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THE RATIONAL CLINICAL EXAMINATION

Does This Patient Have Carpal Tunnel Syndrome? Christopher A. D’Arcy, MD Steven McGee, MD

CLINICAL SCENARIO In the following patient, the clinician would like to know which items from the patient interview and physical ex- amination accurately predict the diag- nosis of carpal tunnel syndrome (CTS):

A 55-year-old woman has difficulty sleeping because of numbness and tin- gling in her right hand for 6 months. On a hand diagram, she uses a pencil to locate precisely her numbness and tingling over the dorsal and palmar as- pects of all 5 fingers, sparing the palm. On inspection the patient has no evi- dence of thenar atrophy, but thumb ab- duction is weak on the affected side. Sensory examination using monofila- ments and a vibrating tuning fork is normal. Tinel sign is positive, and Phalen sign is negative.

Why Is the Diagnosis Important? Carpel tunnel syndrome is an impor- tant cause of pain and functional im- pairment of the hand due to compres- sion of the median nerve at the wrist (FIGURE 1). Patients are usually be- tween their third and fifth decades when diagnosed, and women are affected 3 times as often as men.2,3 About 0.5% of the general population reports being di- agnosed with CTS.2 It is likely, how- ever, that few affected patients con- sult clinicians because population- based studies reveal that about 3% of adults have symptomatic electrodiag- nostically confirmed CTS.4

In many patients, symptoms are self- limited or resolve with conservative measures, such as splinting the wrist, using anti-inflammatory medication,

and modifying their activities. Corti- costeroid injection into or near the car- pal tunnel results in improvement for 49% to 81% of those affected, al- though 50% to 86% of those experi- ence recurrence.5-9 In patients whose condition fails conservative treat- ment, surgical division of the trans- verse carpal ligament, either by an open or endoscopic procedure, promptly im- proves or relieves sensory complaints (dysesthesias) 75% to 99% of the time.10-18 Permanent complications from surgery occur in less than 1%,19 but the

subsequent recovery often requires leave from work lasting days to sev- eral weeks.18

Author Affiliations: University of Washington Health Sciences Center (Dr D’Arcy) and University of Wash- ington, Seattle-Puget Sound Veterans Affairs Health Care System (Dr McGee), Seattle. Corresponding Author and Reprints: Christopher A. D’Arcy, MD, Division of Rheumatology, University of Washington Health Sciences Center, 1959 NE Pacific St, Box 356428, Seattle, WA 98195 (cadarcy@u .washington.edu). The Rational Clinical Examination Section Editors: David L. Simel, MD, MHS, Durham Veterans Affairs Medical Center and Duke University Medical Center, Durham, NC; Drummond Rennie, MD, Deputy Edi- tor, JAMA.

Context History taking and physical examination maneuvers, including Tinel and Phalen signs, are widely used for the diagnosis of carpal tunnel syndrome (CTS).

Objective To systematically review the precision and accuracy of history taking and physical examination in diagnosing CTS in adults.

Data Sources English-language literature was searched using MEDLINE (January 1966-February 2000) as well as bibliographies of relevant articles.

Study Selection Studies of patients presenting to clinicians with symptoms sug- gestive of CTS in which findings from clearly described physical examination maneu- vers were independently compared with electrodiagnostic testing. Twelve of 42 ini- tially identified articles met these criteria and were included in the review.

Data Extraction Two authors independently reviewed and abstracted data from all of the articles and reached consensus about any discrepancies.

Data Synthesis In patients presenting with hand dysesthesias, the findings that best distinguish between patients with electrodiagnostic evidence of CTS and patients with- out it are hypalgesia in the median nerve territory (likelihood ratio [LR], 3.1; 95% con- fidence interval [CI], 2.0-5.1), classic or probable Katz hand diagram results (LR, 2.4; 95% CI, 1.6-3.5), and weak thumb abduction strength (LR, 1.8; 95% CI, 1.4-2.3). Findings that argue against the diagnosis of carpal tunnel syndrome are unlikely Katz hand diagram results (LR, 0.2; 95% CI, 0.0-0.7) and normal thumb abduction strength (LR, 0.5; 95% CI, 0.4-0.7). Several traditional findings of CTS have little or no diag- nostic value, including nocturnal paresthesias; Phalen and Tinel signs; thenar atrophy; and 2-point, vibratory, and monofilament sensory testing. Other less commonly used maneuvers, including the square wrist sign, flick sign, and closed fist sign, require vali- dation by other studies before they can be recommended.

Conclusions Hand symptom diagrams, hypalgesia, and thumb abduction strength testing are helpful in the establishing electrodiagnosis of CTS. The utility of these re- sults is limited, however, by problems inherent in using nerve conduction studies as a criterion standard. JAMA. 2000;283:3110-3117 www.jama.com

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Many conditions, including preg- nancy, rheumatoid arthritis, diabetes mellitus, and previous wrist trauma, are associated with CTS,19 although histo- logic sections from the carpal tunnel of most affected patients are normal.20,21

Many patients have an abnormally high tissue pressure within the carpal tun- nel,22 which presumably causes intra- neural ischemia that leads to dysesthe- sias and abnormal results of sensory testing.23-25

This article systematically reviews the diagnostic accuracy of bedside find- ings for CTS. Presentation of this in- formation, however, first requires un- d e r s t a n d i n g s o m e o f t h e i s s u e s surrounding electrodiagnosis, the cur- rent CTS diagnostic standard.

The Diagnostic Standard for CTS In his original definition of CTS, Phalen26 required patients to have 1 or more of 3 bedside findings: sensory changes restricted to the median nerve distribution of the hand, a positive Ti- nel sign, and a positive Phalen sign (TABLE 1). Though electrodiagnosis was not part of Phalen’s definition, clini- cians now use electrodiagnosis fre- quently to confirm the diagnosis, and some third-party payers require it before compensating claims.34 Consen- sus committees from professional so- cieties have endorsed electrodiagnosis as the diagnostic test of choice.35,36 Di- agnostic standards for nerve conduc- tion studies in CTS have been devel- oped, which report sensitivities of 49% to 84% and specificities of 95% to 99%.37

The sensitivity and specificity of elec- trodiagnosis in CTS need to be care- fully interpreted. For the sensitivity calculation, the criterion standard was bedside findings alone (eg, com- patible symptoms plus a positive Tinel sign),38-40 which then begs the question whether electrodiagnosis or bedside findings are the more accu- rate standard. False-negative test re- sults probably occur because the con- dition is intermittent41 or because the patient’s symptoms emanate from small, unmyelinated fibers that are invisible to surface electrodes (electrodiagno-

sis detects only larger myelinated fibers).42

The high specificity figures in these studies are also misleading, being ar- bitrarily set at 2 SDs above the mean of observations of normal hands. The val- ues of 95% to 99% are based on the as- sumption that nerve conduction re- cordings follow a standard gaussian distribution, which has been shown to be inaccurate.43,44 False-positive test re- sults are well documented when these test thresholds are applied to other populations.10,45-47

It is well documented that many hand surgeons perform carpal tunnel release successfully in patients with normal elec- trodiagnostic findings.15,34,48-50 Even in pa- tients with positive electrodiagnostic findings who undergo surgery, symp- toms usually resolve within days de- spite nerve conduction abnormalities that persist for months or longer.11,17,42,51,52

Nonetheless, most physicians rely on electrodiagnosis as the best available diag- nostic standard. Electrodiagnostic stud- ies may help identify other conditions that also cause hand dysesthesias, such as cervical radiculopathy, polyneuropa- thy, or other median nerve entrapment syndromes.41,53-55 Furthermore, the over- whelming majority of patients in surgi- cal studies have compatible symptoms and electrodiagnostic studies positive for CTS.10,12,17,56 Electrodiagnosis may not predict recovery after carpal tunnel release, but neither does any other clini- cal variable with any certainty. The poten- tial utility of computed tomography, magnetic resonance imaging, and ultra- sonography is still being determined, and they remain primarily research tools.57-61

For these reasons, our review addresses the accuracy of the history and physical examination in diagnosing CTS, as con- firmed by electrodiagnostic studies.

Figure 1. Normal Anatomy of the Carpal Tunnel

Ulnar Artery

Ulnar Nerve Flexor

Retinaculum

Median Nerve

Flexor Tendons

Hamate

Capitate Trapezoid Trapezium

The carpal tunnel consists of the median nerve and 9 flexor tendons surrounded by the rigid carpal bones and transverse carpal ligament (flexor retinaculum). The distal wrist crease marks the proximal edge of the carpal tunnel. Within the tunnel, the median nerve divides into a motor branch that innervates the thenar muscles (opponens, abductor, short flexor) and distal sensory branches that supply the thumb, index, and middle fin- gers, and the radial half of the ring finger. Because the sensory branches to the radial palm do not usually pass through the carpal tunnel, palm sensation is preserved in a classic case of carpal tunnel syndrome.1

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METHODS Using the MEDLINE database for ar- ticles from January 1966 to February 2000, both authors independently used the following search strategy, limited to the English language and human sub- jects, to retrieve all relevant publica- tions on the diagnosis of CTS in adults: exp carpal tunnel syndrome and exp diag- nosis. In addition text word searches were completed for Tinel or Tinels or Hoffman- Tinels, and Phalen or Phalens. Based on review of titles and abstracts, relevant publications were retrieved. To com- plete the search, the authors reviewed the bibliographies of these articles and re- trieved all relevant articles.

To be included in this review, a study had to satisfy the following criteria: (1) the patients presented to a clinician for symptoms suggestive of CTS, (2) the physical examination maneuvers were clearly described, (3) there was an in- dependent comparison with one or more electrodiagnostic parameters (which had to include at least some measurement of motor or sensory nerve conduction), and (4) the authors could extract from fig- ures or tables in the articles the num- bers needed to construct 2 3 2 tables and calculate sensitivity, specificity, and like- lihood ratios (LRs).

Twelve articles met these criteria and are included.27-33,62-66 Thirty articles were

excluded: 14 because the control group was asymptomatic,67-80 8 because the data were incomplete,15,49,57,81-85 4 be- cause the subjects were identified by population surveys,45,86-88 3 because the criterion standard was unacceptable (ie, electromyography alone,89 electrodiag- nosis and abnormal monofilament test- ing,90 or criterion standard missing91), and 1 because the examination maneu- vers were not clearly defined.92

Sensitivity, specificity, and LRs and their confidence intervals (CIs) were cal- culated using conventional defini- tions.93 When a cell of a 2 3 2 table was 0, 0.5 was added to all cells before sum- marizing the data for a particular test. Our summary measures pooled all the data using the Dersimonian and Laird random-effects model,94 which consid- ers both within-study variance and vari- ability among studies. Our test for ho- mogeneity between studies was the effectiveness score, a test of overall accuracy.95

Likelihood ratios are the odds that a given finding would occur in a patient with CTS as opposed to one without CTS. If a particular LR, positive or nega- tive, had a value close to 1 that out- come of the test is unhelpful in making diagnostic decisions at the bedside.

PRECISION AND ACCURACY How to Elicit Symptoms and Signs of CTS

Table 1 summarizes how to elicit the physical examination signs of CTS ana- lyzed in this review. When examining thumb strength, the clinician should focus on abduction of the thumb (FIGURE 2), not flexion or opposition, which sometimes can be accom- plished by muscles innervated by nerves other than the recurrent motor branch of the median nerve.54,59 The Katz hand diagram is a self-administered dia- gram that depicts both the dorsal and palmar aspect of the patient’s hands and arms (FIGURE 3). Patients use this dia- gram to mark the specific location of their symptoms, characterizing them as pain, numbness or tingling, or other. Diagrams are then graded as classic, probable, possible, or unlikely to be

Table 1. Definition of Abnormal Physical Findings

Physical Finding Definition of Abnormal Finding

Motor examination Weak thumb abduction Weakness of resisted abduction, ie, movement of the thumb at right

angles to the palm*

Thenar atrophy A concavity of the thenar muscles when observed from the side

Sensory examination Hypalgesia Diminished ability to perceive painful stimuli applied along the palmar

aspect of the index finger when compared with the ipsilateral little finger†

Diminished 2-point discrimination

Diminished ability to identify correctly the number of points using calipers whose points are set 4 to 6 mm apart, comparing the index with little finger‡

Abnormal vibratory sensation

Diminished ability to perceive vibratory sensations using a standard vibrating tuning fork (128 of 256 Hz), comparing the distal interphalangeal joint of the index finger to the ipsilateral fifth finger

Abnormal monofilament testing

Using a Semmes-Weinstein monofilament applied to the pulp of the index finger, the patient’s threshold is greater than the 2.83 monofilament

Other tests Square wrist sign27 The anteroposterior dimension of the wrist divided by the

mediolateral dimension equals a ratio of greater than 0.70, when measured with calipers at the distal wrist crease

Closed-fist sign28 Paresthesias in the distribution of the median nerve when the patient actively flexes the fingers into a closed fist for 60 seconds

Flick sign29 When asking the patient, “What do you actually do with your hand(s) when the symptoms are at their worst?” the patient demonstrates a flicking movement of the wrist and hand, similar to that used in shaking down a thermometer§

Tinel sign Paresthesias in the distribution of the median nerve when the clinician taps on the distal wrist crease over the median nerve

Phalen sign Paresthesias in the distribution of the median nerve when the patient flexes both wrists 90° for 60 seconds

Pressure provocation test30

Paresthesias in the distribution of the median nerve when the examiner presses with his/her thumb on the palmar aspect of the patient’s wrist at the level of the carpal tunnel for 60 seconds

Tourniquet test31 Paresthesias in the distribution of the median nerve when a blood pressure cuff around the patient’s arm is inflated above systolic pressure for 60 seconds

*Most clinicians define weakness as muscle power less than that of the companion muscle in contralateral hand (which has the disadvantage of assuming the opposite hand has normal strength) or that of a standard of normal strength based on the experience of examining many normal individuals (Figure 2).

†Most clinicians use an open safety pin or broken applicator stick, which must be discarded after use to prevent trans- mission of infection.

‡The studies in this review separated the points of the calipers 4 mm,32 5 mm,33 and 6 mm.31 §Any other response is a negative result.

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CTS based on criteria that appear in Figure 3.32,63

Precision of the History and Physical Examination for CTS Few studies have addressed the preci- sion of findings for CTS. In one study, simple agreement was 84% for 2 physi- cians rating 54 of the Katz hand dia- grams.63 In another small study, the in- terobserver agreement was substantial for Tinel sign (k = 0.77) and Phalen sign (k = 0.65), moderate for vibration (k = 0.40), and fair for motor strength (k = 0.25).96 Tinel test, however, is prob- ably much less precise than these data suggest, because the proportion of healthy, asymptomatic hands with a posi- tive Tinel sign ranges from 0%28 to 45%.71

Some of this variability with Tinel sign may relate to technique; in one study, a greater percussion force increased sen- sitivity at the expense of specificity.89

Diagnostic Accuracy of Physical Findings TABLE 2 summarizes the studies ad- dressing the diagnostic accuracy of the history and physical examination for CTS. Based on the CIs of LRs, the fol- lowing findings favor the electrodiag- nosis of CTS when they are present in patients who present with hand dyses- thesias: decreased sensitivity to pain (hypalgesia) in the median nerve ter- ritory (LR, 3.1; 95% CI, 2.0-5.1), clas-

Figure 2. Testing Thumb Abduction

The patient is instructed to raise his/her thumb per- pendicular to the palm as the examiner applies down- ward pressure on the distal phalanx. This maneuver reliably isolates the strength of the abductor pollicis brevis, which is innervated only by the median nerve.

Figure 3. Katz Hand Diagram

Numbness Pain Tingling Decreased Sensation

Classic Pattern Symptoms affect at least 2 of digits 1, 2, or 3. The classic pattern permits symptoms in the fourth and fifth digits, wrist pain, and radiation of pain proximal to the wrist, but it does not allow symptoms on the palm or dorsum of the hand.

Probable Pattern

Same symptom pattern as classic, except palmar symptoms are allowed unless confined solely to the ulnar aspect. In the possible pattern, not shown, symptoms involve only 1 of digits 1, 2, or 3.

Unlikely Pattern No symptoms are present in digits 1, 2, or 3.

Figure adapted with permission.64

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sic or probable Katz hand diagram re- sults (LR, 2.4; 95% CI, 1.6-3.5), and weak thumb abduction strength (LR, 1.8; 95% CI, 1.4-2.3). Using a slightly different system for grading hand dia- grams, another study also found that the definite or possible hand diagram ar- gued for CTS (LR, 2.1; 95% CI, 1.5-3.0).92

In our analysis, 2 findings argued against the electrodiagnosis of CTS: a Katz hand diagram classified as unlikely (LR, 0.2; 95% CI, 0.0-0.7; not shown in Table 2) and normal thumb abduction strength (LR, 0.5; 95% CI, 0.4-0.7).

The following findings had limited or no value in distinguishing patients with CTS from those without it: the pa- tient’s age, presence of bilateral or noc- turnal symptoms, thenar atrophy, other sensory abnormalities (2-point, vibra- tion, monofilament), Tinel sign, Phalen sign, pressure provocation test, and the tourniquet test.

Several studies addressed the diagnos- tic accuracy of combined findings,32,65,90

but no combination consistently proved significantly more helpful than the indi- vidual findings themselves. One study did find that the combined finding of a posi- tive Tinel sign and a classic or probable hand diagram was slightly more discrimi- nating (LR, 3.6; 95% CI, 1.6-8.1) than ei- ther finding alone (LR, 1.8 for positive Ti- nel sign and 2.4 for classic or probable hand diagram),32 though this result re- quires validation given the problems with Tinel sign in other studies.

According to our analysis, several un- conventional findings—flick sign, closed fist sign, and square wrist sign—show promise in diagnosing CTS. However, these maneuvers are not widely used and have been tested in only 1 or 2 studies. Two letters to the editor have suggested that the sensitivity of the flick sign is much lower (only 25%-36%) than indi- cated in Table 2.84,85 Therefore, before any of these 3 findings can be recom- mended for clinical practice, further sup- portive evidence is necessary.

There are several reasons why some findings are not as helpful diagnosti- cally as traditionally thought. Thenar at- rophy is probably not useful because it occurs only in long-standing or ne-

glected cases of CTS and can also result from lower cervical radiculopathies or polyneuropathies. Tinel intended his sign to be used in patients after blunt traumatic nerve injury to follow the course of the regenerating nerve.30,76,87

The idea that patients with CTS would also have a stub of continually regener- ating nerve at the distal wrist crease seems unlikely, limiting the diagnostic utility of this particular test. Our analy-

sis shows that hypalgesia in the me- dian nerve distribution is a more useful diagnostic finding than abnormalities of other sensory modalities, in part be- cause hypalgesia is a more specific find- ing. It is not clear why this should be, though it may indicate that the thresh- old for abnormal results when testing sensation for vibration, 2-point discrimi- nation, and monofilaments is set too low (in one study, for example, 20% of

Table 2. Diagnostic Accuracy of History and Physical Examination for Carpal Tunnel Syndrome*

Findings by Reference and Year

No. of Hands† Sensitivity Specificity

LR+ (95% CI)

LR− (95% CI)

Patient Interview Classic or probable hand diagram

Katz et al,63 1990 145 0.64 0.73 2.4 (1.6-3.5) 0.5 (0.3-0.7)

Age .40 years Katz et al,32 1990 110* 0.80 0.41 1.3 (1.0-1.7) 0.5 (0.3-1.0)

Nocturnal paresthesia Buch-Jaeger and Foucher,31

1994 112* 0.51 0.68 1.6 (1.0-2.6) 0.7 (0.5-1.0)

Gupta and Benstead,62 1997 92 0.84 0.33 1.2 (1.0-1.6) 0.5 (0.2-1.1)

Katz et al,32 1990 110* 0.77 0.27 1.1 (0.9-1.3) 0.8 (0.4-1.6)

Pooled results . . . . . . . . . 1.2 (1.0-1.4) 0.7 (0.5-0.9)

Bilateral Symptoms Katz et al,32 1990 110* 0.61 0.58 1.4 (1.0-2.1) 0.7 (0.4-1.0)

Motor Examination

Weak thumb abduction Gerr et al,33 1995 115 0.63 0.62 1.7 (1.1-2.4) 0.6 (0.4-0.9)

Kuhlman and Hennessey,30 1997

228 0.66 0.66 2.0 (1.4-2.7) 0.5 (0.4-0.7)

Pooled results . . . . . . . . . 1.8 (1.4-2.3) 0.5 (0.4-0.7)

Thenar atrophy Gerr et al,33 1995 115 0.28 0.82 1.6 (0.8-3.2) 0.9 (0.7-1.1)

Golding et al,64 1986 110 0.04 0.99 5.4 (0.2-129.5) 1.0 (0.9-1.0)

Katz et al,32 1990 110* 0.14 0.90 1.5 (0.5-4.1) 0.9 (0.8-1.1)

Pooled results . . . . . . . . . 1.6 (0.9-2.8) 1.0 (0.9-1.0)

Sensory Examination

Hypalgesia Golding et al,64 1986 110 0.15 0.93 2.2 (0.7-6.7) 0.9 (0.8-1.1)

Kuhlman and Hennessey,30 1997

228 0.51 0.85 3.4 (2.0-5.8) 0.6 (0.5-0.7)

Pooled results . . . . . . . . . 3.1 (2.0-5.1) 0.7 (0.5-1.1)

2-Point discrimination Buch-Jaeger and Foucher,31

1994, 6 mm 167 0.06 0.99 4.5 (0.6-36.9) 1.0 (0.9-1.0)

Gerr et al,33 1995, 5 mm 115 0.28 0.64 0.8 (0.5-1.3) 1.1 (0.9-1.5)

Katz et al,32 1990, 4 mm 110* 0.32 0.80 1.6 (0.8-3.1) 0.8 (0.7-1.1)

Pooled results . . . . . . . . . 1.3 (0.6-2.7) 1.0 (0.9-1.1)

Abnormal vibration Buch-Jaeger and Foucher,31

1994 172 0.20 0.81 1.1 (0.6-2.0) 1.0 (0.8-1.1)

Gerr et al,33 1995 115 0.61 0.71 2.1 (1.3-3.3) 0.5 (0.4-0.8)

Pooled results . . . . . . . . . 1.6 (0.8-3.0) 0.8 (0.4-1.3)

Abnormal monofilament findings Buch-Jaeger and Foucher,31

1994 167 0.59 0.59 1.5 (1.1-2.0) 0.7 (0.5-0.9)

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asymptomatic hands also displayed ab- normal monofilament results76).

In our analysis, only results for Tinel sign were heterogeneous. The hetero- geneity is not explained by differences in the electrodiagnostic parameters used as criterion standards in the individual

studies, variations in examination tech- nique (ie, whether the clinician tapped over the median nerve using his index finger or a reflex hammer), differences in prevalence of CTS in each of the stud- ies (mean prevalence was 57%), differ- ences in the age and sex composition

(mean age was 50 years, 77% were wom- en), or by an apparent workup bias. Ex- cluding the 2 studies that account for the heterogeneity62,64 does not change the summary measure in any meaningful way, and therefore these studies are in- cluded in our analysis.

THE BOTTOM LINE When evaluating patients with hand dysesthesias, the findings most help- ful in predicting the electrodiagnosis of CTS are hand symptom diagrams, hyp- algesia, and weak thumb abduction strength testing. The square wrist sign, flick sign, and closed fist sign also show promise, but require validation by other investigators. Many traditional find- ings, including Phalen and Tinel signs, have limited ability to predict the elec- trodiagnosis of CTS.

The main limitation of the existing lit- erature is the lack of an ideal criterion standard, which complicates all clinical research in the field of CTS. It is also important to note that these data are derived from symptomatic patients pre- senting to an orthopedic surgeon, physi- cal therapist, or an electrodiagnostic labo- ratory. There are no data addressing the value of physical diagnosis in patients presenting to a primary care physician with symptoms suggestive of CTS. Our analysis, therefore, is most applicable to patients with severe enough symptoms to warrant such a referral.

Returning to the case presented at the beginning of the article, the find- ings of a classic hand diagram and thumb abduction weakness both sup- port the diagnosis of CTS. The find- ings of a normal thenar eminence, a positive Tinel sign, and negative Phalen sign do not contribute signifi- cant diagnostic information. Her clini- cian believed she probably had CTS and chose to manage her symptoms by splinting her wrists and recom- mending anti-inflammatory medica- tions. If the patient’s symptoms fail to improve, nerve conduction testing, a d d i t i o n a l e m p i r i c t h e r a p e u t i c modalities (eg, corticosteroid injec- tions), or referral for surgical assess- ment should be considered.

Table 2. Diagnostic Accuracy of History and Physical Examination for Carpal Tunnel Syndrome (cont)*

Findings by Reference and Year

No. of Hands† Sensitivity Specificity

LR+ (95% CI)

LR− (95% CI)

Other Tests

Square wrist sign Kuhlman and

Hennessey,30 1997 228 0.69 0.73 2.6 (1.8-3.7) 0.4 (0.3-0.6)

Radecki,27 1994 665 0.47 0.83 2.8 (2.1-3.8) 0.6 (0.6-0.7)

Pooled results . . . . . . . . . 2.7 (2.2-3.4) 0.5 (0.4-0.8)

Closed fist sign De Smet et al,28 1995 35 0.61 0.92 7.3 (1.1-49.1) 0.4 (0.2-0.7)

Flick sign Pryse-Phillips,29 1984 396 0.93 0.96 21.4 (10.8-42.1) 0.1 (0.0-0.1)

Tinel sign Gerr et al,33 1995 115 0.25 0.67 0.7 (0.4-1.3) 1.1 (0.9-1.4)

Golding et al,64 1986 110 0.26 0.80 1.3 (0.6-2.6) 0.9 (0.7-1.2)

Heller et al,65 1986 80 0.60 0.77 2.7 (1.2-5.9) 0.5 (0.3-0.8)

Katz et al,32 1990 110* 0.59 0.67 1.8 (1.2-2.7) 0.6 (0.4-0.9)

Kuhlman and Hennessey,30 1997

228 0.23 0.87 1.8 (1.0-3.4) 0.9 (0.8-1.0)

Buch-Jaeger and Foucher,31 1994

172 0.42 0.64 1.1 (0.8-1.7) 0.9 (0.7-1.2)

Pooled results . . . . . . . . . 1.4 (1.0-1.9) 0.8 (0.7-1.0)

Phalen sign Buch-Jaeger and

Foucher,31 1994 166 0.58 0.54 1.3 (0.9-1.7) 0.8 (0.6-1.1)

Gerr et al,33 1995 115 0.75 0.33 1.1 (0.9-1.4) 0.7 (0.4-1.3)

Heller et al,65 1986 80 0.67 0.59 1.6 (1.0-2.8) 0.6 (0.3-0.9)

Katz et al,32 1990 110* 0.75 0.47 1.4 (1.1-1.9) 0.5 (0.3-0.9)

Kuhlman and Hennessey,30 1997

228 0.51 0.76 2.1 (1.4-3.2) 0.6 (0.5-0.8)

Golding et al,64 1986 110 0.10 0.86 0.7 (0.2-2.2) 1.0 (0.9-1.2)

Burke et al,66 1999 200 0.51 0.54 1.1 (0.7-1.8) 0.9 (0.6-1.3)

De Smet et al,28 1995 66 0.91 0.33 1.4 (0.9-2.0) 0.3 (0.1-0.9)

Pooled results . . . . . . . . . 1.3 (1.1-1.6) 0.7 (0.6-0.9)

Pressure provocation test Kuhlman and

Hennessey,30 1997 228 0.28 0.74 1.1 (0.7-1.7) 1.0 (0.8-1.1)

Burke et al,66 1999 205 0.52 0.38 0.8 (0.6-1.2) 1.3 (0.7-2.2)

Buch-Jaeger and Foucher,31 1994

155 0.49 0.54 1.1 (0.8-1.5) 0.9 (0.7-1.3)

De Smet et al,28 1995 66 0.63 0.33 0.9 (0.6-1.5) 1.1 (0.5-2.7)

Pooled results . . . . . . . . . 1.0 (0.8-1.3) 1.0 (0.9-1.1)

Tourniquet test Buch-Jaeger and

Foucher,31 1994 145 0.52 0.36 0.8 (0.6-1.1) 1.3 (0.9-2.0)

Golding et al,64 1986 110 0.21 0.87 1.6 (0.7-3.9) 0.9 (0.8-1.1)

Pooled results . . . . . . . . . 1.0 (0.5-1.9) 1.0 (0.7-1.5)

*LR indicates likelihood ratio; CI, confidence interval; and ellipses, not applicable. A positive LR indicates a positive finding for carpal tunnel syndrome; a negative LR indicates either a negative finding or an absent finding.

†Refers to individual subjects instead of individual hands.

CARPAL TUNNEL SYNDROME

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Acknowledgment: We thank Jaya Rao, MD, MHS, and Richard W. Tim, MD, who reviewed this article and provided many helpful comments.

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Science cannot solve the ultimate mystery of nature. And that is because, in the last analysis, we ourselves are part of nature and therefore part of the mystery that we are trying to solve.

—Max Planck (1858-1947)

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methylnaltrexone levels. Mean (SD [range]) peak plasma level for the other 4 patients (1 from the 1.0 mg/kg group and 3 from the 3.0 mg/kg group) was 17.8 (6.6 [10-26]) ng/mL.

Comment. Tertiary opioid antagonists, such as naloxone, cross the blood-brain barrier and reverse both the pain-relieving ben- efits and the adverse effects of opiates. Although oral naloxone may relieve opioid-induced constipation, the therapeutic index is very narrow,5 and naloxone may induce opioid withdrawal symptoms. Many patients receiving opioid pain medications face a difficult choice between burdensome adverse effects or inef- fective analgesia. Methylnaltrexone may allow for more aggres- sive use of opioid analgesics with fewer adverse effects. The low methylnaltrexone plasma levels observed in our study suggest that this charged compound acts directly in the gut. Oral methylnal- trexone has potential clinical utility in managing opioid- induced constipation with minimal adverse effects.

Chun-Su Yuan, MD, PhD Joseph F. Foss, MD Departments of Anesthesia and Critical Care University of Chicago Chicago, Ill

Funding/Support: This work was supported in part by a grant from the Interna- tional Anesthesia Research Society, National Institutes of Health grants R0I CA79042 and M01 RR00055. Methylnaltrexone was originally formulated and subse- quently modified by faculty at the University of Chicago. The University of Chi- cago and Drs Yuan and Foss stand to benefit financially from the further devel- opment of methylnaltrexone.

1. Levy MH. Pharmacologic treatment of cancer pain. N Engl J Med. 1996;335: 1124-1131. 2. Glare P, Lickiss JN. Unrecognized constipation in patients with advanced can- cer: a recipe for therapeutic disaster. J Pain Symptom Manage. 1992;7:369-371. 3. Yuan CS, Foss JF, O’Connor M, et al. Methylnaltrexone for reversal of consti- pation due to chronic methadone use. JAMA. 2000;283:367-372. 4. Basilisco G, Camboni G, Bozzani A, Paravicini M, Bianchi PA. Oral naloxone

antagonizes loperamide-induced delay of orocecal transit. Dig Dis Sci. 1987;32: 829-832. 5. Sykes NP. Oral naloxone in opioid-associated constipation. Lancet. 1991;337: 1475.

CORRECTIONS

Incorrect Wording and Footnote Symbol: In The Rational Clinical Examination en- titled “Does This Patient Have Carpal Tunnel Syndrome?” published in the June 21, 2000, issue of THE JOURNAL (2000;283:3110-3117), there was incorrect word- ing in the abstract. In the Conclusion paragraph on page 3110, the first sentence should have read, “Hand symptom diagrams, hypalgesia, and thumb abduction strength testing are helpful in establishing the electrodiagnosis of CTS.” Also, in Table 2 on pages 3114 and 3115, the “No. of Hands” columns should include dagger symbols (†) instead of asterisks (*) down the column to indicate which stud- ies used subjects instead of individual hands. Incorrect Wording and Data Presentation and Omitted Acknowledgment: In the Original Contribution entitled “Effect of Metformin and Rosiglitazone Combina- tion Therapy in Patients With Type 2 Diabetes Mellitus: A Randomized Controlled Trial” published in the April 5, 2000, issue of THE JOURNAL (2000;283:1695- 1702), incorrect wording and incorrect data presentation were printed. On page 1695, in the “Results” section of the Abstract, the sentence that read “28.1% achieved a glycosylated hemoglobin of less than 7%” should have read “7% or less.” On page 1698, the last sentence in the “Glycemic Control” section should have read “Nine patients (7.9%) in the control group, 25 (21.6%) in the 4-mg/d, and 33 (30.0%) in the 8-mg/d rosiglitazone groups achieved FPG concentrations of less than 7.8 mmol/L (140 mg/dL).” On page 1699 in the “Other Metabolic Effects” section, in the penultimate paragraph, which reports triglyceride find- ings, the phrase that read “in the rosiglitazone groups, the median baseline tri- glyceride value increased. . . by 0.07 mmol/L (6 mg/dL) from 1.34-mmol/L (119 mg/dL) in 55 patients taking 8-mg/d,” should have read “decreased by 0.72 mmol/L (64 mg/dL) from 9.16 mmol/L (280 mg/dL) in 37 patients taking 8 mg/d.” The last sentence of the penultimate paragraph of the “Other Metabolic Effects” sec- tion was repeated from the prior paragraph and should be deleted. In Table 2, the “Total cholesterol–HDL ratio” section should not have been converted to mmol/L. To calculate the proper ratio, divide the values in that section by 0.0259. In the footnote of Table 2, the cholesterol conversion factor should have read “0.0259.” On page 1701 in the “Comment” section in the third column, the line that read “Among patients in the 8-mg/d rosiglitazone group. . . there was a significant sta- tistical decrease observed (6.4-mg/dL)” should have read “(64 mg/dL).” In ad- dition, Sylvia K. Chai, PhD, should have been included in the acknowledgment for her significant contributions to the preparation and review of the article.

Figure. Dose-Related Changes in Oral-Cecal Transit Times

180

150

120

30 Placebo Methylnaltrexone,

0.3 mg/kg

O ra

l- C

ec al

T ra

n si

t T

im e,

m in

Placebo Methylnaltrexone, 1.0 mg/kg

Placebo Methylnaltrexone, 3.0 mg/kg

Changes in individual oral-cecal transit times of 12 patients receiving long-term methadone treatment after placebo and 3 oral methylnaltrexone doses (4 patients in each dose group). Squares represent mean values.

LETTERS

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methylnaltrexone levels. Mean (SD [range]) peak plasma level for the other 4 patients (1 from the 1.0 mg/kg group and 3 from the 3.0 mg/kg group) was 17.8 (6.6 [10-26]) ng/mL.

Chun-Su Yuan, MD, PhD Joseph F. Foss, MD Departments of Anesthesia and Critical Care University of Chicago Chicago, Ill

antagonizes loperamide-induced delay of orocecal transit. Dig Dis Sci. 1987;32: 829-832. 5. Sykes NP. Oral naloxone in opioid-associated constipation. Lancet. 1991;337: 1475.

CORRECTIONS

Figure. Dose-Related Changes in Oral-Cecal Transit Times

180

150

120

30 Placebo Methylnaltrexone,

0.3 mg/kg

O ra

l- C

ec al

T ra

n si

t T

im e,

m in

Placebo Methylnaltrexone, 1.0 mg/kg

Placebo Methylnaltrexone, 3.0 mg/kg

LETTERS

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