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Carpal tunnel syndrome (CTS) is the most prevalent human entrapment neuropathy, encompassing 45% of all non-traumatic nerve lesions.1 Despite the high direct medical, nancial, and
occupational costs associated with CTS,2,3 the
pathophysiology still remains a subject of debate.
The key factors that appear to underlie the pathophysiology and consequent symptoms are primarily
linked to the effects of nerve compression and
ischemia.46 Pathological studies in CTS have demonstrated focal disturbances in myelin and paranodal demyelination,79 perhaps suggesting that pure
compression is the more signicant contributor. In
support of such an hypothesis, nerve conduction
studies demonstrate focal slowing of the median
nerve at the level of the wrist, and compound
amplitudes may be reduced in the absence of
objective sensory loss.10,11
Recently, it was demonstrated that focal compression applied to the median nerve in healthy
individuals resulted in axonal depolarization.12,13
Although focal slowing of median nerve conduction in CTS may suggest evidence of altered restAbbreviations: ATPase, adenosine triphosphatase; CTS, carpal tunnel
syndrome; CV, conduction velocity; FNC, focal nerve compression; K,
potassium ion; Kv, voltage-dependent potassium (channel); Na, sodium
ion; NCS, nerve conduction studies; SDTC, short-duration threshold
change; SNAP, sensory nerve action potential; vFF, von Frey filament
Key words: carpal tunnel syndrome, nerve compression, nerve excitability,
numbness, paresthesiae
Correspondence to: M. C. Kiernan; e-mail: m.kiernan@unsw.edu.au
C 2011 Wiley Periodicals, Inc.
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402
Sensory nerve excitability was monitored before, during, and after focal nerve compression in patients
diagnosed with CTS. Studies were approved by
the South East Sydney Area Health Service Human
Research Ethics Committee (Eastern Section) and
the human research ethics committee of University
of New South Wales. Informed consent was provided
by each subject, and studies were undertaken in
accordance with the Declaration of Helsinki.
Patients were diagnosed with CTS based on the
combination of clinical presentation, ndings on
neurological examination, and the results of nerve
conduction studies (NCS). For inclusion in this
study, in addition to a typical clinical presentation,
NCS were required to demonstrate objective slowing of median sensory conduction at the level of
the wrist and, similarly, focal slowing of the median nerve when compared with ulnar and radial
nerve studies, as per established practice parameters.10,14 A positive result for electrophysiological
diagnosis of CTS was derived from a combination
of electrodiagnostic studies as follows14,15:
1 The orthodromic proximal and distal median
sensory conduction velocity (CV), and distal
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2
3
4
5
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403
Table 1. Results of standard nerve conduction studies recorded from the 11 CTS patients.
Patient
Digit IIwrist
CV (m/s)
Median forearm
CV (m/s)
Digit Vwrist
CV (m/s)
Latency
difference (ms)
1
2
3
4
5
6
7
8
9
10
11
Mean
13.5
11.1
6.1
5.7
22.7
13.7
22
16
19.9
16
18.5
15.0 6 1.7
42.6
52.7
43.5
38.4
50.5
39.3
44.7
38.2
40.7
41.4
47.1
43.6 6 1.5
67.8
57.3
65.0
58.8
61.5
62.1
58.5
61.2
48.8
55.3
56.6
59.4 6 1.5
53.5
52.7
45.6
54.9
56.5
55.3
54.4
50.0
52.3
48.6
55.2
52.6 6 1.0
1.50
0.60
0.30
1.15
0.60
0.65
1.10
0.75
0.90
0.90
0.30
0.80 6 0.11
SNAP amplitudes were measured peak to peak. Latency difference was calculated as the mean difference between median/radial and median/ulnar comparisons (see Methods).
(Marstocknervtest; Fruhstorfer, Schriesheim, Germany) were applied to the tip of the third digit every minute to objectively rate the development of
numbness. Again, tactile sensitivity was tested prior
to FNC during the baseline recording of nerve
excitability. A von Frey lament (vFF) force scale
was used to assess tactile sensitivity.11,12
Analysis. All results were expressed as mean 6
standard error of the mean. Measurements
recorded during FNC were normalized to the rst
measurements obtained after stabilization of FNC
to eliminate any artifact that may have resulted
during the process of applying compression.
Paired t-tests were used for single comparisons of
excitability parameters, with P < 0.05 considered
signicant.
For the purpose of comparing FNC-induced
excitability changes in CTS patients with controls,
data from a previous series were utilized.12 This
previous series involved monitoring 10 control subjects (5 men and 5 women, aged 2245 years,
mean 31.5 years) for changes in nerve excitability
before, during, and after the application of FNC.
The experimental paradigm and protocols used to
record nerve excitability were identical to those utilized in this study.
RESULTS
Experimental protocols were successfully completed in all 11 CTS patients (5 men and 6
women, aged 4766 years, mean 55.5 years). Each
study lasted, on average, 47.7 6 1.3 min. The
results of standard NCS, conrmatory for the CTS
patient cohort, are detailed in Table 1. Prior to
application of FNC, baseline sensory excitability of
CTS patients established a strengthduration time
constant (0.55 6 0.03 ms), refractoriness (14.5 6
2.7%), and superexcitability (16.7 6 0.9%). Skin
temperature was recorded at the site of stimulation
404
and monitored throughout each study (mean temperature 32.7 6 0.2 C for CTS patients and 32.7 6
0.4 C for controls).
Changes in Threshold Induced by Focal Nerve Compression. A stimulusresponse curve was recorded
prior to undertaking excitability measures and was
utilized to determine changes in maximal SNAP
amplitude that may develop in association with
application of FNC. During FNC, for both shortand long-duration stimuli, there were minor reductions in threshold, as illustrated for a representative CTS patient (Fig. 2A and B). In most patients,
threshold reached greatest reduction in the early
phase of FNC. Despite an apparently minimal
reduction in threshold, SNAP amplitude decreased
rapidly (Fig. 2C). Mean data conrmed this signicant reduction in SNAP amplitude for CTS
patients (32.4 6 3.9%; P < 0.001), with 1 patient
developing conduction block (amplitude reduction
56.2%).
Associated with these changes in threshold and
SNAP amplitude, latency increased accordingly
during FNC (Fig. 2D), with signicant prolongation for the CTS cohort (7.7 6 0.5%; P < 0.001).
Associated with these indications of gradual inactivation of Na channels, thresholds started to
increase toward the end of the FNC period.2729
With release of FNC, the threshold for the shortand long-duration stimuli increased above baseline
levels, indicative of the development of axonal hyperpolarization (Fig. 2A and B). Analysis of mean
data for CTS patients established that this increase
in threshold was signicant for both short-duration
(20.1 6 4.1%; P < 0.005) and long-duration (26.4
6 5.9%; P < 0.005) stimuli.
This increase in threshold was relatively
reduced in CTS patients, as supported by measurement of the maximal threshold change after
release of compression for CTS patients (short
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FIGURE 1. (A) Stimulation paradigm: threshold tracking (indicated by vertical arrows) in channels 1, 6, 10, and 12 aimed to elicit a
SNAP amplitude corresponding to the steepest portion of the stimulusresponse curve in channel 7. (B) Focal nerve compression
(FNC) and nerve excitability setup: a custom-designed and purpose-built compression device was utilized for achieving both electrical
stimulation and focal nerve compression. The SNAP generated from stimulation of the median nerve at the wrist was recorded from
the second digit. (C) The profile of compression achieved during FNC. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
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FIGURE 4. Correlation of nerve excitability parameters with normalized threshold during 10 min of FNC in the CTS patient cohort.
Changes in (A) SDTC, (B) refractoriness, (C) SNAP amplitude, and (D) superexcitability were sensitive to threshold.
and becomes hyperpolarized with release. This pattern of change was qualitatively similar to that
observed in healthy individuals. However, the magnitude of change in nerve excitability parameters
differed for CTS patients. In addition, the development of clinical symptoms during FNC suggests
FIGURE 6. Rating of symptoms associated with FNC (filled diamond: CTS patients; open triangles: healthy controls). Black
horizontal bar indicates period of FNC. (A) Paresthesiae (010).
(B) Numbness objectively assessed by von Frey filaments.
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lower baseline SNAP amplitude in patients, particularly given that the changes in excitability and
amplitude also corresponded with the severity of
CTS (Fig. 5). However, it is also noted that FNC
resulted in more rapid development of paresthesiae in CTS patients and that CTS patients experienced more prominent numbness. Such processes
may provide a basis for understanding the mechanisms of symptomatic therapy in CTS. Specically,
the use of wrist splints has remained the hallmark
of conservative therapy for CTS. Splints maintain
the wrist in a neutral or slightly extended position,
thereby preventing the development and subsequent release of compression, to provide symptomatic relief.
Given that focal nerve compression is also
known to paralyze the axonal Na/K pump, the
quantitatively greater effects documented for CTS
patients may suggest a greater reliance of axons on
normal pump function. Previous studies have demonstrated that inhibition of the Na/K pump
results in axonal depolarization.35 If the Na/K
pump exerts a hyperpolarizing inuence on resting membrane potential,36,37 inhibition of pump
function would further predispose to the development of axonal depolarization and development of
spontaneous activity such as paresthesiae, a typical
symptom of CTS.
This study was supported by a Prince of Wales Clinical School Postgraduate Research Scholarship, the National Health and Medical
Research Council of Australia (Project Grant 400938, Biomedical
Postgraduate Scholarship), and a Medical Advances without Animals Doctoral Research Scholarship.
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