nerve compression, membrane excitability, and symptoms of cts

7/26/2019 Nerve Compression, Membrane Excitability, And Symptoms of Cts

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NERVE COMPRESSION, MEMBRANE EXCITABILITY, AND SYMPTOMS

OF CARPAL TUNNEL SYNDROME

S. ERIC HAN, BE, CINDY S.-Y. LIN, PhD, ROBERT A. BOLAND, PhD, and MATTHEW C. KIERNAN, DSc

Neuroscience Research Australia & Prince of Wales Clinical School, University of New South Wales,Barker Street, Randwick, New South Wales 2031, Australia

Accepted 15 February 2011

ABSTRACT: Introduction: In this study we investigated thechanges in axonal excitability and the generation of neurologicalsymptoms in response to focal nerve compression (FNC) of themedian nerve in carpal tunnel syndrome (CTS). Methods: Sen-sory excitability recordings were undertaken in 11 CTS patientswith FNC being applied at the wrist using a custom-designedelectrode. Results: During FNC, refractoriness increased signifi-cantly (62.4 6 3.4%;P < 0.001), associated with a rapid reduc-tion in superexcitability (16.9 6 2.8%; P < 0.001) and sensorynerve action potential amplitude (SNAP) (32.4 6 3.9%; P 0.4 ms between radial and me-dian, or ulnar and median sensory latenciestaken at a distance of 100140 mm.16,17

Prolongation of median motor terminal latency

>4.6 ms.16,18

Previously established values from our laboratorywere used as normative values.19 Patients with coex-isting peripheral neuropathy, cervical radiculopathy,or metabolic disorders known to affect nerve func-tion, such as diabetes or renal impairment, wereexcluded.2022 Patients with an orthodromic medianSNAP amplitude


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(Marstocknervtest; Fruhstorfer, Schriesheim, Ger-many) were applied to the tip of the third digit ev-ery minute to objectively rate the development ofnumbness. Again, tactile sensitivity was tested priorto FNC during the baseline recording of nerveexcitability. A von Frey filament (vFF) force scale

was used to assess tactile sensitivity.11,12

Analysis. All results were expressed as mean 6standard error of the mean. Measurementsrecorded during FNC were normalized to the firstmeasurements obtained after stabilization of FNCto eliminate any artifact that may have resultedduring the process of applying compression.Paired t-tests were used for single comparisons ofexcitability parameters, with P < 0.05 consideredsignificant.

For the purpose of comparing FNC-inducedexcitability changes in CTS patients with controls,data from a previous series were utilized.12 Thisprevious series involved monitoring 10 control sub-

jects (5 men and 5 women, aged 2245 years,mean 31.5 years) for changes in nerve excitabilitybefore, during, and after the application of FNC.The experimental paradigm and protocols used torecord nerve excitability were identical to those uti-lized in this study.

RESULTS

Experimental protocols were successfully com-pleted in all 11 CTS patients (5 men and 6

women, aged 4766 years, mean 55.5 years). Eachstudy lasted, on average, 47.7 6 1.3 min. Theresults of standard NCS, confirmatory for the CTSpatient cohort, are detailed in Table 1. Prior toapplication of FNC, baseline sensory excitability ofCTS patients established a strengthduration timeconstant (0.55 6 0.03 ms), refractoriness (14.5 62.7%), and superexcitability (16.7 6 0.9%). Skintemperature was recorded at the site of stimulation

and monitored throughout each study (mean tem-perature 32.7 60.2C for CTS patients and 32.7 60.4C for controls).

Changes in Threshold Induced by Focal Nerve Com-

pression. A stimulusresponse curve was recordedprior to undertaking excitability measures and wasutilized to determine changes in maximal SNAPamplitude that may develop in association withapplication of FNC. During FNC, for both short-and long-duration stimuli, there were minor reduc-tions in threshold, as illustrated for a representa-tive CTS patient (Fig. 2A and B). In most patients,threshold reached greatest reduction in the earlyphase of FNC. Despite an apparently minimal

reduction in threshold, SNAP amplitude decreasedrapidly (Fig. 2C). Mean data confirmed this signifi-cant reduction in SNAP amplitude for CTSpatients (32.4 6 3.9%; P < 0.001), with 1 patientdeveloping conduction block (amplitude reduction56.2%).

Associated with these changes in threshold andSNAP amplitude, latency increased accordinglyduring FNC (Fig. 2D), with significant prolonga-tion for the CTS cohort (7.7 6 0.5%; P < 0.001).

Associated with these indications of gradual inacti-vation of Na channels, thresholds started toincrease toward the end of the FNC period.2729

With release of FNC, the threshold for the short-and long-duration stimuli increased above baselinelevels, indicative of the development of axonal hy-perpolarization (Fig. 2A and B). Analysis of meandata for CTS patients established that this increasein threshold was significant for both short-duration(20.1 6 4.1%; P < 0.005) and long-duration (26.46 5.9%; P< 0.005) stimuli.

This increase in threshold was relativelyreduced in CTS patients, as supported by measure-ment of the maximal threshold change afterrelease of compression for CTS patients (short

Table 1. Results of standard nerve conduction studies recorded from the 11 CTS patients.

Patient

Digit IIwrist SNAP

amplitude (lV)

Digit IIwrist

CV (m/s)

Median forearm

CV (m/s)

Digit Vwrist

CV (m/s)

Latency

difference (ms)

1 13.5 42.6 67.8 53.5 1.50

2 11.1 52.7 57.3 52.7 0.60

3 6.1 43.5 65.0 45.6 0.30

4 5.7 38.4 58.8 54.9 1.155 22.7 50.5 61.5 56.5 0.60

6 13.7 39.3 62.1 55.3 0.65

7 22 44.7 58.5 54.4 1.10

8 16 38.2 61.2 50.0 0.75

9 19.9 40.7 48.8 52.3 0.90

10 16 41.4 55.3 48.6 0.90

11 18.5 47.1 56.6 55.2 0.30

Mean 15.0 6 1.7 43.6 6 1.5 59.4 6 1.5 52.6 6 1.0 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 com-

parisons (see Methods).

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duration: 21.2 6 3.6%; long duration: 27.1 65.4%; Fig. 3A and B), when compared with con-trols [short duration: 39.5 6 7.4% (P< 0.05); longduration: 51.4 6 9.1% (P < 0.05)]. Furthermore,

within the first 10 min of FNC application, SNAPamplitude reduction developed more rapidly inCTS patients (9.9 6 2.8%; Fig. 3C) compared withcontrols (2.2 6 0.9%; P


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scores (0.25, 0.5, 1, 2, 4, 8, 16512 mN) indicatedlower tactile sensitivity, concurrent with the devel-opment of prominent numbness. Patients withCTS had a mean score of 4.7 6 1.6 mN at rest

(Fig. 6B), indicating significantly impaired tactilesensitivity compared with controls (0.8 6 0.4 mN;P< 0.05). During the period of FNC there was anoverall increase in the mean vFF score (14.1 6 4.7mN), greater than the changes observed incontrols.

Similarly, paresthesiae developed more rapidlyand intensely in CTS patients than controls. Dur-ing the first 10 minutes of FNC application, the cu-mulative score of paresthesiae for CTS patients was43.6 6 6.6, compared with 22.7 6 6.7 for controls(P < 0.05). During the same duration of FNC,CTS patients demonstrated a more pronouncedincrease in vFF score (7.4 6 1.8; Fig. 6B), com-pared with controls (2.1 6 0.8; P


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and becomes hyperpolarized with release. This pat-tern of change was qualitatively similar to thatobserved in healthy individuals. However, the mag-nitude of change in nerve excitability parametersdiffered for CTS patients. In addition, the develop-ment of clinical symptoms during FNC suggests

that CTS patients had a greater sensitivity to theeffects of compression. Overall, these differencessuggest impaired axonal function in CTS inresponse to compression and would support anhypothesis of greater reliance on the function ofthe axonal Na/K-ATPase. Altered sensitivity and

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.

FIGURE 5. Correlation of baseline nerve excitability parameters

compared with conventional NCS measures of CTS severity.

(A) Pre-FNC SNAP amplitude correlated with refractoriness at

baseline. (B) Distal median velocity correlated with superexcit-

ability at baseline.

FIGURE 6. Rating of symptoms associated with FNC (filled dia-

mond: CTS patients; open triangles: healthy controls). Black

horizontal bar indicates period of FNC. (A) Paresthesiae (010).

(B) Numbness objectively assessed by von Frey filaments.

Focal Nerve Compression in CTS MUSCLE & NERVE September 2011 407


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axonal function in response to FNC in CTSpatients may further contribute to the pathophysio-logical processes responsible for the clinical fea-tures associated with this most common entrap-ment neuropathy.

Prior to interpretation of findings, it is worth

noting that we recruited patients with SNAP ampli-tudes >5 lV. As such, patients would be classifiedas mild or moderate CTS. Although patients withsevere CTS were not studied, the effects of mor-phological factors, such as axonal loss, axonalattenuation, disordered myelination, and intraneu-ral fibrosis, may also contribute to symptoms inthis group, at least as much as the effects of ische-mia and between compression. Furthermore, cor-relation between severity of CTS (reflected bySNAP amplitude and median nerve conduction ve-locity) and baseline nerve excitability parametersmay suggest that, although SNAP amplitude corre-

lated with refractoriness, an excitability parameterdependent on nodal transient Na conductan-ces,3033 it did not correlate as well with superexcit-ability, an excitability parameter determined byparanodal properties (Fig. 5A).30 As such, thestudy enrollment requirement of having SNAP am-plitude >5 lV may have ensured a level of nodalintegrity (i.e., being morphologically intact).Similarly, paranodal integrity, and thereby func-tion, may also exert an influence on the interpreta-tion of findings from CTS patients, given the likelyredistribution of juxtaparanodal fast K (Kv) chan-nels that may occur with paranodal demyelination.

For instance, it is now known that juxtaparanodalKvchannels become exposed below damaged mye-lin.34 Consequently the membrane potential maycome to lie closer to the K equilibrium potential,

with an overall reduction in excitability.34 Itremains plausible that such morphological andfunctional processes may also contribute to thelimited extent of depolarization that developed inCTS patients during FNC, as observed here.

Nerve Compression and Axonal Excitability. Theapplication of nerve compression in this studyresulted in reduction in threshold and prolonga-tion in latency. These changes were associated withan increase in refractoriness and reduction insuperexcitability. Excitability changes were indica-tive of axonal depolarization, with subsequentreduction in SNAP amplitude, and development ofdepolarization conduction block.

Although the changes in threshold appearedless prominent in CTS patients than in controls,there were correspondingly greater reductions inamplitude of the SNAPs (Fig. 3). However, itremains plausible that these greater reductionsobserved in CTS patients may simply reflect a

lower baseline SNAP amplitude in patients, partic-ularly given that the changes in excitability andamplitude also corresponded with the severity ofCTS (Fig. 5). However, it is also noted that FNCresulted in more rapid development of paresthe-siae in CTS patients and that CTS patients experi-

enced more prominent numbness. Such processesmay provide a basis for understanding the mecha-nisms of symptomatic therapy in CTS. Specifically,the use of wrist splints has remained the hallmarkof conservative therapy for CTS. Splints maintainthe wrist in a neutral or slightly extended position,thereby preventing the development and subse-quent release of compression, to provide sympto-matic relief.

Given that focal nerve compression is alsoknown to paralyze the axonal Na/K pump, thequantitatively greater effects documented for CTSpatients may suggest a greater reliance of axons on

normal pump function. Previous studies have dem-onstrated that inhibition of the Na/K pumpresults in axonal depolarization.35 If the Na/K

pump exerts a hyperpolarizing influence on rest-ing membrane potential,36,37 inhibition of pumpfunction would further predispose to the develop-ment of axonal depolarization and development ofspontaneous activity such as paresthesiae, a typicalsymptom of CTS.

This study was supported by a Prince of Wales Clinical School Post-graduate Research Scholarship, the National Health and MedicalResearch Council of Australia (Project Grant 400938, BiomedicalPostgraduate Scholarship), and a Medical Advances without Ani-

malsDoctoral ResearchScholarship.

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nerve compression, membrane excitability, and symptoms of cts

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