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Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies
Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies Adeniyi A. Borire a,c,d,⇑, Andrew R. Hughes a,b, Christian J. Lueck a,b, James G. Colebatch c,d, Arun V. Krishnan c,d a
Australian National University Medical School, Canberra, ACT, Australia Department of Neurology, The Canberra Hospital, Canberra, ACT, Australia Institute of Neurological Sciences, Prince of Wales Hospital, Sydney, NSW, Australia d Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia b c
a r t i c l e
i n f o
Article history: Received 2 February 2016 Accepted 8 May 2016 Available online xxxx Keywords: Carpal tunnel syndrome Cross-sectional area Median nerve Nerve conduction studies Ultrasound
a b s t r a c t We evaluated the differences in sonographic parameters in carpal tunnel syndrome (CTS) patients with normal and mildly abnormal nerve conduction studies (NCS). This was a prospective cross-sectional study. We assessed 169 wrists (101 patients) with a clinical diagnosis of carpal tunnel syndrome (CTS), as well as 20 healthy controls (40 wrists). 49 wrists were classified as mild NCS-positive and 38 as NCS-negative based on our laboratory NCS normal values. The cross-sectional area (CSA) of the median nerve at the carpal tunnel inlet and mid-forearm were measured and the wrist-to-forearm ratio (WFR) was calculated. 26% of the NCS-negative group had abnormal CSA. The CSA and WFR also differed significantly between the two groups. There was significant correlation between the sonographic and electrophysiologic variables. Ultrasound was diagnostic for CTS in a third of the NCS-negative wrists. Ultrasound may be useful in clinical CTS patients with normal or borderline NCS. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Carpal tunnel syndrome (CTS) is the commonest entrapment neuropathy and is due to compression of the median nerve at the wrist [1]. There is still no gold standard for the diagnosis of CTS and a clinical diagnosis is usually reached on the basis of characteristic symptoms and signs, with confirmation by nerve conduction studies (NCS) [2]. However, NCS remains normal in 15% of patients with characteristic clinical features of CTS [3]. In the last few years, ultrasonography (US) has been shown to be a useful diagnostic tool in CTS [4–6]. Ultrasound is painless, non-invasive, and provides a view of the anatomy of the nerve, as well as of surrounding structures. There is currently Class A evidence showing that sonographic measurement of the median nerve cross-sectional area (CSA) may be used as a diagnostic test for CTS [7]. Furthermore, several studies have shown that the median nerve CSA at the wrist correlates well with clinical and electrophysiological severity [8–13]. A few studies have also reported on the diagnostic utility of ultrasound in clinical CTS patients in whom NCS are normal
⇑ Corresponding author. Tel.: +61 400563705. E-mail address: [email protected] (A.A. Borire).
[14–16]. These patients often referred to as NCS-negative CTS patients have typical clinical features of CTS, including positive provocative testing, and yet electrodiagnostic testing for CTS may be normal. Some studies have reported sonographic abnormalities (diagnostic of CTS) in up to 50% of this population. Most of the studies that have evaluated the sonographic characteristics of NCS-positive and NCS-negative CTS have included patients with varying grades of severity, ranging from mild lesions to severe (or sometimes complete) lesions. The inclusion of patients with severe lesions has the tendency to overstate the sonographic differences between these groups. A less biased approach will be to include only NCS-positive CTS patients with mild NCS abnormalities. In this study, our aim was to explore potential differences between CTS patients with mild electrophysiological abnormalities and CTS patients who had completely normal NCS. Our aim was to determine if there were differences in the sonographic parameters between these two groups. 2. Methods We examined 169 wrists from 101 consecutive patients referred to our Neurophysiology laboratory with a clinical diagnosis of CTS which met the American Academy of Neurology (AAN)/
http://dx.doi.org/10.1016/j.jocn.2016.05.024 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
2
A.A. Borire et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) clinical diagnostic criteria. These can be summarized as nocturnal and/or activity-related sensory symptoms, sensory deficits in the median nerve distribution, and weakness and/or atrophy of median-innervated thenar muscles [3]. Patients with peripheral neuropathy, traumatic nerve injury and previous wrist or CTS surgery as well as those less than 18 years of age were excluded from this study. The study was approved by the local research ethics committee and informed consent was obtained from all study participants. A cohort of 20 age and gender-matched healthy controls (40 wrists) were also examined. 2.1. Nerve conduction studies All studies were conducted with skin temperature maintained above 32°C. Orthodromic recording of the median nerve sensory nerve action potential (SNAP) was obtained following stimulation of the index finger with ring electrodes. The onset latency, peak amplitude, and sensory conduction velocity (SCV) were noted. The median nerve compound muscle action potential (CMAP) was recorded from the abductor pollicis brevis muscle following median nerve stimulation at the wrist. The distal motor latency (DML) and peak amplitude of the CMAP were also measured. Comparative sensory studies (orthodromic median and radial conduction with ring electrode stimulation from the thumb and recording from the wrist; orthodromic median and ulnar conduction with ring electrode stimulation from the 4th digit and recording from the wrist) and needle electromyography were performed when indicated. The severity of CTS was graded as mild, moderate, or severe based on the following criteria [17]: Mild – prolonged median sensory distal latency. No evidence of axon loss. Moderate – prolonged median sensory and motor distal latency. No evidence of axon loss. Severe – Any of the aforementioned NCS abnormalities with evidence of axon loss as defined by either: (1) an absent or low-amplitude SNAP; (2) a low-amplitude or absent thenar CMAP; or (3) a needle EMG with fibrillation potentials or motor unit potential changes (large amplitude, long-duration motor unit potentials, or excessive polyphasia). 2.2. Ultrasonography Sonographic examination of all the subjects was performed using a MyLabOne system with a 10–18 MHz probe (Whiteley Diagnostics, Esaote, Italy). The median nerve in the carpal tunnel and mid-forearm were imaged in both the transverse and longitudinal planes. The ultrasound probe was kept perpendicular to the nerve in order to maintain reproducibility of results. The median nerve cross-sectional area (CSA) was measured (in mm2) at the carpal tunnel inlet (at the level of the pisiform bone) and mid-forearm (junction of the middle and distal third) by outlining the inner margin of the epineurium using the continuous trace method [7], and a wrist-forearm ratio (WFR) was then calculated [18]. (Fig. 1). For bifid nerves, both CSAs were recorded and averaged. Two separate CSA measurements were obtained at each site and the average value was used. 2.3. Data analysis Statistical analyses were conducted using SPSS (version 22.0, SPSS Inc., Chicago, IL, USA). Normality of all continuous variables was tested using the Shapiro–Wilk and Kolmogorov–Smirnov tests.
Descriptive statistics (mean and standard deviation) were applied for data analysis. The Wilcoxon signed-rank test was used to test the differences between the means of the groups and statistical significance was defined as p < 0.05. Spearman coefficients were calculated to determine the correlation between ultrasonographic (median nerve CSA and WFR) and NCS parameters of CTS. 3. Results Of the 169 wrists with a clinical diagnosis of CTS, 131 (77.5%) were confirmed to have CTS on NCS. The remaining 38 (22.5%) had negative NCS. 20 healthy controls (40 wrists) were also studied. Of the 131 NCS-positive wrists 49, 41 and 41 were classified as having mild, moderate and severe CTS respectively. We determined the optimal cut-off value for the detection of mild CTS using the median nerve CSA to be 11.4 mm2 (sensitivity = 71%; specificity = 97.5%). For the WFR, the cut-off value for mild CTS was estimated to be 1.53 (sensitivity = 60%; specificity = 92.5%). Data obtained from mild NCS-positive patients was compared with the NCS-negative group. Two patients had complete lesions with no recordable sensory or motor potentials. The baseline characteristics are listed in Table 1. The mean median nerve CSA was 13.2 ± 3.5 mm2 for the mild NCS-positive group, 10.1 ± 2.4 mm2 for NCS-negative wrists and 9.3 ± 1.2 mm2 for the healthy controls. Similarly, the mean WFRs were 1.63 ± 0.38, 1.38 ± 0.30 and 1.19 ± 0.17 respectively. As shown in Figure 2, there was a significant difference between the median nerve CSA of the mild NCS-positive group, NCS-negative group and healthy controls. The WFR also differed significantly between all groups. There was a strong correlation between the CSA and WFR (r = 0.726, p < 0.001). In the mild NCS-positive group, 67% had enlarged CSA at the wrist compared with 26% of the NCSnegative wrists (p < 0.0001). Similarly, 57% of the mild NCSpositive group had abnormal WFR compared to 32% in the NCSnegative group (p < 0.0001). As shown in Table 2, the following variables correlated well with the median nerve CSA at the carpal tunnel inlet: SCV (r = 0.564, p < 0.0001), SNAP amplitude (r = 0.574, p < 0.0001), DML (r = 0.523, p < 0.0001) and CMAP amplitude (r = 0.216, p < 0.01). Furthermore, the following variables were correlated with the WFR: SCV (r = 0.552, p < 0.0001) SNAP amplitude (r = 0.465, p < 0.0001) and DML (r = 0.454, p < 0.0001). In the moderate and severe NCS-positive groups, the mean median nerve CSA was 14.0 ± 3.0 mm2 and 18.2 ± 6.2 mm2 respectively. Similarly, the mean WFR for both groups was 1.81 ± 0.33 and 2.23 ± 0.71 respectively. There was significant correlation between the sonographic parameters and electrophysiological severity (r = 0.608, p < 0.0001 for CSA, r = 0.547, p < 0.0001 for WFR). This further demonstrates the relationship between nerve structure and function, as well as the potential benefit of ultrasonography in assessing CTS severity. Bifid median nerves were found in 16 wrists (10%) but there was no significant difference between NCS-positive group, NCSnegative group and healthy controls (p = 0.63). A persistent median artery was identified in two NCS-positive patients and one NCSnegative patient. Analysis of the data with and without these patients made no difference to the overall conclusions. 4. Discussion This study has shown that there are significant sonographic differences between clinical CTS patients with normal NCS and those with mild NCS abnormalities. We have demonstrated that the CSA (and hence WFR) is smaller at the wrist in NCS-negative patients than in mild NCS-positive patients. The significance of these
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
A.A. Borire et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
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Fig. 1. Measurement of the median nerve cross-sectional area at the carpal tunnel inlet showing nerve enlargement.
Table 1 Baseline characteristics of carpal tunnel syndrome study patients and controls Demographic and sonographic variables
Mild NCSpositive (n = 49)
NCSnegative (n = 38)
Healthy controls (n = 40)
Age (years) Height (cm) Weight (kg) Body mass index (kg/m2) CSA (mm2)* WFR*
55.0 ± 11.8 165.9 ± 9.08 83.7 ± 21 30.4 ± 7.5 13.2 ± 3.5 1.63 ± 0.38
51.5 ± 15.1 166.7 ± 9.3 80.0 ± 20.8 28.8 ± 7.4 10.1 ± 2.4 1.38 ± 0.30
51.1 ± 8.2 173 ± 10.3 87.3 ± 16.2 29.0 ± 5.0 9.3 ± 1.2 1.19 ± 0.17
Except where indicated otherwise, the data are presented as mean ± SD. * p < 0.001. CSA = cross-sectional area, NCS = nerve conduction studies, WFR = wrist-to-forearm ratio.
findings is that, unlike in earlier studies [14–16], these sonographic differences have been demonstrated in a cohort consisting of only mild NCS-positive CTS patients. Previous studies have included patients with severe electrophysiological changes which may potentially amplify the differences between the two groups. Therefore, limiting the population of NCS-positive patients to those with mild abnormalities alone reduces bias and is a more accurate reflection of the relationship between NCS abnormalities and early changes in median nerve morphology. The use of only mild NCSpositive patients is also appropriate as majority of patients who present to the EMG laboratory have mild disease. Furthermore, diagnostic uncertainty in CTS usually involves patients with the typical clinical features of CTS, but who have normal, borderline or mildly abnormal NCS results. Most of the CSA abnormalities in the NCS-negative group were relatively mild, with only two patients having CSA >14 mm2. This is in agreement with earlier studies which have reported a tendency for milder US abnormalities in this population [16,19]. This also supports the comparison of this group with mild NCS-positive patients. One limitation of this study is a lack of long-term data about the NCS-negative
group. A future study would need to focus on the NCS-negative patients to determine the proportion that becomes NCS-positive and whether US has any predictive value in this group. The lack of a gold standard for the diagnosis of CTS limits the accuracy of various diagnostic techniques. Moreover, due to technical reasons and variations in normative values between centres, it is possible that a clinical CTS patient may be classified as mild NCS-positive in one laboratory, and as NCS-negative in another. In these borderline patients, the added information that ultrasound provides may increase the diagnostic accuracy, thus reducing the false negative rate of NCS. Our findings show that there are clear differences between mild NCS-positive and NCS-negative patients and, the presence of an enlarged nerve in this situation therefore further improves the certainty of CTS diagnosis. The present study demonstrates that up to a third of the NCS-negative hands had ultrasound abnormalities with both the mild NCS-positive patients and NCS-negative patients manifesting significantly larger CSA and WFR, compared to the healthy controls. In addition, there were significant correlations that were noted between sonographic parameters and electrophysiological indices, consistent with earlier studies [8–13]. Previous studies have found that 10–25% of patients with clinical CTS may have negative NCS [3]. Kitsis et al. [2] proposed that this discrepancy arose because the pressure on the median nerve was high enough to cause symptoms but not high enough to cause disturbance in electrical function. Normal pressure in the carpal tunnel ranges between 3 and 5 mmHg [20]. A rise in pressure to 20–30 mmHg reduces epineurial blood flow, but a further rise to 30–40 mmHg is required before electrophysiological abnormalities can be detected [22]. Epineurial oedema and axonal transport block begin to occur at pressures associated with reduced blood flow, even before NCS abnormalities appear. Complete intraneural ischemia and motor and sensory block occur at about 60 mmHg [21,22]. It is possible that patients in the negative NCS group in our study had carpal tunnel pressures in the intermediate range of 20–30 mmHg, a level at which symptoms may occur in the absence of alterations in NCS parameters that assess impulse
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
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A.A. Borire et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Fig. 2. Box plot showing the median nerve cross-sectional area (CSA) at the carpal tunnel inlet (left) and the wrist-to-forearm ratio (right) in mild nerve conduction studies (NCS)-positive patients, NCS-negative patients and healthy controls. Gradual increase in CSA was noted with worsening electrophysiologic severity. Significant differences were noted in the CSA and wrist-forearm ratio (WFR) between all the groups. Bold black lines indicate medians, whiskers indicate error bars and s indicates outliers. X-axis reference line represents the cut-off values, set at 11.7 mm2 for CSA and 1.53 for WFR. CSA = cross-sectional area, CTS = carpal tunnel syndrome, NCS = nerve conduction studies.
Table 2 Correlation between NCS and US parameters in clinical carpal tunnel syndrome patients CSA Coefficient (r) (n = 131) SCV DML MCV SNAP amplitude CMAP amplitude Electrophysiological severity
0.564 0.523 * 0.384 0.574 0.216 0.608 *
*
* * *
WFR Coefficient (r) (n = 131) 0.552 0.454 * 0.199 0.465 0.169 0.547 *
*
y * y
* p < 0.01. p < 0.05. CMAP = compound muscle action potential, CSA = cross-sectional area, DML = distal motor latency, MCV = motor conduction velocity, NCS = Nerve conduction studies, SCV = sensory conduction velocity, SNAP = sensory nerve action potential, US = ultrasound, WFR = wrist to forearm ratio. y
conduction. The importance of this finding is that it implies that normal NCS findings do not exclude CTS which could be demonstrated by the finding of an enlarged nerve on US. In conclusion, the present study demonstrates that there are differences in US parameters between CTS patients who have mild abnormalities on NCS and in those who have normal NCS. The study also shows that a proportion of the NCS-negative group may manifest changes in US parameters. This suggests that US may prove to be a useful adjunctive test in patients with early CTS, including those in whom nerve conduction abnormalities are not present.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
References [1] Katz JN, Simmons BP. Clinical practice. Carpal tunnel syndrome. N Engl J Med 2002;346:1807–12. http://dx.doi.org/10.1056/NEJMcp013018. [2] Kitsis CK, Savvidou O, Alam A, et al. Carpal tunnel syndrome despite negative neurophysiological studies. Acta Orthop Belg 2002 Apr;68:135–40.
[3] Practice parameter for electrodiagnostic studies in carpal tunnel syndrome: summary statement. Muscle Nerve 2002;25:918–22. http://dx.doi.org/ 10.1002/mus.10185. [4] Lee D, van Holsbeeck MT, Janevski PK, et al. Diagnosis of carpal tunnel syndrome: ultrasound versus electromyography. Radiol Clin North Am 1999;37:859–72. [5] Beekman R, Visser LH. Sonography in the diagnosis of carpal tunnel syndrome: a critical review of the literature. Muscle Nerve 2003;27:26–33. [6] Sarria L, Cabada T, Cozcolluela R, et al. Carpal tunnel syndrome: usefulness of sonography. Eur Radiol 2000;10:1920–5. [7] Cartwright MS, Hobson-Webb LD, Boon AJ, et al. Evidence-based guideline: neuromuscular ultrasound for the diagnosis of carpal tunnel syndrome. Muscle Nerve 2012;46:287–93. http://dx.doi.org/10.1002/mus.23389. [8] Visser LH, Smidt MH, Lee ML. High-resolution sonography versus EMG in the diagnosis of carpal tunnel syndrome. J Neurol Neurosurg Psychiatry 2008;79:63–7. [9] Buchberger W, Judmaier W, Birbamer G, et al. Carpal tunnel syndrome: diagnosis with high-resolution sonography. AJR 1992;159:793–8. [10] Duncan I, Sullivan P, Lomas F. Sonography in the diagnosis of carpal tunnel syndrome. AJR 1999;173:681–4. [11] Wong SM, Griffith JF, Hui AC, et al. Discriminatory sonographic criteria for the diagnosis of carpal tunnel syndrome. Arthritis Rheum 2002;46:1914–21. [12] Swen WA, Jacobs JW, Bussemaker FE, et al. Carpal tunnel sonography by the rheumatologist versus nerve conduction study by the neurologist. J Rheumatol 2001;28:62–9. [13] Keberle M, Jenett M, Kenn W, et al. Technical advances in ultrasound and MR imaging of carpal tunnel syndrome. Eur Radiol 2000;10:1043–50. [14] Al-Hashel JY, Rashad HM, Nouh MR, et al. Sonography in carpal tunnel syndrome with normal nerve conduction studies. Muscle Nerve 2015;51:592–7. [15] Claes F, Kasius KM, Meulstee J, et al. Comparing a new ultrasound approach with electrodiagnostic studies to confirm clinically defined carpal tunnel syndrome: a prospective, blinded study. Am J Phys Med Rehabil 2013;92:1005–11. [16] Mhoon JT, Juel VC, Hobson-Webb LD. Median nerve ultrasound as a screening tool in carpal tunnel syndrome: correlation of cross-sectional area measures with electrodiagnostic abnormality. Muscle Nerve 2012;46:861–70. http://dx. doi.org/10.1002/mus.23426. [17] Stevens JC. AAEM minimonograph #26: the electrodiagnosis of carpal tunnel syndrome. Muscle Nerve 1997;20:1477–86. [18] Hobson-Webb LD, Massey JM, Juel VC, et al. The ultrasonographic wrist-toforearm median nerve area ratio in carpal tunnel syndrome. Clin Neurophysiol 2008;119:1353–7. [19] Klauser AS, Halpern EJ, De Zordo T, et al. Carpal tunnel syndrome assessment with US: value of additional cross-sectional area measurements of the median nerve in patients versus healthy volunteers. Radiology 2009;250:171–7. [20] Gelberman RH, Hergenroeder PT, Hargens AR, et al. The carpal tunnel syndrome. A study of carpal canal pressures. J Bone Joint Surg Am 1981;63:380–3. [21] Szabo RM, Gelberman RH. Pathophysiology of nerve entrapment syndromes. J Hand Surg Am 1987;12:880–4. http://dx.doi.org/10.1016/S0363-5023(87) 80254-X. [22] Powell HC, Myers RR. Pathology of experimental nerve compression. Lab Invest 1986;55:91–100.
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies Adeniyi A. Borire a,c,d,⇑, Andrew R. Hughes a,b, Christian J. Lueck a,b, James G. Colebatch c,d, Arun V. Krishnan c,d a
Australian National University Medical School, Canberra, ACT, Australia Department of Neurology, The Canberra Hospital, Canberra, ACT, Australia Institute of Neurological Sciences, Prince of Wales Hospital, Sydney, NSW, Australia d Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia b c
a r t i c l e
i n f o
Article history: Received 2 February 2016 Accepted 8 May 2016 Available online xxxx Keywords: Carpal tunnel syndrome Cross-sectional area Median nerve Nerve conduction studies Ultrasound
a b s t r a c t We evaluated the differences in sonographic parameters in carpal tunnel syndrome (CTS) patients with normal and mildly abnormal nerve conduction studies (NCS). This was a prospective cross-sectional study. We assessed 169 wrists (101 patients) with a clinical diagnosis of carpal tunnel syndrome (CTS), as well as 20 healthy controls (40 wrists). 49 wrists were classified as mild NCS-positive and 38 as NCS-negative based on our laboratory NCS normal values. The cross-sectional area (CSA) of the median nerve at the carpal tunnel inlet and mid-forearm were measured and the wrist-to-forearm ratio (WFR) was calculated. 26% of the NCS-negative group had abnormal CSA. The CSA and WFR also differed significantly between the two groups. There was significant correlation between the sonographic and electrophysiologic variables. Ultrasound was diagnostic for CTS in a third of the NCS-negative wrists. Ultrasound may be useful in clinical CTS patients with normal or borderline NCS. Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction Carpal tunnel syndrome (CTS) is the commonest entrapment neuropathy and is due to compression of the median nerve at the wrist [1]. There is still no gold standard for the diagnosis of CTS and a clinical diagnosis is usually reached on the basis of characteristic symptoms and signs, with confirmation by nerve conduction studies (NCS) [2]. However, NCS remains normal in 15% of patients with characteristic clinical features of CTS [3]. In the last few years, ultrasonography (US) has been shown to be a useful diagnostic tool in CTS [4–6]. Ultrasound is painless, non-invasive, and provides a view of the anatomy of the nerve, as well as of surrounding structures. There is currently Class A evidence showing that sonographic measurement of the median nerve cross-sectional area (CSA) may be used as a diagnostic test for CTS [7]. Furthermore, several studies have shown that the median nerve CSA at the wrist correlates well with clinical and electrophysiological severity [8–13]. A few studies have also reported on the diagnostic utility of ultrasound in clinical CTS patients in whom NCS are normal
⇑ Corresponding author. Tel.: +61 400563705. E-mail address: [email protected] (A.A. Borire).
[14–16]. These patients often referred to as NCS-negative CTS patients have typical clinical features of CTS, including positive provocative testing, and yet electrodiagnostic testing for CTS may be normal. Some studies have reported sonographic abnormalities (diagnostic of CTS) in up to 50% of this population. Most of the studies that have evaluated the sonographic characteristics of NCS-positive and NCS-negative CTS have included patients with varying grades of severity, ranging from mild lesions to severe (or sometimes complete) lesions. The inclusion of patients with severe lesions has the tendency to overstate the sonographic differences between these groups. A less biased approach will be to include only NCS-positive CTS patients with mild NCS abnormalities. In this study, our aim was to explore potential differences between CTS patients with mild electrophysiological abnormalities and CTS patients who had completely normal NCS. Our aim was to determine if there were differences in the sonographic parameters between these two groups. 2. Methods We examined 169 wrists from 101 consecutive patients referred to our Neurophysiology laboratory with a clinical diagnosis of CTS which met the American Academy of Neurology (AAN)/
http://dx.doi.org/10.1016/j.jocn.2016.05.024 0967-5868/Ó 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
2
A.A. Borire et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) clinical diagnostic criteria. These can be summarized as nocturnal and/or activity-related sensory symptoms, sensory deficits in the median nerve distribution, and weakness and/or atrophy of median-innervated thenar muscles [3]. Patients with peripheral neuropathy, traumatic nerve injury and previous wrist or CTS surgery as well as those less than 18 years of age were excluded from this study. The study was approved by the local research ethics committee and informed consent was obtained from all study participants. A cohort of 20 age and gender-matched healthy controls (40 wrists) were also examined. 2.1. Nerve conduction studies All studies were conducted with skin temperature maintained above 32°C. Orthodromic recording of the median nerve sensory nerve action potential (SNAP) was obtained following stimulation of the index finger with ring electrodes. The onset latency, peak amplitude, and sensory conduction velocity (SCV) were noted. The median nerve compound muscle action potential (CMAP) was recorded from the abductor pollicis brevis muscle following median nerve stimulation at the wrist. The distal motor latency (DML) and peak amplitude of the CMAP were also measured. Comparative sensory studies (orthodromic median and radial conduction with ring electrode stimulation from the thumb and recording from the wrist; orthodromic median and ulnar conduction with ring electrode stimulation from the 4th digit and recording from the wrist) and needle electromyography were performed when indicated. The severity of CTS was graded as mild, moderate, or severe based on the following criteria [17]: Mild – prolonged median sensory distal latency. No evidence of axon loss. Moderate – prolonged median sensory and motor distal latency. No evidence of axon loss. Severe – Any of the aforementioned NCS abnormalities with evidence of axon loss as defined by either: (1) an absent or low-amplitude SNAP; (2) a low-amplitude or absent thenar CMAP; or (3) a needle EMG with fibrillation potentials or motor unit potential changes (large amplitude, long-duration motor unit potentials, or excessive polyphasia). 2.2. Ultrasonography Sonographic examination of all the subjects was performed using a MyLabOne system with a 10–18 MHz probe (Whiteley Diagnostics, Esaote, Italy). The median nerve in the carpal tunnel and mid-forearm were imaged in both the transverse and longitudinal planes. The ultrasound probe was kept perpendicular to the nerve in order to maintain reproducibility of results. The median nerve cross-sectional area (CSA) was measured (in mm2) at the carpal tunnel inlet (at the level of the pisiform bone) and mid-forearm (junction of the middle and distal third) by outlining the inner margin of the epineurium using the continuous trace method [7], and a wrist-forearm ratio (WFR) was then calculated [18]. (Fig. 1). For bifid nerves, both CSAs were recorded and averaged. Two separate CSA measurements were obtained at each site and the average value was used. 2.3. Data analysis Statistical analyses were conducted using SPSS (version 22.0, SPSS Inc., Chicago, IL, USA). Normality of all continuous variables was tested using the Shapiro–Wilk and Kolmogorov–Smirnov tests.
Descriptive statistics (mean and standard deviation) were applied for data analysis. The Wilcoxon signed-rank test was used to test the differences between the means of the groups and statistical significance was defined as p < 0.05. Spearman coefficients were calculated to determine the correlation between ultrasonographic (median nerve CSA and WFR) and NCS parameters of CTS. 3. Results Of the 169 wrists with a clinical diagnosis of CTS, 131 (77.5%) were confirmed to have CTS on NCS. The remaining 38 (22.5%) had negative NCS. 20 healthy controls (40 wrists) were also studied. Of the 131 NCS-positive wrists 49, 41 and 41 were classified as having mild, moderate and severe CTS respectively. We determined the optimal cut-off value for the detection of mild CTS using the median nerve CSA to be 11.4 mm2 (sensitivity = 71%; specificity = 97.5%). For the WFR, the cut-off value for mild CTS was estimated to be 1.53 (sensitivity = 60%; specificity = 92.5%). Data obtained from mild NCS-positive patients was compared with the NCS-negative group. Two patients had complete lesions with no recordable sensory or motor potentials. The baseline characteristics are listed in Table 1. The mean median nerve CSA was 13.2 ± 3.5 mm2 for the mild NCS-positive group, 10.1 ± 2.4 mm2 for NCS-negative wrists and 9.3 ± 1.2 mm2 for the healthy controls. Similarly, the mean WFRs were 1.63 ± 0.38, 1.38 ± 0.30 and 1.19 ± 0.17 respectively. As shown in Figure 2, there was a significant difference between the median nerve CSA of the mild NCS-positive group, NCS-negative group and healthy controls. The WFR also differed significantly between all groups. There was a strong correlation between the CSA and WFR (r = 0.726, p < 0.001). In the mild NCS-positive group, 67% had enlarged CSA at the wrist compared with 26% of the NCSnegative wrists (p < 0.0001). Similarly, 57% of the mild NCSpositive group had abnormal WFR compared to 32% in the NCSnegative group (p < 0.0001). As shown in Table 2, the following variables correlated well with the median nerve CSA at the carpal tunnel inlet: SCV (r = 0.564, p < 0.0001), SNAP amplitude (r = 0.574, p < 0.0001), DML (r = 0.523, p < 0.0001) and CMAP amplitude (r = 0.216, p < 0.01). Furthermore, the following variables were correlated with the WFR: SCV (r = 0.552, p < 0.0001) SNAP amplitude (r = 0.465, p < 0.0001) and DML (r = 0.454, p < 0.0001). In the moderate and severe NCS-positive groups, the mean median nerve CSA was 14.0 ± 3.0 mm2 and 18.2 ± 6.2 mm2 respectively. Similarly, the mean WFR for both groups was 1.81 ± 0.33 and 2.23 ± 0.71 respectively. There was significant correlation between the sonographic parameters and electrophysiological severity (r = 0.608, p < 0.0001 for CSA, r = 0.547, p < 0.0001 for WFR). This further demonstrates the relationship between nerve structure and function, as well as the potential benefit of ultrasonography in assessing CTS severity. Bifid median nerves were found in 16 wrists (10%) but there was no significant difference between NCS-positive group, NCSnegative group and healthy controls (p = 0.63). A persistent median artery was identified in two NCS-positive patients and one NCSnegative patient. Analysis of the data with and without these patients made no difference to the overall conclusions. 4. Discussion This study has shown that there are significant sonographic differences between clinical CTS patients with normal NCS and those with mild NCS abnormalities. We have demonstrated that the CSA (and hence WFR) is smaller at the wrist in NCS-negative patients than in mild NCS-positive patients. The significance of these
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
A.A. Borire et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
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Fig. 1. Measurement of the median nerve cross-sectional area at the carpal tunnel inlet showing nerve enlargement.
Table 1 Baseline characteristics of carpal tunnel syndrome study patients and controls Demographic and sonographic variables
Mild NCSpositive (n = 49)
NCSnegative (n = 38)
Healthy controls (n = 40)
Age (years) Height (cm) Weight (kg) Body mass index (kg/m2) CSA (mm2)* WFR*
55.0 ± 11.8 165.9 ± 9.08 83.7 ± 21 30.4 ± 7.5 13.2 ± 3.5 1.63 ± 0.38
51.5 ± 15.1 166.7 ± 9.3 80.0 ± 20.8 28.8 ± 7.4 10.1 ± 2.4 1.38 ± 0.30
51.1 ± 8.2 173 ± 10.3 87.3 ± 16.2 29.0 ± 5.0 9.3 ± 1.2 1.19 ± 0.17
Except where indicated otherwise, the data are presented as mean ± SD. * p < 0.001. CSA = cross-sectional area, NCS = nerve conduction studies, WFR = wrist-to-forearm ratio.
findings is that, unlike in earlier studies [14–16], these sonographic differences have been demonstrated in a cohort consisting of only mild NCS-positive CTS patients. Previous studies have included patients with severe electrophysiological changes which may potentially amplify the differences between the two groups. Therefore, limiting the population of NCS-positive patients to those with mild abnormalities alone reduces bias and is a more accurate reflection of the relationship between NCS abnormalities and early changes in median nerve morphology. The use of only mild NCSpositive patients is also appropriate as majority of patients who present to the EMG laboratory have mild disease. Furthermore, diagnostic uncertainty in CTS usually involves patients with the typical clinical features of CTS, but who have normal, borderline or mildly abnormal NCS results. Most of the CSA abnormalities in the NCS-negative group were relatively mild, with only two patients having CSA >14 mm2. This is in agreement with earlier studies which have reported a tendency for milder US abnormalities in this population [16,19]. This also supports the comparison of this group with mild NCS-positive patients. One limitation of this study is a lack of long-term data about the NCS-negative
group. A future study would need to focus on the NCS-negative patients to determine the proportion that becomes NCS-positive and whether US has any predictive value in this group. The lack of a gold standard for the diagnosis of CTS limits the accuracy of various diagnostic techniques. Moreover, due to technical reasons and variations in normative values between centres, it is possible that a clinical CTS patient may be classified as mild NCS-positive in one laboratory, and as NCS-negative in another. In these borderline patients, the added information that ultrasound provides may increase the diagnostic accuracy, thus reducing the false negative rate of NCS. Our findings show that there are clear differences between mild NCS-positive and NCS-negative patients and, the presence of an enlarged nerve in this situation therefore further improves the certainty of CTS diagnosis. The present study demonstrates that up to a third of the NCS-negative hands had ultrasound abnormalities with both the mild NCS-positive patients and NCS-negative patients manifesting significantly larger CSA and WFR, compared to the healthy controls. In addition, there were significant correlations that were noted between sonographic parameters and electrophysiological indices, consistent with earlier studies [8–13]. Previous studies have found that 10–25% of patients with clinical CTS may have negative NCS [3]. Kitsis et al. [2] proposed that this discrepancy arose because the pressure on the median nerve was high enough to cause symptoms but not high enough to cause disturbance in electrical function. Normal pressure in the carpal tunnel ranges between 3 and 5 mmHg [20]. A rise in pressure to 20–30 mmHg reduces epineurial blood flow, but a further rise to 30–40 mmHg is required before electrophysiological abnormalities can be detected [22]. Epineurial oedema and axonal transport block begin to occur at pressures associated with reduced blood flow, even before NCS abnormalities appear. Complete intraneural ischemia and motor and sensory block occur at about 60 mmHg [21,22]. It is possible that patients in the negative NCS group in our study had carpal tunnel pressures in the intermediate range of 20–30 mmHg, a level at which symptoms may occur in the absence of alterations in NCS parameters that assess impulse
Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024
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A.A. Borire et al. / Journal of Clinical Neuroscience xxx (2016) xxx–xxx
Fig. 2. Box plot showing the median nerve cross-sectional area (CSA) at the carpal tunnel inlet (left) and the wrist-to-forearm ratio (right) in mild nerve conduction studies (NCS)-positive patients, NCS-negative patients and healthy controls. Gradual increase in CSA was noted with worsening electrophysiologic severity. Significant differences were noted in the CSA and wrist-forearm ratio (WFR) between all the groups. Bold black lines indicate medians, whiskers indicate error bars and s indicates outliers. X-axis reference line represents the cut-off values, set at 11.7 mm2 for CSA and 1.53 for WFR. CSA = cross-sectional area, CTS = carpal tunnel syndrome, NCS = nerve conduction studies.
Table 2 Correlation between NCS and US parameters in clinical carpal tunnel syndrome patients CSA Coefficient (r) (n = 131) SCV DML MCV SNAP amplitude CMAP amplitude Electrophysiological severity
0.564 0.523 * 0.384 0.574 0.216 0.608 *
*
* * *
WFR Coefficient (r) (n = 131) 0.552 0.454 * 0.199 0.465 0.169 0.547 *
*
y * y
* p < 0.01. p < 0.05. CMAP = compound muscle action potential, CSA = cross-sectional area, DML = distal motor latency, MCV = motor conduction velocity, NCS = Nerve conduction studies, SCV = sensory conduction velocity, SNAP = sensory nerve action potential, US = ultrasound, WFR = wrist to forearm ratio. y
conduction. The importance of this finding is that it implies that normal NCS findings do not exclude CTS which could be demonstrated by the finding of an enlarged nerve on US. In conclusion, the present study demonstrates that there are differences in US parameters between CTS patients who have mild abnormalities on NCS and in those who have normal NCS. The study also shows that a proportion of the NCS-negative group may manifest changes in US parameters. This suggests that US may prove to be a useful adjunctive test in patients with early CTS, including those in whom nerve conduction abnormalities are not present.
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
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Please cite this article in press as: Borire AA et al. Sonographic differences in carpal tunnel syndrome with normal and abnormal nerve conduction studies. J Clin Neurosci (2016), http://dx.doi.org/10.1016/j.jocn.2016.05.024