andary et al. (1992, 1996) Stetson et al. (1993) Stevens (1987) Mills (1985) (8.5–11 cm) Robinson et al. (1998) Andary et al. (1992, 1996) Jackson and Clifford (1989) Redmond and Rivner (1988) Stetson et al. (1993) Buschbacher (1999) Johnson et al. (1987) Carroll (1987) Robinson et al. (1998) Jackson and Clifford (1989) Andary et al. (1992, 1996) Kimura (1983) Sander et al. (1999) Logigian et al. (1987) Sander (1998)

Threshold defining abnormal (ms)

$0.5 $0.4 $0.6 $0.5 $0.4

$0.5 . 0.5 $0.8 $1.0 $0.4

$0.5 . 0.6 $0.2 $0.3 $0.4

$0.5

$0.5

$0.4

$1.7 . 1.2 $0.4 $0.8

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ulnar to the ring finger; and (c) median and ulnar to the thumb. The sum of the 3 latency differences was used as a summary index to define a median mononeuropathy; greater than 1.0 ms was the cutoff that maximized the sensitivity and specificity. Another technique to decrease the rate of false positives is to define the cut off defining abnormal as $ 2.5 SD from the mean. It should be noted that all attempts to decrease the false positive rate (which increases specificity) will have the adverse effect of increasing the number of false negatives (thus lowering the sensitivity). NCS do have a relatively high sensitivity and modest specificity but this is not the only quantitative neurophysiologic technique available to assess the median nerve across the wrist. Unfortunately, all of the alternative methods have some subjective component as part of the testing technique and therefore are subject to more variability and also subject to abuse. The alternative techniques are less reliable in defining or diagnosing CTS than NCS and none of these tests can accurately localize the lesion. These tests could be abnormal because of a problem in the forearm, arm, shoulder or neck. 3.3. Vibratory threshold testing The vibratory threshold has been suggested as the earliest detectable objective sign in patients with CTS. This arose out of human experimental studies with acute, controlled, external pressure over the carpal canal (Lundborg et al., 1982). In these studies, the vibratory threshold closely corresponded to patients’ subjective changes in sensation as well as the loss of the sensory nerve response. Vibratory thresholds have been most useful in evaluating and following individuals with a generalized peripheral polyneuropathy such as diabetes (Dyck et al., 1987; Geregerson 1968; Daniel et al., 1977), uremia (Ludvigsson et al., 1979; Read et al., 1983; Tegner and Lindholm, 1985), or drug induced neuropathy (Elderson et al., 1989; van der Hoop et al., 1990). In these individuals there is a need for repeated evaluations over time and vibrometry offers a less noxious means of following the individual’s response to treatments. The role of vibrometry in evaluation of CTS is less well defined. Criteria for aiding in the diagnosis are poorly defined. Several investigators use an absolute threshold criteria for making the diagnosis, while others suggest comparison of digit 2 and digit 5 or the contra lateral digit 2 (Bleecker, 1986; Borg and Lindblom, 1988; Merchut et al., 1990; Spindler and Dellon, 1982; Szabo et al., 1984a,b). Both NCS and vibrometry study the large myelinated fibers in the median nerve but the correlations between vibratory thresholds and electrophysiologic measures have been relatively low and only NCS can detect slowing of the nerve (Geregerson, 1968; Tegner and Lindholm, 1985; Gerr et al., 1991; Werner et al., 1994, 1995). The primary process in CTS seems to be slowing of the median nerve across the wrist (loss of the myelin insulation) with little axonal loss except in the more severe cases. Mild cases of CTS would

have slowing of conduction but not axon loss. Vibratory sensation remains intact until a critical mass of axons are lost and thus will remain normal in mild cases of CTS. This, coupled with the actual clinical data, strongly suggests that vibrometry is not a tool that is helpful in screening for CTS. 3.4. Current perception testing Another approach to testing nerve function is current perception threshold (CPT) testing. This device tests an individual’s perception of electrical current at 3 distinct frequencies, recording the milliamperes of current necessary to perceive cutaneous stimulation. Franzblau et al. (1994b) described the results of a field survey of active workers who were screened for CTS using a CPT device in conjunction with a symptom survey and limited electrodiagnostic testing. Based on determination of a ‘normal’ or ‘abnormal’ CPT, the CPT test device had low sensitivity, specificity, and positive predictive values for identifying subjects with slowing of median nerve function, symptoms consistent with CTS, or both. 3.5. Symptom surveys/hand diagrams/physical examination and other quantitative sensory testing Hand diagrams have been reported as having a very high sensitivity and specificity in relationship to the diagnosis of CTS. This is true in the clinical setting such as a hand clinic but it is not very clear when used as a screening tool in an industrial setting. Franzblau et al. (1994a) demonstrated that only half of the workers who had a hand diagram that was graded as classic or probable had any evidence of slowing of the median nerve at the wrist. Therefore, at best, it has a sensitivity of 50% if confirmation of a prolonged median nerve conduction is used as a gold standard. Likewise the findings on physical examination do not demonstrate a high sensitivity (Homan et al., 1999). Less than half of individuals with a clear-cut case of CTS will have one of the provocative tests for CTS (Phalen’s, Carpal compression or Tinel’s) be positive (Homan et al., 1999). Other studies confirm this problem (D’Arcy and McGee, 2000). Additionally there is a significant amount of variability in how the testing is performed which makes reliability a problem. Quantitative sensory testing (Semmes–Weinstein monofilaments, two-point discrimination, and tactile sensation) have a low sensitivity, again on the order of 30–50%. The two-point discrimination is probably the worst since it is only found in more severe cases and rarely in the early stages. 3.6. Asymptomatic median mononeuropathy Several studies have demonstrated that approximately 15% of the general population has evidence of a median mononeuropathy but do not report any hand symptoms (Bingham et al., 1996; Franzblau et al., 1994a; Atroshi et al., 1999). Additionally, diabetics frequently have an abnormal median nerve across the wrist and do not report any

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symptoms (Albers et al., 1996). This suggests a specificity of only 85%, which is different than the specificity reported on most convenience samples, which is 97–99% (Jablecki et al., 1993). It is reasonable to ask if the individuals with evidence of a median mononeuropathy but no symptoms were pre-clinical cases of CTS, i.e. they had a diseased nerve that has not yet caused symptoms, but will in the future develop into symptomatic cases of CTS. Werner et al. (1997b, 2001) studied this question using a case control study of active workers at 5 different work sites was initiated. Cases were defined as asymptomatic workers with electrodiagnostic findings of a median mononeuropathy in either hand using a comparison of median and ulnar sensory evoked peak latencies (14 cm distance from wrist to finger). Controls were age and sex matched, asymptomatic workers from the same site with normal NCS in both hands. This study demonstrated that NCS were not useful to determine the risk for developing CTS among asymptomatic workers within the first 2 years. Asymptomatic workers with an abnormal median sensory evoked response were no more likely to develop symptoms consistent with CTS than workers with a normal median sensory nerve conduction during the first 2 years but when this study was carried out for a total of 6 years, there was an association between a median mononeuropathy and future CTS symptoms. (Werner et al., 2001) After approximately 6 years, there was an increased risk of developing CTS symptoms if the worker had an abnormal finding earlier. In addition, the more abnormal the median nerve function at baseline was, the more likely was the risk of developing symptoms consistent with CTS. These findings are in accordance with the study of Nathan et al. (1998). In each study, approximately 25% of asymptomatic workers with a finding of a median mononeuropathy went on to develop symptoms of CTS after 6–11 years. The vast majority of workers with an abnormal median sensory latency at baseline did not go on to develop symptoms of CTS. A possible explanation for the unexpectedly high prevalence of slowing of the median nerve across the wrist in subjects without symptoms is that the slowly progressive problems of the median nerve within the wrist develop a pathophysiologic abnormality, but because it occurs so insidiously, these individuals are not aware and do not report the same symptoms of numbness and tingling that is associated with acute CTS. There may also be a pathophysiologic difference in these groups that is at this time unclear. For example, in the slowly progressive people there may not be complete ischemia of the nerve causing the parasthesias. Stetson et al. (1993) did report a group difference in the NCS among asymptomatic industrial workers compared to business executives. A group of industrial workers, with a high exposure to hand intensive activity, had a smaller median sensory amplitude and longer median sensory latencies compared to a group of executives with minimal exposure to repetitive hand activity. They implied that work

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activity placed the median nerve at risk due to repetitive activity and subsequent changes within the carpal canal.

4. Conclusions There are variable symptoms associated with CTS. Most of these symptoms are probably due to median nerve compression at the wrist, but the variability of some symptoms suggests alternative etiologies. The pathophysiology involves a combination of mechanical trauma and ischemic injury to the median nerve within the carpal canal but the role of tendonitis and tendinosis is not well defined. NCS are the best means for assessing the function of the median nerve and therefore confirming a suspected case of CTS. The sensitivity ranges from 80 to 92% and the specificity ranges from 80 to 99% depending on criteria for abnormality and patient populations studied. This is quite good but not perfect. There are still cases of clinical CTS where the NCS cannot confirm the abnormality of median nerve function. Conversely there are people with abnormality of median nerve conduction with no symptoms that appear to be at a slightly higher risk to develop symptoms over the next 2–6 years. If we attempt to increase the sensitivity of the testing protocol, we always increase the number offalse positives, i.e. we decrease the specificity. The development of normative reference groups for some subpopulations, i.e. active workers and diabetics, allows for a more accurate assessment of these individuals. The use of other quantitative sensory techniques to assess the median nerve do not provide added sensitivity or specificity to the diagnosis of CTS.

Acknowledgements Support for this research is provided by the National Institute on Disability and Rehabilitation Research of the United States Department of Education, Grant #H133E980007, ‘Rehabilitation Engineering Research Center’. The opinions contained in this publication are those of the grantee and do not necessarily reflect those of the United States Department of Education.

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