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The role of ultrasound imaging in the evaluation of peripheral nerve in systemic sclerosis (scleroderma)
European Journal of Radiology 77 (2011) 377–382
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
The role of ultrasound imaging in the evaluation of peripheral nerve in systemic sclerosis (scleroderma) Alberto Tagliafico a,∗ , Nicoletta Panico b , Eugenia Resmini c , Lorenzo E. Derchi a , Massimo Ghio b , Carlo Martinoli a a b c
Department of Radiology, University of Genova, Genova, Italy Division of Immunology, Department of Internal Medicine, University of Genoa, Genoa, Italy Department of Endocrinological & Medical Sciences (DiSEM), Center of Excellence for Biomedical Research, University of Genova, Genova, Italy
a r t i c l e
i n f o
Article history: Received 19 April 2009 Received in revised form 14 August 2009 Accepted 26 August 2009 Keywords: Scleroderma Nerve Ultrasound Carpal tunnel syndrome Cubital tunnel syndrome
a b s t r a c t Background: Patients affected by scleroderma may complain of sensory disturbances especially in the hands. Purpose: To study the imaging features of upper limb nerves in patients affected by scleroderma (SSc). Materials and method: Twenty-five patients affected only by SSc were prospectively evaluated with highresolution US and magnetic resonance (MRI) or computer tomography (CT) when necessary (2 patients). Median and ulnar nerves were evaluated bilaterally. Nerve conduction studies were performed in the symptomatic patients (n = 10). Results of imaging studies were correlated with disease duration, autoimmunity and immunosuppression. Nerves of SSc patients were compared with a control group of 90 patients matched for age and body mass index. Results: The prevalence of sensory disturbances revealed by clinical examination was 40%. In symptomatic SSc patients (n = 10) US evaluation revealed nerve abnormalities in 70% of cases (n = 7/10). n = 2 had a carpal tunnel syndrome. n = 5 had cubital tunnel syndrome. In two of them CT and MR were necessary to identify the compressed nerve at the level of the elbow due to the presence of calcifications. There was no association between the presence of an entrapment neuropathy and disease duration, autoantibodies and immunosuppression. Conclusion: Ultrasound, CT and MR may detect nerve abnormalities in 70% of SSc patients complaining of neurologic disturbances in the hands. The results of imaging studies support the hypothesis of a vascular dependent neuropathy in SSc. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Systemic sclerosis (SSc) is a rare multisystem disorder of complex and not completely understood etiology, characterized by thickening of the skin, due to accumulation of connective tissue [1]. The diagnostic criteria adopted in 1980 by the American College of Rheumatology (ACR; formerly the American Rheumatism Association or ARA) received several modifications. Now at least three subsets of SSc are identified: diffuse form of SSc, when the major criterion is present, limited SSc (three minor criteria) divided in “SSc sine scleroderma” (without cutaneous involvement) and limited cutaneous SSc (with cutaneous involvement) [2,3]. The prognosis of the disease largely depends on visceral involvement (particularly the lung and the kidney), musculoskeletal symptoms are a major cause of disability in SSc [4]. The earliest
∗ Corresponding author. Tel.: +39 034 79745122. E-mail address: atagliafi[email protected] (A. Tagliafico). 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.08.010
manifestations of the disease can be divided radiographically as soft tissue involvement, bone involvement, joint and tendon involvement, and vascular involvement [5]. Peripheral nerve involvement had been estimated to be present in up to 16% of patients and trigeminal neuropathy had been described as associated with SSc more rarely such as polyneuropathy, brachial plexopathy, and lumbosacral radiculopathy [4]. Only few cases of ulnar nerve entrapment at the level of the Guyon tunnel due to calcinosis have been described [6,7]. High-resolution sonography is a suitable method for the diagnostic workup of different types of nerve lesions, such as nerve entrapments, nerve tumours, and traumatic nerve injuries. Highresolution sonography of nerves has also been used to characterize and evaluate hereditary neuropathies and metabolic disorders [8–11]. On the basis of our knowledge, there are no reports describing the imaging features of nerves in SSc. Patients affected by SSc may complain of sensory disturbances especially in the hand.
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Table 1 Clinical characteristics of SSc population and control group. Data are mean ± SD or percentage. W: women; M: men; DD: disease duration; ACA: serum anticentromere antibodies; Scl-70: antitopoisomerase antibodies. dSSc: diffuse SSc; lSSc: limited SSc.
Age W/M DD ACA (%) Scl-70 (%)
dSSc (n = 9)
lSSc (n = 16)
Controls (n = 90)
50.4 ± 9.9 8/1 7.1 ± 5.2 18.2 81.8
54.8 ± 13.7 11/2 15.1 ± 11.2 44.2 38.8
55.0 ± 9.0 30/60
The aim of the study was to study the imaging features of upper limb nerves in patients affected by SSc. 2. Materials and methods Between January 2007 and August 2008, 25 patients (22 women, 3 men) who did not complain of diseases other than SSc (American College Rheumatology classification criteria [2] and more recently proposed criteria for early SSc [3]) were recruited out of 120 consecutive patients with SSc at the outpatient division of clinical immunology of our institution. Duration of disease in the SSc population was calculated from the onset of first non-Raynaud’s phenomenon. According to the values of the oral glucose tolerance testing (OGTT) and haemoglobin A1C , no patient with diabetes mellitus was recruited in this study, to avoid possible interference with diabetic neuropathy [10]. Similarly, based on thyroid hormone levels, patients with hypothyroidism were not included [12]. At the beginning of the study, five patients had symptoms related to carpal tunnel syndrome (CTS-like symptoms) such as: paraesthesia; pain; swelling; weakness or clumsiness of the hand provoked or worsened by sleep, sustained hand or arm position; repetitive action of the hand or wrist that is mitigated by changing posture or by shaking the hand; sensory deficit or hypotrophy of the median innervated thenar muscle. Seven other patients complained of sensory disturbances (numbness and paresthesias) in the territory of distribution of the ulnar nerve. The remaining ones were free of symptoms in the areas supplied by the median and the ulnar nerve. A control group included healthy volunteers matched for sex, gender, age and body mass (80 women and 10 men). They were non-diabetic and free from peripheral neuropathies. Informed consent was obtained from all subjects involved in this study. Patient and controls’ characteristics are presented in Table 1. 2.1. Autoantibody detection We tested all patients for serum antitopoisomerase I antibodies (Scl-70) and for anticentromere antibodies (ACA). Antinuclear antibodies were detected by indirect immunofluorescence using HEp-2 cells as substrate (Euroimmun, Lubeck, Germany). ACA and Scl-70 were measured using an ELISA (Euroimmun). 2.2. Physical examination Each patient was systematically assessed for the presence of sensory disturbances, carpal tunnel syndrome or cubital tunnel syndrome by a musculoskeletal radiologists experienced in peripheral neuropathy as previously reported [11,14].
band, 17–5 MHz) linear array transducer. US criteria for nerve identification were based on anatomical landmarks and detection of the fascicular echotexture according to criteria described elsewhere [14]. Interpretation of the US images was based on measurement of the nerve cross-sectional area (CSA), as calculated according to the ellipse formula (anteroposterior diameter × laterolateral diameter × /4). During measurements, care was taken to place the probe perpendicular to the long-axis of the nerve to improve visualization of the hypoechoic fascicles and optimize differentiation between the nerve bundle and surrounding tissues [13]. In each study, the median nerve was evaluated in the entire upper limb, bilaterally. Quantitative measurements were taken at the proximal carpal tunnel (MN-Ct) and at the middle third of the forearm (MN-f) while keeping the dorsal forearm and the dorsal wrist lying on the examination table, palm up. To standardize the level of examination, its CSA was calculated both at the level of the pisiform (carpal tunnel level) and 10 cm proximal to the wrist crease (mid-forearm level). Then, the ulnar nerve was also examined in the entire course in the upper limb and quantitative measurements (CSA) were taken at the level of the cubital tunnel and 10 cm proximal to the wrist crease (mid-distal forearm level), where the nerve is reached by the ulnar artery. Overall, two measurement were obtained at the carpal tunnel level and at the level of the cubital tunnel and two measurements outside the tunnels in order to minimize the influence of osteofibrous tunnel-related abnormalities that could affect the nerve CSA, including attritional swelling, joint effusions, tenosynovitis, narrowing of the space contained in the tunnel due to calcific deposits. Cut offs for carpal tunnel syndrome and cubital tunnel syndrome were assumed at 10 and 7.5 mm2 [14]. A total of n = 104 CSAs of sclerodermic patients’ nerves were compared with the control group. All US studies were performed by the same examiner (A.T.), who is a radiologist experienced in musculoskeletal US, to avoid interobserver variability. Nerve CSAs were then correlated with the patient’s body type using the body mass index (BMI). The index obtained was matched with nerve measurements. 2.4. CT and MR examinations When the ultrasound examination was not diagnostic due to the presence of calcifications at the level of the medial epicondyle, MR and CT were performed. CT examination was performed in two patients with a sixteendetector row CT (General Electric Healthcare, Milwaukee, WI) with 120 kV and 10 mA, 0.7 s rotation time, section thickness 1.25 mm, and table speed 8.75 (mm per rotation). Correlative MRI was performed in the same two patients using a 1.5-T unit (Magnetom Avanto Syngo MR 2004V, Siemens Medical Solutions) with a flexible surface coil (gradients of 25 mT/m, slew rate of 800 T/m/s, rise time of 400 m/s). The protocol included the following sequences: T1-weighted spin-echo (SE) (TR range/TE, 500–650/15; matrix, 384 × 384; slice thickness, 3.5 mm; field of view, 11.0 cm × 11.0 cm; number of excitations, 4), fat-suppressed T2-weighted turbo SE, T2-weigthed turbo SE, and contrast-enhanced fat-suppressed T1-weighted SE sequences. All acquisitions were obtained in axial planes. Patients were examined in the supine position while keeping the upper arm alongside the body with an extended elbow and supinated wrist. 2.5. Neurophysiological examination
2.3. Ultrasound studies US examination of the median and ulnar nerves was performed with a commercially available digital scanner (IU 22; Philips, Eindhoven, the Netherlands) equipped with a broadband (frequency
In every patient with sensory or motor disturbances (12/25), electrophysiological studies (NCS) of motor and sensory function of the median and ulnar nerves were performed bilaterally. Electrodiagnostic studies of the motor fibers were performed registering
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muscular responses of sub-maximal stimulations on nerves by means of surface electrodes. Response latency, negative phase amplitude and nerve conduction velocity (m/s) were evaluated. Fwave testing was done with maximal stimulation. Briefly, median nerves were evaluated at wrist and elbow, the recording obtained at the level of the opponens pollicis. Ulnar nerves were stimulated at wrist, at elbow, proximal and distal to the cubital tunnel, and at the superior third of the arm, with recording obtained at the level of the abductor digiti quinti. Electrodiagnostic studies of sensory fibers were performed with the antidromic method based on nerve stimulation with a surface electrode and recording by means of ring electrodes from the digital nerves. Latency referred to both the first positive peak and amplitude peak-to-peak was evaluated. Nerve conduction velocity (m/s) was also analyzed. Median nerves were stimulated at wrist and elbow to be recorded at the index finger. Ulnar nerves were stimulated at wrist, at elbow, proximal and distal to the cubital tunnel, and at the third superior of the arm: recording was obtained at the little finger. When the distal motor latency of the median nerve was increased suggesting initial abnormality of the nerve function at the carpal tunnel level, an orthodromic sensory test was performed comparing the median and the ulnar nerve in the palm–wrist area. Values of the distal motor and sensory latencies, motor and sensory nerve conduction velocities, amplitude of evoked potentials were adjusted according to the patients’ age and the nerve examined as described elsewhere [14]. 2.6. Statistical analysis Statistical analysis was performed using the Mann–Whitney Utest for unpaired data to compare patients and healthy controls. Values were expressed as mean ± standard deviation (SD). Probability (p) values <0.05 were considered statistically significant. To correlate nerve CSAs with other parameters, the Pearson’s test and linear regression analysis were used. Non-parametric statistic was used to confirm or exclude other associations.
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Table 2 Comparison of cross-sectional areas between SSc patients enrolled in this study and controls, at the four points of measurement. MN-Ct = median nerve at the proximal carpal tunnel; MN-f = median nerve at the middle forearm; UN-f = ulnar nerve at the middle forearm; UN-cubtn = ulnar nerve at the cubital tunnel. Comparison of CSA of median and ulnar nerves in SSc patients and controls Nerves
SSc (n = 25) Mean (mm2 ) ± SD
MN-Ct MN-f UN-f UN-cubtn
8.2 5.4 6.2 9.5
± ± ± ±
3.4 2.4 3.0 3.5
Controls (n = 90) Mean (mm2 ) ± SD 7.3 5.4 5.2 6.7
± ± ± ±
1.6 1.3 1.2 1.4
p-Values 0.21 0.18 0.42 0.09
3. Results The presence of sensory disturbances was the main symptom and only two patients with severe cubital tunnel had motor involvement. The prevalence of sensory disturbances in our series was 40%. In SSc patients, the imaging modalities used revealed an increased nerve cross-sectional area and features suggestive of entrapment neuropathies in 7 out of 10 patients consistent with carpal tunnel syndrome or cubital tunnel syndrome. Subjective US evaluation revealed apparently normal nerves outside the osteofibrous tunnels in the upper limbs of the patients. Within both groups, no significant difference in the nerve CSA was found as regard gender and side (left vs. right). 3.1. Comparison between SSc patients and control group As shown in Table 2 CSAs of nerves of SSc patients had results similar to the control group at the four measurement sites, when compared with the control group. Moreover, at the carpal tunnel level, the CSA of median nerves and ulnar nerves in SSc patients did
Fig. 1. 54-Year-old female patient with severe cubital tunnel syndrome. (A) The ulnar nerve (void arrow and dotted circle) is seen only at the entrance of the cubital tunnel. At a more distal level the nerve is covered by the calcific deposits. (B) The CT demonstrates the extent of the calcific deposits but the ulnar nerve is not clearly depicted. In C the T1-w tSE sequence shows the nerve clearly defined and in D the T2-w tSE sequence demonstrates the hyperintensity of the ulnar nerve suggestive of compression.
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Table 3 results concerning carpal tunnel syndrome and cubital tunnel syndrome. D: diffuse SSc; L: limited SSc; Imm: immunosuppressive therapy; yes: the evaluation is positive, NCS: nerve conduction study; imaging: ultrasound, CT or MR; asterisk: CT or MR were used to confirm the diagnosis. The empty box means that the examination is negative. All the entrapment syndromes were monolateral. Patient
Diagnosis
Therapy
Carpal tunnel syndrome Clinical
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 25 25
D L L D L L D D L L L L L L D D D D L L L L L L D
NCS
Cubital tunnel syndrome Imaging
Imm
Clinical
NCS
Imaging
Yes Yes
Yes Yes
Yes Yes*
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes*
Imm Imm Imm
Yes Yes Yes
Yes
Yes
Imm
Imm Imm
Yes
Yes
Yes
Yes
not correlate with clinical symptoms, disease duration and nerve conduction studies.
of the results concerning carpal tunnel syndrome and cubital tunnel syndrome is reported in Table 3.
3.2. Carpal tunnel syndrome-like symptoms
4. Discussion
Five of 25 patients had CTS-like symptoms. Considering 10 mm2 as a widely accepted threshold value of median nerve CSA for carpal tunnel syndrome, 2/25 SSc patients were over this threshold value. In these two patients nerve conduction studies confirmed CTS. Three of 25 SSc patients referred symptoms related to carpal tunnel syndrome, but all of them had a negative electrophysiologic examination and a negative imaging study. All these patients had a negative X-ray examination of the cervical spine.
The pathogenesis of peripheral nervous system involvement is not fully defined and the main hypothesis to explain the neuropathy are at least three: a vascular dependent mechanism, a compression dependent mechanism and an autoimmune-dependent neuropathy. The first considers the unique microvascular involvement in SSc and the involvement of vasa nervorum. Indeed, the axonal degeneration may indirectly favor the hypothesis of a vascular genesis of nerve involvement. The second is supposed by the observation of nerve demyelination in SSc: it is well known that compressive conditions such as carpal tunnel syndromes induce progressive demyelination with edema in the first stages of the disease and fibrosis in the late stages [16]. According to another study the presence of a non-length-dependent (focal or multifocal) pure sensory peripheral neuropathy in patients with scleroderma who have neurologic symptoms is typical of SSc [17]. To our knowledge there are no reports in literature evaluating peripheral nerves of SSc patients with imaging techniques and our study is the first that evaluates extensively upper limb nerves in patients affected by SSc with ultrasound. In our series the presence of sensory disturbances was the main symptom and the prevalence of sensory disturbances (40%: 10/25 patients) was higher than previously reported [16]. Imaging modalities used revealed abnormalities in 7 out of 10 patients with either carpal tunnel syndrome or cubital tunnel syndrome symptoms. In the majority of patients with nerve symptoms a cause explaining the symptoms was identified by imaging. The high-resolution ultrasound examination of SSc patients did not identify diffuse enlargements such as in other patients with sensory disturbances (ex. acromegalic patients [11]) and surprisingly did not find any focal or multifocal abnormality except for the increased nerve cross-sectional areas at the level of the osteofibrous tunnels.
3.3. Cubital tunnel syndrome-like symptoms Five patients had symptoms related to cubital tunnel syndrome. Considering 7.5 mm2 as a threshold value for ulnar nerve CSA for cubital tunnel syndrome, 3/25 SSc patients were over this threshold value. In these patients nerve conduction studies confirmed a mild cubital tunnel syndrome. In 2 of 25 SSc patients with symptoms related to severe cubital tunnel syndrome, a positive electrophysiological examination and hypotenar muscles atrophy, the ulnar nerve was not visible due to the presence of calcifications, therefore CT and MR were performed to confirm ulnar nerve compression at the level of the cubital tunnel (Fig. 1). All these patients had a negative X-ray examination of the cervical spine. We did not find any correlations of the US findings with the clinical parameters such as disease duration, immunosuppressive therapy and autoantibodies. We did not find any differences between the group of patients with SScL and SScD. There was no association between the presence of an entrapment neuropathy and disease duration, autoantibodies and immunosuppressive therapy (chi-square test, data not shown). A complete description
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Fig. 2. 44-Year-old female patient with moderate cubital tunnel syndrome. (A) The ulnar nerve is seen at the entrance of the cubital tunnel with an increased cross-sectional area and a hypoechoic appearance with initial loss of the fascicular echotexture. (B) The ulnar nerve of a 62-year-old female patient with a mild cubiltal tunnel syndrome is depicted. Note that the ulnar nerve is less hypoechoic than in A, but the cross-sectional area is increased.
Fig. 3. 66-Year-old female with carpal tunnel syndrome. (A) The median nerve is enlarged proximally to the carpal tunnel (cross-sectional area: 14 mm2 ) and the fascicular echotexture is not completely preserved. (B) A normal median nerve in a 55-year-old female control shows the normal fascicular echotexture.
Our data differ from the hypothesis of a non-length-dependent (focal or multifocal) pure sensory peripheral neuropathy that affects SSc patients [17]. The possible reason is that nerve abnormalities of SSc patients may not be evident on high-resolution ultrasound. This observation may be in line with the hypothesis of a vascular or autoimmune dependent neuropathy with an involvement of the vasa nervorum. The absence of diffuse or focal nerve enlargement support the hypothesis of a vascular-based neuropathy in the patients with carpal tunnel syndrome-like symptoms but no diagnosis of carpal tunnel and this explains why carpal tunnel syndrome-like symptoms in SSc patients are not always associated with the diagnosis of carpal tunnel syndrome. Moreover, the presence of cubital tunnel syndrome in patients with SSc has never been evaluated extensively. In literature there are only anecdotal reports describing ulnar nerve entrapment at the elbow [18]. In our patients the prevalence of cubital tunnel syndrome was quite high, 20% of patients, and the severity of the entrapment ranged from moderate to severe as demonstrated by the fact that the electrophysiology was always positive. In fact it is known that only in mild cubital tunnel syndrome ultrasound may be able to find ulnar nerve enlargement while electrophysiology is not able to find abnormalities [15] (Figs. 2 and 3). We demonstrated that cubital tunnel syndrome in SSc may be related to calcific deposits at the level of the elbow or idiopathic. In case of calcific deposits CT and MR are required to identify bone, calcification and the nerve entrapped. The lack of relationships between the two entrapment neuropathies observed (carpal tunnel syndrome and cubital tunnel syndrome) and disease duration or autoantibodies reinforces the hypothesis of a vascular dependent neuropathy. According to literature, tissue edema may cause peripheral nerve compression and therefore entrapment neuropathies especially at the beginning of the disease [16], but the lack of correlation between disease duration and entrapment neuropathies is against this hypothesis. The automimmune-dependent neuropathy is more likely to be related
to autonomic nervous system involvement than peripheral nervous system involvement [16]. A possible limitation of our study is the use of standard protocols for the diagnosis of ultrasonographic carpal tunnel syndrome and not the new techniques such as the wrist–forearm ratio or delta cross-sectional area [19,20]. The use of these techniques may have increased the diagnostic accuracy of ultrasound. Moreover we also performed normal tests for the diagnosis of cubital tunnel syndrome and not a new test that increases the accuracy of the diagnosis [21]. In conclusion the results of imaging studies support the hypothesis of a vascular dependent neuropathy in scleroderma. Imaging allowed to identify and differentiate carpal tunnel syndrome and cubital tunnel syndrome that have different therapeutical approaches. Imaging studies of patients affected by SSc helped the clinician in the evaluation of hand sensory disturbances. References [1] Gilliland Bruce C. Systemic sclerosis (scleroderma) and related disorders. In: Harrison’s principles of internal medicine. 16th ed. McGraw-Hill; 2005. p. 197990. [2] Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581–90. [3] LeRoy EC, Medsger Jr TA. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–7. [4] Boutry N, Hachulla E, Zanetti-Musielak C, et al. Imaging features of musculoskeletal involvement in systemic sclerosis. Eur Radiol 2007;17:1172–80. [5] Pope JE. Musculoskeletal involvement in scleroderma. Rheum Dis Clin North Am 2003;29:391–408. [6] Chammas M, Meyer zu Reckendorf G, Allieu Y. Compression of the ulnar nerve in Guyon’s canal by pseudotumoral calcinosis in systemic scleroderma. J Hand Surg [Br] 1995;20:794–6. [7] Thurman RT, Jindal P, Wolff TW. Ulnar nerve compression in Guyon’s canal caused by calcinosis in scleroderma. J Hand Surg [Am] 1991;16:739–41. [8] Martinoli C, Schenone A, Bianchi S, et al. Sonography of the median nerve in Charcot-Marie-Tooth Disease. AJR 2002;178:1553–6.
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[9] Martinoli C, Derchi LE, Bertolotto M, et al. US and MR imaging of peripheral nerves in leprosy. Skeletal Radiol 2000;29:142–50. [10] Lee D, Dauphinee DM. Morphological and functional changes in the diabetic peripheral nerve: using diagnostic ultrasound and neurosensory testing to select candidate for nerve decompression. J Am Podiatr Med Assoc 2005;95:433–7. [11] Tagliafico A, Resmini E, Nizzo R, et al. Ultrasound measurement of median and ulnar nerve cross-sectional area in acromegaly. J Clin Endocrinol Metab 2008;93:905–9. [12] El-Salem K, Ammari F. Neurophysiological changes in neurologically asymptomatic hypothyroid patients: a prospective cohort study. J Clin Neurophysiol 2006;23:568–72. [13] Tagliafico A, Rubino M, Autuori A, et al. Wrist and hand ultrasound. Semin Musculoskelet Radiol 2007;11:95–104. [14] American Academy of Neurology, American Association of Electrodiagnostic Medicine, American Academy of Physical Medicine and Rehabilitation. Practice parameter for carpal tunnel syndrome (summary statement). Neurology 1993;43:2406–9.
[15] Tagliafico A, Resmini E, Nizzo R, et al. The pathology of the ulnar nerve in acromegaly. Eur J Endocrinol 2008;159:369–73. [16] Cerinic MM, Generini S, Pignone A, et al. The nervous system in systemic sclerosis (scleroderma). Clinical features and pathogenetic mechanisms. Rheum Dis Clin North Am 1996;22:879–82. [17] Poncelet AN, Connolly MK. Peripheral neuropathy in scleroderma. Muscle Nerve 2003;28:330–5. [18] Mouthon L, Halimi C, Muller GP, et al. Systemic scleroderma associated with bilateral ulnar nerve entrapment at the elbow. Rheumatology 2000;39:682. [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] 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. [21] Caliandro P, Foschini M, Pazzaglia C, et al. In-ratio: a new test to increase diagnostic sensitivity in ulnar nerve entrapment at elbow. Clin Neurophysiol 2008;119:1600–6.
Contents lists available at ScienceDirect
European Journal of Radiology journal homepage: www.elsevier.com/locate/ejrad
The role of ultrasound imaging in the evaluation of peripheral nerve in systemic sclerosis (scleroderma) Alberto Tagliafico a,∗ , Nicoletta Panico b , Eugenia Resmini c , Lorenzo E. Derchi a , Massimo Ghio b , Carlo Martinoli a a b c
Department of Radiology, University of Genova, Genova, Italy Division of Immunology, Department of Internal Medicine, University of Genoa, Genoa, Italy Department of Endocrinological & Medical Sciences (DiSEM), Center of Excellence for Biomedical Research, University of Genova, Genova, Italy
a r t i c l e
i n f o
Article history: Received 19 April 2009 Received in revised form 14 August 2009 Accepted 26 August 2009 Keywords: Scleroderma Nerve Ultrasound Carpal tunnel syndrome Cubital tunnel syndrome
a b s t r a c t Background: Patients affected by scleroderma may complain of sensory disturbances especially in the hands. Purpose: To study the imaging features of upper limb nerves in patients affected by scleroderma (SSc). Materials and method: Twenty-five patients affected only by SSc were prospectively evaluated with highresolution US and magnetic resonance (MRI) or computer tomography (CT) when necessary (2 patients). Median and ulnar nerves were evaluated bilaterally. Nerve conduction studies were performed in the symptomatic patients (n = 10). Results of imaging studies were correlated with disease duration, autoimmunity and immunosuppression. Nerves of SSc patients were compared with a control group of 90 patients matched for age and body mass index. Results: The prevalence of sensory disturbances revealed by clinical examination was 40%. In symptomatic SSc patients (n = 10) US evaluation revealed nerve abnormalities in 70% of cases (n = 7/10). n = 2 had a carpal tunnel syndrome. n = 5 had cubital tunnel syndrome. In two of them CT and MR were necessary to identify the compressed nerve at the level of the elbow due to the presence of calcifications. There was no association between the presence of an entrapment neuropathy and disease duration, autoantibodies and immunosuppression. Conclusion: Ultrasound, CT and MR may detect nerve abnormalities in 70% of SSc patients complaining of neurologic disturbances in the hands. The results of imaging studies support the hypothesis of a vascular dependent neuropathy in SSc. © 2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Systemic sclerosis (SSc) is a rare multisystem disorder of complex and not completely understood etiology, characterized by thickening of the skin, due to accumulation of connective tissue [1]. The diagnostic criteria adopted in 1980 by the American College of Rheumatology (ACR; formerly the American Rheumatism Association or ARA) received several modifications. Now at least three subsets of SSc are identified: diffuse form of SSc, when the major criterion is present, limited SSc (three minor criteria) divided in “SSc sine scleroderma” (without cutaneous involvement) and limited cutaneous SSc (with cutaneous involvement) [2,3]. The prognosis of the disease largely depends on visceral involvement (particularly the lung and the kidney), musculoskeletal symptoms are a major cause of disability in SSc [4]. The earliest
∗ Corresponding author. Tel.: +39 034 79745122. E-mail address: atagliafi[email protected] (A. Tagliafico). 0720-048X/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ejrad.2009.08.010
manifestations of the disease can be divided radiographically as soft tissue involvement, bone involvement, joint and tendon involvement, and vascular involvement [5]. Peripheral nerve involvement had been estimated to be present in up to 16% of patients and trigeminal neuropathy had been described as associated with SSc more rarely such as polyneuropathy, brachial plexopathy, and lumbosacral radiculopathy [4]. Only few cases of ulnar nerve entrapment at the level of the Guyon tunnel due to calcinosis have been described [6,7]. High-resolution sonography is a suitable method for the diagnostic workup of different types of nerve lesions, such as nerve entrapments, nerve tumours, and traumatic nerve injuries. Highresolution sonography of nerves has also been used to characterize and evaluate hereditary neuropathies and metabolic disorders [8–11]. On the basis of our knowledge, there are no reports describing the imaging features of nerves in SSc. Patients affected by SSc may complain of sensory disturbances especially in the hand.
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A. Tagliafico et al. / European Journal of Radiology 77 (2011) 377–382
Table 1 Clinical characteristics of SSc population and control group. Data are mean ± SD or percentage. W: women; M: men; DD: disease duration; ACA: serum anticentromere antibodies; Scl-70: antitopoisomerase antibodies. dSSc: diffuse SSc; lSSc: limited SSc.
Age W/M DD ACA (%) Scl-70 (%)
dSSc (n = 9)
lSSc (n = 16)
Controls (n = 90)
50.4 ± 9.9 8/1 7.1 ± 5.2 18.2 81.8
54.8 ± 13.7 11/2 15.1 ± 11.2 44.2 38.8
55.0 ± 9.0 30/60
The aim of the study was to study the imaging features of upper limb nerves in patients affected by SSc. 2. Materials and methods Between January 2007 and August 2008, 25 patients (22 women, 3 men) who did not complain of diseases other than SSc (American College Rheumatology classification criteria [2] and more recently proposed criteria for early SSc [3]) were recruited out of 120 consecutive patients with SSc at the outpatient division of clinical immunology of our institution. Duration of disease in the SSc population was calculated from the onset of first non-Raynaud’s phenomenon. According to the values of the oral glucose tolerance testing (OGTT) and haemoglobin A1C , no patient with diabetes mellitus was recruited in this study, to avoid possible interference with diabetic neuropathy [10]. Similarly, based on thyroid hormone levels, patients with hypothyroidism were not included [12]. At the beginning of the study, five patients had symptoms related to carpal tunnel syndrome (CTS-like symptoms) such as: paraesthesia; pain; swelling; weakness or clumsiness of the hand provoked or worsened by sleep, sustained hand or arm position; repetitive action of the hand or wrist that is mitigated by changing posture or by shaking the hand; sensory deficit or hypotrophy of the median innervated thenar muscle. Seven other patients complained of sensory disturbances (numbness and paresthesias) in the territory of distribution of the ulnar nerve. The remaining ones were free of symptoms in the areas supplied by the median and the ulnar nerve. A control group included healthy volunteers matched for sex, gender, age and body mass (80 women and 10 men). They were non-diabetic and free from peripheral neuropathies. Informed consent was obtained from all subjects involved in this study. Patient and controls’ characteristics are presented in Table 1. 2.1. Autoantibody detection We tested all patients for serum antitopoisomerase I antibodies (Scl-70) and for anticentromere antibodies (ACA). Antinuclear antibodies were detected by indirect immunofluorescence using HEp-2 cells as substrate (Euroimmun, Lubeck, Germany). ACA and Scl-70 were measured using an ELISA (Euroimmun). 2.2. Physical examination Each patient was systematically assessed for the presence of sensory disturbances, carpal tunnel syndrome or cubital tunnel syndrome by a musculoskeletal radiologists experienced in peripheral neuropathy as previously reported [11,14].
band, 17–5 MHz) linear array transducer. US criteria for nerve identification were based on anatomical landmarks and detection of the fascicular echotexture according to criteria described elsewhere [14]. Interpretation of the US images was based on measurement of the nerve cross-sectional area (CSA), as calculated according to the ellipse formula (anteroposterior diameter × laterolateral diameter × /4). During measurements, care was taken to place the probe perpendicular to the long-axis of the nerve to improve visualization of the hypoechoic fascicles and optimize differentiation between the nerve bundle and surrounding tissues [13]. In each study, the median nerve was evaluated in the entire upper limb, bilaterally. Quantitative measurements were taken at the proximal carpal tunnel (MN-Ct) and at the middle third of the forearm (MN-f) while keeping the dorsal forearm and the dorsal wrist lying on the examination table, palm up. To standardize the level of examination, its CSA was calculated both at the level of the pisiform (carpal tunnel level) and 10 cm proximal to the wrist crease (mid-forearm level). Then, the ulnar nerve was also examined in the entire course in the upper limb and quantitative measurements (CSA) were taken at the level of the cubital tunnel and 10 cm proximal to the wrist crease (mid-distal forearm level), where the nerve is reached by the ulnar artery. Overall, two measurement were obtained at the carpal tunnel level and at the level of the cubital tunnel and two measurements outside the tunnels in order to minimize the influence of osteofibrous tunnel-related abnormalities that could affect the nerve CSA, including attritional swelling, joint effusions, tenosynovitis, narrowing of the space contained in the tunnel due to calcific deposits. Cut offs for carpal tunnel syndrome and cubital tunnel syndrome were assumed at 10 and 7.5 mm2 [14]. A total of n = 104 CSAs of sclerodermic patients’ nerves were compared with the control group. All US studies were performed by the same examiner (A.T.), who is a radiologist experienced in musculoskeletal US, to avoid interobserver variability. Nerve CSAs were then correlated with the patient’s body type using the body mass index (BMI). The index obtained was matched with nerve measurements. 2.4. CT and MR examinations When the ultrasound examination was not diagnostic due to the presence of calcifications at the level of the medial epicondyle, MR and CT were performed. CT examination was performed in two patients with a sixteendetector row CT (General Electric Healthcare, Milwaukee, WI) with 120 kV and 10 mA, 0.7 s rotation time, section thickness 1.25 mm, and table speed 8.75 (mm per rotation). Correlative MRI was performed in the same two patients using a 1.5-T unit (Magnetom Avanto Syngo MR 2004V, Siemens Medical Solutions) with a flexible surface coil (gradients of 25 mT/m, slew rate of 800 T/m/s, rise time of 400 m/s). The protocol included the following sequences: T1-weighted spin-echo (SE) (TR range/TE, 500–650/15; matrix, 384 × 384; slice thickness, 3.5 mm; field of view, 11.0 cm × 11.0 cm; number of excitations, 4), fat-suppressed T2-weighted turbo SE, T2-weigthed turbo SE, and contrast-enhanced fat-suppressed T1-weighted SE sequences. All acquisitions were obtained in axial planes. Patients were examined in the supine position while keeping the upper arm alongside the body with an extended elbow and supinated wrist. 2.5. Neurophysiological examination
2.3. Ultrasound studies US examination of the median and ulnar nerves was performed with a commercially available digital scanner (IU 22; Philips, Eindhoven, the Netherlands) equipped with a broadband (frequency
In every patient with sensory or motor disturbances (12/25), electrophysiological studies (NCS) of motor and sensory function of the median and ulnar nerves were performed bilaterally. Electrodiagnostic studies of the motor fibers were performed registering
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muscular responses of sub-maximal stimulations on nerves by means of surface electrodes. Response latency, negative phase amplitude and nerve conduction velocity (m/s) were evaluated. Fwave testing was done with maximal stimulation. Briefly, median nerves were evaluated at wrist and elbow, the recording obtained at the level of the opponens pollicis. Ulnar nerves were stimulated at wrist, at elbow, proximal and distal to the cubital tunnel, and at the superior third of the arm, with recording obtained at the level of the abductor digiti quinti. Electrodiagnostic studies of sensory fibers were performed with the antidromic method based on nerve stimulation with a surface electrode and recording by means of ring electrodes from the digital nerves. Latency referred to both the first positive peak and amplitude peak-to-peak was evaluated. Nerve conduction velocity (m/s) was also analyzed. Median nerves were stimulated at wrist and elbow to be recorded at the index finger. Ulnar nerves were stimulated at wrist, at elbow, proximal and distal to the cubital tunnel, and at the third superior of the arm: recording was obtained at the little finger. When the distal motor latency of the median nerve was increased suggesting initial abnormality of the nerve function at the carpal tunnel level, an orthodromic sensory test was performed comparing the median and the ulnar nerve in the palm–wrist area. Values of the distal motor and sensory latencies, motor and sensory nerve conduction velocities, amplitude of evoked potentials were adjusted according to the patients’ age and the nerve examined as described elsewhere [14]. 2.6. Statistical analysis Statistical analysis was performed using the Mann–Whitney Utest for unpaired data to compare patients and healthy controls. Values were expressed as mean ± standard deviation (SD). Probability (p) values <0.05 were considered statistically significant. To correlate nerve CSAs with other parameters, the Pearson’s test and linear regression analysis were used. Non-parametric statistic was used to confirm or exclude other associations.
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Table 2 Comparison of cross-sectional areas between SSc patients enrolled in this study and controls, at the four points of measurement. MN-Ct = median nerve at the proximal carpal tunnel; MN-f = median nerve at the middle forearm; UN-f = ulnar nerve at the middle forearm; UN-cubtn = ulnar nerve at the cubital tunnel. Comparison of CSA of median and ulnar nerves in SSc patients and controls Nerves
SSc (n = 25) Mean (mm2 ) ± SD
MN-Ct MN-f UN-f UN-cubtn
8.2 5.4 6.2 9.5
± ± ± ±
3.4 2.4 3.0 3.5
Controls (n = 90) Mean (mm2 ) ± SD 7.3 5.4 5.2 6.7
± ± ± ±
1.6 1.3 1.2 1.4
p-Values 0.21 0.18 0.42 0.09
3. Results The presence of sensory disturbances was the main symptom and only two patients with severe cubital tunnel had motor involvement. The prevalence of sensory disturbances in our series was 40%. In SSc patients, the imaging modalities used revealed an increased nerve cross-sectional area and features suggestive of entrapment neuropathies in 7 out of 10 patients consistent with carpal tunnel syndrome or cubital tunnel syndrome. Subjective US evaluation revealed apparently normal nerves outside the osteofibrous tunnels in the upper limbs of the patients. Within both groups, no significant difference in the nerve CSA was found as regard gender and side (left vs. right). 3.1. Comparison between SSc patients and control group As shown in Table 2 CSAs of nerves of SSc patients had results similar to the control group at the four measurement sites, when compared with the control group. Moreover, at the carpal tunnel level, the CSA of median nerves and ulnar nerves in SSc patients did
Fig. 1. 54-Year-old female patient with severe cubital tunnel syndrome. (A) The ulnar nerve (void arrow and dotted circle) is seen only at the entrance of the cubital tunnel. At a more distal level the nerve is covered by the calcific deposits. (B) The CT demonstrates the extent of the calcific deposits but the ulnar nerve is not clearly depicted. In C the T1-w tSE sequence shows the nerve clearly defined and in D the T2-w tSE sequence demonstrates the hyperintensity of the ulnar nerve suggestive of compression.
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Table 3 results concerning carpal tunnel syndrome and cubital tunnel syndrome. D: diffuse SSc; L: limited SSc; Imm: immunosuppressive therapy; yes: the evaluation is positive, NCS: nerve conduction study; imaging: ultrasound, CT or MR; asterisk: CT or MR were used to confirm the diagnosis. The empty box means that the examination is negative. All the entrapment syndromes were monolateral. Patient
Diagnosis
Therapy
Carpal tunnel syndrome Clinical
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 25 25
D L L D L L D D L L L L L L D D D D L L L L L L D
NCS
Cubital tunnel syndrome Imaging
Imm
Clinical
NCS
Imaging
Yes Yes
Yes Yes
Yes Yes*
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes*
Imm Imm Imm
Yes Yes Yes
Yes
Yes
Imm
Imm Imm
Yes
Yes
Yes
Yes
not correlate with clinical symptoms, disease duration and nerve conduction studies.
of the results concerning carpal tunnel syndrome and cubital tunnel syndrome is reported in Table 3.
3.2. Carpal tunnel syndrome-like symptoms
4. Discussion
Five of 25 patients had CTS-like symptoms. Considering 10 mm2 as a widely accepted threshold value of median nerve CSA for carpal tunnel syndrome, 2/25 SSc patients were over this threshold value. In these two patients nerve conduction studies confirmed CTS. Three of 25 SSc patients referred symptoms related to carpal tunnel syndrome, but all of them had a negative electrophysiologic examination and a negative imaging study. All these patients had a negative X-ray examination of the cervical spine.
The pathogenesis of peripheral nervous system involvement is not fully defined and the main hypothesis to explain the neuropathy are at least three: a vascular dependent mechanism, a compression dependent mechanism and an autoimmune-dependent neuropathy. The first considers the unique microvascular involvement in SSc and the involvement of vasa nervorum. Indeed, the axonal degeneration may indirectly favor the hypothesis of a vascular genesis of nerve involvement. The second is supposed by the observation of nerve demyelination in SSc: it is well known that compressive conditions such as carpal tunnel syndromes induce progressive demyelination with edema in the first stages of the disease and fibrosis in the late stages [16]. According to another study the presence of a non-length-dependent (focal or multifocal) pure sensory peripheral neuropathy in patients with scleroderma who have neurologic symptoms is typical of SSc [17]. To our knowledge there are no reports in literature evaluating peripheral nerves of SSc patients with imaging techniques and our study is the first that evaluates extensively upper limb nerves in patients affected by SSc with ultrasound. In our series the presence of sensory disturbances was the main symptom and the prevalence of sensory disturbances (40%: 10/25 patients) was higher than previously reported [16]. Imaging modalities used revealed abnormalities in 7 out of 10 patients with either carpal tunnel syndrome or cubital tunnel syndrome symptoms. In the majority of patients with nerve symptoms a cause explaining the symptoms was identified by imaging. The high-resolution ultrasound examination of SSc patients did not identify diffuse enlargements such as in other patients with sensory disturbances (ex. acromegalic patients [11]) and surprisingly did not find any focal or multifocal abnormality except for the increased nerve cross-sectional areas at the level of the osteofibrous tunnels.
3.3. Cubital tunnel syndrome-like symptoms Five patients had symptoms related to cubital tunnel syndrome. Considering 7.5 mm2 as a threshold value for ulnar nerve CSA for cubital tunnel syndrome, 3/25 SSc patients were over this threshold value. In these patients nerve conduction studies confirmed a mild cubital tunnel syndrome. In 2 of 25 SSc patients with symptoms related to severe cubital tunnel syndrome, a positive electrophysiological examination and hypotenar muscles atrophy, the ulnar nerve was not visible due to the presence of calcifications, therefore CT and MR were performed to confirm ulnar nerve compression at the level of the cubital tunnel (Fig. 1). All these patients had a negative X-ray examination of the cervical spine. We did not find any correlations of the US findings with the clinical parameters such as disease duration, immunosuppressive therapy and autoantibodies. We did not find any differences between the group of patients with SScL and SScD. There was no association between the presence of an entrapment neuropathy and disease duration, autoantibodies and immunosuppressive therapy (chi-square test, data not shown). A complete description
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Fig. 2. 44-Year-old female patient with moderate cubital tunnel syndrome. (A) The ulnar nerve is seen at the entrance of the cubital tunnel with an increased cross-sectional area and a hypoechoic appearance with initial loss of the fascicular echotexture. (B) The ulnar nerve of a 62-year-old female patient with a mild cubiltal tunnel syndrome is depicted. Note that the ulnar nerve is less hypoechoic than in A, but the cross-sectional area is increased.
Fig. 3. 66-Year-old female with carpal tunnel syndrome. (A) The median nerve is enlarged proximally to the carpal tunnel (cross-sectional area: 14 mm2 ) and the fascicular echotexture is not completely preserved. (B) A normal median nerve in a 55-year-old female control shows the normal fascicular echotexture.
Our data differ from the hypothesis of a non-length-dependent (focal or multifocal) pure sensory peripheral neuropathy that affects SSc patients [17]. The possible reason is that nerve abnormalities of SSc patients may not be evident on high-resolution ultrasound. This observation may be in line with the hypothesis of a vascular or autoimmune dependent neuropathy with an involvement of the vasa nervorum. The absence of diffuse or focal nerve enlargement support the hypothesis of a vascular-based neuropathy in the patients with carpal tunnel syndrome-like symptoms but no diagnosis of carpal tunnel and this explains why carpal tunnel syndrome-like symptoms in SSc patients are not always associated with the diagnosis of carpal tunnel syndrome. Moreover, the presence of cubital tunnel syndrome in patients with SSc has never been evaluated extensively. In literature there are only anecdotal reports describing ulnar nerve entrapment at the elbow [18]. In our patients the prevalence of cubital tunnel syndrome was quite high, 20% of patients, and the severity of the entrapment ranged from moderate to severe as demonstrated by the fact that the electrophysiology was always positive. In fact it is known that only in mild cubital tunnel syndrome ultrasound may be able to find ulnar nerve enlargement while electrophysiology is not able to find abnormalities [15] (Figs. 2 and 3). We demonstrated that cubital tunnel syndrome in SSc may be related to calcific deposits at the level of the elbow or idiopathic. In case of calcific deposits CT and MR are required to identify bone, calcification and the nerve entrapped. The lack of relationships between the two entrapment neuropathies observed (carpal tunnel syndrome and cubital tunnel syndrome) and disease duration or autoantibodies reinforces the hypothesis of a vascular dependent neuropathy. According to literature, tissue edema may cause peripheral nerve compression and therefore entrapment neuropathies especially at the beginning of the disease [16], but the lack of correlation between disease duration and entrapment neuropathies is against this hypothesis. The automimmune-dependent neuropathy is more likely to be related
to autonomic nervous system involvement than peripheral nervous system involvement [16]. A possible limitation of our study is the use of standard protocols for the diagnosis of ultrasonographic carpal tunnel syndrome and not the new techniques such as the wrist–forearm ratio or delta cross-sectional area [19,20]. The use of these techniques may have increased the diagnostic accuracy of ultrasound. Moreover we also performed normal tests for the diagnosis of cubital tunnel syndrome and not a new test that increases the accuracy of the diagnosis [21]. In conclusion the results of imaging studies support the hypothesis of a vascular dependent neuropathy in scleroderma. Imaging allowed to identify and differentiate carpal tunnel syndrome and cubital tunnel syndrome that have different therapeutical approaches. Imaging studies of patients affected by SSc helped the clinician in the evaluation of hand sensory disturbances. References [1] Gilliland Bruce C. Systemic sclerosis (scleroderma) and related disorders. In: Harrison’s principles of internal medicine. 16th ed. McGraw-Hill; 2005. p. 197990. [2] Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581–90. [3] LeRoy EC, Medsger Jr TA. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–7. [4] Boutry N, Hachulla E, Zanetti-Musielak C, et al. Imaging features of musculoskeletal involvement in systemic sclerosis. Eur Radiol 2007;17:1172–80. [5] Pope JE. Musculoskeletal involvement in scleroderma. Rheum Dis Clin North Am 2003;29:391–408. [6] Chammas M, Meyer zu Reckendorf G, Allieu Y. Compression of the ulnar nerve in Guyon’s canal by pseudotumoral calcinosis in systemic scleroderma. J Hand Surg [Br] 1995;20:794–6. [7] Thurman RT, Jindal P, Wolff TW. Ulnar nerve compression in Guyon’s canal caused by calcinosis in scleroderma. J Hand Surg [Am] 1991;16:739–41. [8] Martinoli C, Schenone A, Bianchi S, et al. Sonography of the median nerve in Charcot-Marie-Tooth Disease. AJR 2002;178:1553–6.
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