Journal of the Neurological Sciences 347 (2014) 44–49

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Ultrasound of the peripheral nerves in systemic vasculitic neuropathies Alexander Grimm a,c,⁎, Bernhard F. Décard a, Antje Bischof a,b, Hubertus Axer c,d a

Department of Neurology, Basel University Hospital, Switzerland Clinical Immunology, Basel University Hospital Basel, Switzerland c Hans Berger Department of Neurology, Jena University Hospital, Jena, Germany d Center for Sepsis Control and Care (CSCC), Jena University Hospital, Germany b

a r t i c l e

i n f o

Article history: Received 1 August 2014 Received in revised form 5 September 2014 Accepted 12 September 2014 Available online 18 September 2014 Keywords: Nerve ultrasound Axonal polyneuropathy Vasculitic polyneuropathy Vasculitis Mononeuritis multiplex Peripheral nerve system

a b s t r a c t Introduction: Ultrasound of the peripheral nerves (PNUS) can be used to visualize nerve pathologies in polyneuropathies (PNP). The aim of this study was to investigate, whether PNUS provides additional information in patients with proven systemic vasculitic neuropathies (VN). Material and methods: Systematic ultrasound measurements of several peripheral nerves, the vagal nerve and the 6th cervical nerve root were performed in 14 patients and 22 healthy controls. Nerve conduction studies of the corresponding nerves were undertaken. Finally, the measured results were compared to a study population of demyelinating immune-mediated and axonal neuropathies. Results: Patients with VN displayed significant smaller amplitudes of compound muscle action potentials (CMAP) (p b 0.05) and sensory nerve action potentials (SNAP) compared to healthy controls, while conduction velocity did not differ between groups. The mean nerve cross-sectional areas (CSA) were increased in several peripheral nerves compared to the controls, most prominent in tibial and fibular nerve (p b 0.01). PNUS revealed nerve enlargement in most of the clinically and electrophysiologically affected nerves (22 out of 31) in VN. Nerve enlargement was more often seen in vasculitic neuropathies than in other axonal neuropathies, but significantly rarer than in demyelinating neuropathies. Conclusion: Focal CSA enlargement in one or more nerves in electrophysiologically axonal neuropathies can be a hint for VN and thus facilitate diagnostic and therapeutic procedures. © 2014 Elsevier B.V. All rights reserved.

1. Introduction The vasculitides comprise a heterogeneous spectrum of disorders involving different organs including skin and nerve system due to inflammatory destruction of vessel walls and focal ischemia [1,2]. Vasculitides may be classified according to involvement of small, medium, or large vessels and granulomatous or non-granulomatous inflammation. Primary or secondary systemic or non-systemic vasculitis can be differentiated [3,4]. Primary vasculitides can be divided in antineutrophil cell antibodies (ANCA) associated vasculitides (AAV) and non ANCA associated vasculitides. The non-systemic vasculitides show no signs of systemic involvement including organ involvement, certain laboratory findings (e.g. ANCAs), cryoglobulins, or reasons for secondary systemic vasculitis (e.g. connective tissue diseases, drugs, and underlying infections). A major neurological focus is the affection of the peripheral nervous system – so-called vasculitic neuropathy (VN). Patients often present with sensory and/or motor deficits as well as pain in different nerve regions – called mononeuritis multiplex. Involvement is mostly ⁎ Corresponding author at: Department of Neurology, Basel University Hospital, University Basel, Petersgraben 4, CH-4000 Basel, Switzerland. Tel.: +41 61 5565130. E-mail address: [email protected] (A. Grimm).

http://dx.doi.org/10.1016/j.jns.2014.09.017 0022-510X/© 2014 Elsevier B.V. All rights reserved.

asymmetric, lower limb- and distal-predominant. However, it should be appreciated that the majority of patients have a confluence of multiple mononeuropathies, producing a generalized but multifocal and asymmetric polyneuropathy [5]. Also distal-symmetric polyneuropathies are described in rare cases. Some patients are rapidly progressive; others show mild symptoms only for many years prior to diagnosis [2]. The diagnostic gold standard for vasculitic neuropathy consists of clinical examination, nerve conduction studies (NCS), and laboratory tests such as ANCA, erythrocyte sedimentation rate (ESR), antinuclear antibodies (ANA) and rheumatoid factor (RF). Definite diagnosis can only be done by a peripheral nerve biopsy, e.g. the sural nerve [2]. However the sensitivity of nerve biopsy is no more than 50–60% [3]. In nonsystemic cases skin biopsy may have additional diagnostic value [6]. The value of the peripheral nerve ultrasound (PNUS) for the diagnosis of peripheral nerve damage and for evaluating polyneuropathy (PNP) has been proved recently in inherited and acquired neuropathies [7–17]. In inherited neuropathies, above all in Charcot-Marie-Tooth (CMT) 1A, but also in rarer forms of mostly demyelinating pathology, diffuse, generalized nerve enlargement occurs [14–17], whereas in immune-mediated neuropathies different patterns of nerve alteration exist – ranging from normal to focal and diffuse [18]. The pathophysiology of nerve enlargement remains quite unclear so far. In very chronic neuropathies it has been assumed that nerve enlargement due to de-

A. Grimm et al. / Journal of the Neurological Sciences 347 (2014) 44–49

and remyelination may cause increased cross-sectional areas (CSA) of the peripheral nerves in ultrasonography, which may be in correlation with onion bulbs seen in histology [19]. In acute and subacute neuropathies focal edema, increased blood flow and focal inflammation could cause focal nerve enlargement. In all, nerve enlargement and increased echogenicity occur mostly in chronic and acute demyelinating neuropathies, whereas in non-immune-mediated axonal neuropathies such alterations have regularly not been found. Therefore, PNUS can be used to differentiate between axonal and demyelinating neuropathies [20,21]. In contrast, vasculitic neuropathy may be an exception of these findings as Ito et al. [22] and Boehm et al. [23] described several cases with enlarged distal tibial or ulnar nerves in PNUS. Therefore, the aim of this study was to determine, whether nerve enlargement is a characteristic in clinically and/or electrophysiologically involved nerves in patients suffering from vasculitic neuropathy. The second study objective was the comparison of the ultrasonic findings in VN to the partly already published results of demyelinating immune-mediated and axonal non-immune-mediated neuropathies of our study group [20]. 2. Methods 2.1. Subjects Between June 2013 and July 2014, we prospectively performed standardized nerve ultrasound examinations in patients who suffered from polyneuropathy (PNP) with primary or secondary systemic vasculitis, defined by the American College of Rheumatology [24] and according to the revised Chapel-Hill Consensus Conference [25]. Diagnosis of vasculitic neuropathy was ascertained by clinical examination, organ and/ or nerve biopsy, laboratory findings, and electrophysiological examinations. The study was registered in the German Clinical Trials Register (DRKS0005253) and was approved by the local ethics committee (3663-01/13). Informed consent was obtained from all patients and controls. Inclusion criterion was the diagnosis of vasculitic neuropathy. All patients received a clinical neurological examination and nerve ultrasound, and nerve conduction studies as recommended [26]. All healthy controls received the same protocol. Furthermore, laboratory analysis, analysis of cerebrospinal fluid (CSF) and biopsy of sural nerve, or kidney and other organs were performed in patients for clinical reasons. 2.2. Nerve conduction studies Nerve conduction studies were performed using a standard electroneurophysiologic device (Synergy 15.0, VIASYS Healthcare UK Ltd.). Measurements were carried out on the right median nerve including F-waves, left ulnar nerve including F-waves, right tibial nerve including F-waves, left fibular nerve, and both sural nerves. This is the standard examination scheme for electrophysiological assessment at our institution for detecting acute and chronic neuropathies. In addition, clinically involved nerves were analyzed. 2.3. Ultrasound Ultrasonography was performed using a high frequency 14 MHz probe real-time linear array scanner (ZONARE Ultrasound systems). Ultrasonography was performed bilaterally in different nerves of the upper and lower limbs and the neck. The nerves were scanned in axial planes, and the cross-sectional area (CSA) of each nerve was measured at standardized anatomical points as described before [15]. In short: median nerve in axilla (proximal), before pronator teres muscle (middle), and at the mid-forearm (distal); ulnar nerve at mid-humerus (proximal) and at the mid-forearm (distal); tibial nerve in popliteal space (proximal) and at medial malleolus before the nerve division

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into plantar nerves (distal); fibular nerve 2 cm above fibular head; and sural nerve between lateral and medial gastrocnemic head. In addition, the CSA of the vagal nerve in carotid sheath beneath the carotid bifurcation and the longitudinal diameter of the 6th cervical nerve root after leaving the processus transversus were measured. CSA was traced inside the hyperechoic rim of the nerve. Analysis of ultrasound data was performed both online and offline. Approximately 40 min is needed for a complete ultrasound examination of each patient. A second examiner evaluated all ultrasound measurements offline for a second time. Both examiners were blinded to the electrophysiological measurements of the patients. 2.4. Statistics IBM SPSS Statistics, version 19 (Chicago, IL) was used for statistical analysis. Student's t-test was used for evaluating differences concerning epidemiological data (age, gender, disease duration, height and weight). One-way ANOVA was used to detect differences of nerve CSAs and electrodiagnostic studies between patients and healthy controls and to calculate differences concerning mean CSAs of vasculitic neuropathies in comparison to axonal neuropathies of other origin and immunemediated demyelinating neuropathies. Pearson correlation coefficients were calculated to quantify correlations between electrodiagnostic studies, ultrasonic findings and clinical course as well as laboratory findings. Chi-square-test was used for comparing the frequency of pathological nerve or root enlargement in vasculitic patients compared to healthy controls and other neuropathies. Intraclass correlation coefficients (ICC) were calculated to evaluate interrater and intrarater reliability for the evaluation of nerve CSA as well as 6th cervical nerve root diameter. 3. Results Fourteen patients with vasculitic PNP and 22 healthy controls were enrolled in the study. Baseline characteristics of both groups are shown in Table 1. The groups were of similar age, height, weight, and gender. All patients fulfilled the peripheral nerve society guidelines for vasculitic PNP [3,26]. Twelve out of 14 patients had an initial asymmetric beginning pointing to mononeuritis multiplex. None of the patients showed cranial nerve involvement. In 8 patients diagnosis was ensured by sural nerve biopsy, and in 4 patients by other organ biopsy. In two patients diagnosis was made by clinical course, laboratory findings, and therapy response. Eleven patients had primary and 3 patients had secondary systemic VN (rheumatoid arthritis, systemic lupus erythematosus, and Sjögren's syndrome). No patient has been diagnosed with NSVN during screening period. Table 2 shows conduction velocities and amplitudes of median and tibial nerves in the different study groups. Results of the other nerve measurements are not shown in this table but were used for diagnosis of the different types of neuropathy according to the literature [3,26]. ANOVA revealed a significant reduction of CMAP amplitudes in all motor nerves compared to healthy controls (p b 0.05), endorsing the diagnosis of axonal neuropathy as required [3]. Furthermore, in tibial nerve distal motor latency, F-wave-latency, and conduction velocity were significantly affected compared to healthy controls (p b 0.05). According to EFNS criteria [27], 9 out of 14 patients (64.3%) showed slight signs of demyelinating neuropathy in at least one nerve (such as prolongation of motor distal latency, reduction of conduction velocity, abnormal temporal dispersion, F-wave latency prolongation, and conduction blocks), mainly conduction blocks as a sign of focal ischemia. Intrarater intraclass correlation coefficient (ICC) of the offline nerve ultrasound measurements was 0.995, and interrater ICC was 0.990. Table 3 shows CSA measurements of median, ulnar, fibular, tibial, vagal, and sural nerves as well as the 6th cervical nerve root diameter in each group. ANOVA revealed significant enlarged mean CSA values

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A. Grimm et al. / Journal of the Neurological Sciences 347 (2014) 44–49

Table 1 Baseline characteristics of the study population.

N Mean age in years ± SD Gender men:women Mean height in cm Mean weight in kg Disease duration in months ± SD Laboratorya Diagnosis confirmed by

Vasculitic neuropathies

Healthy control

14 62.0 ± 15.0 (range 33.4–83.6) 5:9 169.0 ± 3.2 (range 165–175) 65.0 ± 11.4 (range 45.2–86.5) 28.2 ± 25.2 (range 2–60) (median 16.0) p-ANCA n = 3; c-ANCA n = 3; cryoglobulins n = 4; ANA n = 4; anti-CCP n = 1; anti-dsDNA n = 1 Sural nerve biopsy n = 8; other organ biopsy n = 4; N.A. = 2

22 54.7 ± 15.7 (range 33.5–74.4) 10:11 173.9 ± 6.3 (range 165–182) 67.0 ± 12.9 (range 46.4–97.2) N.A. N.A.

Student's t-test p p p p

= = = =

0.113 0.500 0.052 0.637

Abbreviations: cm = centimeter; kg = kilogram; ANA = antinuclear antibodies; ANCA = anti-neutrophil cell antibodies (c = cytoplasmatic; p = perinuclear); anti-CCP = anti-cyclic citrullinated peptide antibodies; anti-dsDNA = anti-double stranded DNA antibodies; N.A. = not applicable; SD = standard deviation. a Several patients had more antibodies, and 2 patients had no autoimmune antibodies.

in all nerves in patients compared to healthy controls (p b 0.05), except for the distal median, distal ulnar, and vagal nerves. The 6th cervical nerve root diameter was normal (b3.5 mm) in 12 patients. In vasculitic neuropathies significantly more nerve enlargements – according to boundary values of the literature [20] – were detected by ultrasound than in the control group (2.9 ± 1.9 vs. 0.7 ± 1.0; p b 0.001). Overall chi-square test revealed significant differences of the number of detected nerve enlargements between these groups (χ2 11.725, df 5, p b 0.05). Overall, 31 nerves were clinically involved with paresis and sensory symptoms. Twenty-eight out of these nerves had pathological NCS indicating mainly axonal damage of these nerves (90.3%). In 22 out of these nerves (70.9%) focal nerve enlargement was detected in at least one measurement point according to literature [20]; in 2 more nerves only marginal enlargement was found. Three out of the clinically involved nerves had normal NCS and pathological CSA, 6 nerves had pathological NCS and normal CSA, 1 patient had pathological NCS and CSA in median nerve, while patient showed no symptoms of median nerve involvement. Increased CSA was also detected in clinically and electrophysiologically unaffected nerves in 3 patients (median and ulnar nerve). Equivalently, electrophysiological measurements were pathological in 2 nerves in 2 patients without ultrasonic CSA enlargement and symptoms (peroneal nerve and ulnar nerve, not shown). In one patient neither NCS nor PNUS was pathological in peroneal nerve, although the patient showed clinically peroneus paresis. Chi-square test revealed no significant differences concerning the detection of nerve pathology between both techniques (in detail: median nerve χ2 4.052, df 1, p = 0.088; ulnar nerve: χ2 0.900, df 1, p = 0.524; fibular nerve χ2 0.014, df 1, p = 1.0; tibial nerve χ2 3.993, df 1, p = 0.273). Table 4 shows the involvement of peripheral nerves in respect to clinical symptoms, NCS, and ultrasonic findings in each patient. No correlation was found between disease duration, therapy, laboratory findings and nerve enlargement. Finally, the ultrasonic nerve measurements from patients with VN were compared with the measurements of patients with axonal

neuropathy (e.g. diabetic or critical-illness polyneuropathy) and demyelinating, immune-mediated neuropathy (e.g. CIDP). Some of these patients were already included and described in a previous study of our study group [20]. The ultrasonic measurement methods, instrumentation, probe and electrophysiological devices were exactly the same as in this study. Some patients had to be excluded, because of missing nerve measurements such as the sural and vagal nerve and the 6th cervical nerve root, which were not part of the standard protocol in the former study. Baseline characteristics differed not significantly for age, height and weight as well as disease duration, but for gender with predominantly females in this study group (p b 0.01). In comparison to other axonal neuropathies CSA values are significantly increased in sural nerve and the proximal part of tibial nerve (p b 0.05), whereas no differences could be found in other nerves. In demyelinating neuropathies mean CSA values are significantly increased in all nerves as well as in the 6th cervical root diameter in comparison to vasculitic and axonal neuropathies except the sural nerve, which showed similar mean CSA values in both vasculitic and demyelinating neuropathies (mean 3.6 ± 0.7 vs. 3.3 ± 1.4 mm2). Nerve enlargement – as defined in literature [20] – was seen significantly more often in arm and leg nerves (in detail: median, ulnar, fibular and tibial nerve) in demyelinating neuropathies compared to axonal and vasculitic neuropathies (p b 0.001). Using chi-square test significantly more patients with demyelinating neuropathies showed nerve enlargement in at least 5 out of 8 measurement points in the nerves of the arms and legs with motor function as described above compared to axonal and vasculitic neuropathies (χ2 = 11.852, df 2, p = 0.003). 4. Discussion The value of PNUS in acquired immune-mediated neuropathies such as Guillain-Barré syndrome (GBS) [8,13], chronic inflammatory demyelinating polyneuropathy (CIDP) [10,12], multifocal acquired demyelinating sensory and motor neuropathy [28], and multifocal motor neuropathy [7] has been reported in several studies. In immunemediated neuropathies the pattern of CSA enlargement and altered

Table 2 Nerve conduction studies.

Motor CV median nerve (m/s) CMAP amplitude median nerve (mV) Distal motor latency median nerve(ms) Median F-wave latency (ms) Motor CV tibial nerve (m/s) CMAP amplitude tibial nerve (mV) Distal motor latency tibial nerve(ms) Tibial nerve F-wave latency (ms)

Vasculitic neuropathies

Control

Mean 51.5 Mean 5.7 Mean 3.8 Mean 30.4

± ± ± ±

SD 5.6 SD 2.7 SD 0.4 SD 4.8

Mean 53.3 Mean 10.7 Mean 3.8 Mean 27.4

± ± ± ±

SD 4.1 SD 4.1 SD 0.4 SD 3.0

ANOVA p p p p

= = = =

0.260 0.035 0.900 0.670

Mean 36.2 Mean 3.3 Mean 5.5 Mean 64.2

± ± ± ±

SD 7.3 SD 4.5 SD 1.2 SD 1.7

Mean 43.6 Mean 13.2 Mean 4.4 Mean 51.8

± ± ± ±

SD 2.4 SD 5.0 SD 0.6 SD 5.1

p= pb p= p=

0.018 0.001 0.052 0.007

Abbreviations: CV = conduction velocity, CMAP = composed motor action potential, ms = millisecond, mV = millivolt, m/s = meter per second, SD = standard deviation. Significance was set p b 0.05. Significant differences are shown in bold print.

A. Grimm et al. / Journal of the Neurological Sciences 347 (2014) 44–49 Table 3 Ultrasonic measurements. Mean CSA in mm2

Vasculitic neuropathies

Control

Median nerve, proximal Median nerve, middle Median nerve, distal Ulnar nerve, proximal Ulnar nerve, distal Fibular nerve Tibial nerve, proximal Tibial nerve, distal Sural nerve Vagal nerve C6 in mm

11.0 11.6 8.4 8.5 7.1 10.7 31.9 11.9 3.3 2.0 3.1

9.0 9.6 7.5 6.9 6.3 8.0 21.0 8.8 2.1 2.2 3.1

± ± ± ± ± ± ± ± ± ± ±

2.5 2.5 1.4 2.1 1.8 2.4 5.7 2.6 1.4 0.4 0.6

± ± ± ± ± ± ± ± ± ± ±

ANOVA 1.6 2.1 1.7 2.2 1.5 1.8 3.9 2.3 0.7 0.7 0.4

p= p= p= p= p= p= pb p= p= p= p=

0.028 0.044 0.165 0.039 0.152 0.006 0.001 0.008 0.043 0.785 0.989

Abbreviations: C6 = cervical root 6, CSA = cross-sectional area, mm2 = square millimeter; SD = standard deviation. Significance was set p b 0.05. Significant differences are shown in bold print.

echogenicity is quite heterogeneous (normal, unifocal, multifocal or generalized), whereas in most of ther inherited neuropathies CSA enlargement is diffuse and generalized affecting all nerves [7–10,14–18]. In a recent study of our group for evaluating the value of PNUS, differentiation between axonal and demyelinating neuropathies of different origin was possible, as non-immune-mediated axonal PNPs showed no

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generalized nerve enlargement [20]. Although diffuse nerve enlargement has not been described in vasculitic PNP, circumscribed focal nerve enlargement in the ulnar and the distal tibial nerves have been reported and epineural edema and focal inflammation have been suggested as a possible pathomechanism for these findings [22,23]. This is to our best knowledge the first study, which describes results of systematic peripheral nerve measurements in vasculitic neuropathies using ultrasound. PNUS is able to detect focal nerve enlargement often caused by enlarged fascicles in clinically affected nerves of vasculitic neuropathy with high sensitivity in several peripheral nerves, which may support the diagnosis of mononeuritis multiplex. The nerves of the legs are affected the most using PNUS. NCS and PNUS show good correlation in most cases with enlargement in affected nerves and missing enlargement in non-affected nerves. Ultrasound seems to be able to visualize nerve alteration in electrophysiologically involved nerves as described before in cases of autoimmune neuropathy [28], but also in electrophysiologically unaffected nerves. In vasculitic neuropathy no generalized nerve enlargement – as described in demyelinating neuropathies [9,10,14–18,20] – can be found, although mean CSA values were slightly but significantly increased in patients compared to healthy controls in this study. Vasculitic neuropathies show mainly signs of axonal damage in NCS and biopsy [2]. Whereas in other axonal, non-immune-mediated

Table 4 Clinical, ultrasonic, and electrophysiological nerve pathologies. Patient/Age/Gender

Diagnosis/Laboratory/Biopsy

Nerve

Clinical involvement

NCS pathology

Ultrasonic CSA enlargement

ET/73/w

Sjoegren's syndrome/ANA/glandula submandibularis

JK/33/w

Necrotizing SLE-vasculitis/anti-DNS; ANA/nerve

RG/83/w

Rheumatoid arthritis/anti-CCP/nerve

JS/82/m

Churg-Strauss Syndrome/eosinophiles/n.d.

KH/67/w

Essential mixed cryoglobulinemic vasculitis/ANA; cryoglobulins/nerve

DS/44/w

Wegener's disease/c-ANCA/nose; nerve

MM/76/w

Wegener's disease/c-ANCA/n.d.

RN/72/m

Microscopic polyangiitis/p-ANCA/kidney

GM61/w

Microscopic polyangiitis/p-ANCA; cryoglobulins/nerve

AB/65/m

Wegener's disease/c-ANCA/nerve

Fib Tib Uln Med Fib Tib Med Fib Tib Med Per Tib Uln Fib Tib Med Uln Fib Tib Fib Tib Med Uln Fib Tib Med Fib Tib Med Fib

PS/50/m LC/61/m

Microscopic polyangiitis/p-ANCA/kidney Giant cell arteritis/none/arteria temporalis

AW/40/w

Essential mixed cryoglobulinemic vasculitis/cryoglobulins/nerve

OG/57/w

Essential mixed cryoglobulinemic vasculitis/cryoglobulins; ANA/nerve

+ + + + + + + + + + 0 + 0 + + + + + + + + 0 0 + + 0 + + 0 + None + + + + + + + 31

+ + + + + + + + + NA + + + + + NA + + + 0 + 0 0 0 + 0 + + + + None + + + + + + + 30

0 + (dis 12 mm2) + (14 mm2) + (16 mm2) + (14 mm2) + (dis 15 mm2) 0/+ (10 mm2)* 0 + (37 mm2) + (16 mm2) 0 + (32 mm2) 0 + (13 mm2) 0 + (12 mm2) + (10 mm2) 0 + (dis 13 mm2) 0 + (33 mm2) + (15 mm2) + (10 mm2) + (18 mm2) + (42 mm2) + (14 mm2) 0/+ (11 mm2)* + (dis 17 mm2) + (14 mm2) + (14 mm2) None# 0 + (13 mm2) + (39 mm2) + (14 mm2) + (dis 16 mm2) 0 + (40 mm2) 26 (28)*

Number of involved nerves

Uln Fib Tib Fib Tib Fib Tib

Abbreviations: ANA = antinuclear antibodies; ANCA = anti-neutrophil cell antibodies; dis = distal; Fib = fibular nerve; Med = median nerve; n = number; NA = not applicable; NCS = nerve conduction studies; pop = popliteal; prox = proximal; SLE = systemic lupus erythematosus; Tib = Tibial nerve; Uln = Ulnar nerve+ = pathological; 0 = non-pathological Corresponding results concerning clinical course, NCS and US are in bold print; those concerning two examinations are in italics. Borderline values and number of enlarged nerves including borderline values are marked with an asterisk (*). One patient with no symptoms at examination time point is marked with a number sign (#).

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A. Grimm et al. / Journal of the Neurological Sciences 347 (2014) 44–49

Fig. 1. Axial ultrasound of the ulnar nerve in the upper arm in a patient with vasculitic neuropathy (A) and a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (B) compared to a healthy control (C). In both patients the nerve cross-sectional area (CSA) is increased (14 mm2 and 34 mm2 compared to 8 mm2 in the control). In CIDP the echogenicity of the nerve is increased, whereas in vasculitic neuropathy the fascicles are enlarged, but show normal echo intensity, comparable to the healthy control.

neuropathies CSA enlargement does not occur usually, nerve enlargement might be an expression of focal edema, perivascular hemorrhage, increased vascularization and focal inflammation in vasculitis. Furthermore intimal and adventitial fibrosis of the vasa nervorum could play a role in nerve enlargement. The enlargement of single nerve fascicles (Fig. 1A) remains quite unclear, but it might be a consequence out of small vessel infarction and restricted segmental vessel necrosis, which harms circumscribed nerve fascicles only [29]. Consequently, transmural inflammation develops and causes fascicular edema or swelling. In histopathology also ovoids or giant axons are described as well as increase of the connective tissue (epineural sclerosis, [30]). In comparison to other neuropathies mean CSA is most prominent in demyelinating neuropathies (Table 5; see Fig. 1). Thus, demyelinating neuropathies show significantly more often focal or generalized nerve enlargement than axonal and vasculitic neuropathies, which makes it difficult to define a clear-cut reference value for vasculitic neuropathy. Thus, the pattern of ultrasonic involvement of different peripheral nerves with increased fascicles might be of diagnostic value. Nerve echogenicity was normal in all nerves in vasculitic neuropathies, whereas in immune-mediated chronic neuropathies increased echogenicity has been described ([10], Fig. 1). The study has several limitations. The relatively small patient group is heterogeneous concerning etiology of vasculitis, disease duration (range 2 months to 5 years), and therapy. Moreover, NSVN patients are missing in this study. The finding that not all nerves, which were clinically and electrophysiologically involved showed ultrasonic enlargement may suggest that the value of PNUS in the differential diagnosis of vasculitic neuropathy may be limited. However, CSA measurements and NCS were pathological in some nerves, in which patients had no symptoms. This enlargement may represent a diagnostic hint for subclinical nerve involvement. PNUS and NCS might reveal different kinds of pathologies as similar findings were also described in CIDP and GBS [13,31]. The exact time schedule and origin of pathology are unknown so far. The comparison of axonal and demyelinating neuropathies from another study with the vasculitis population is quite unusual and has some bias potential. Otherwise, baseline characteristics are almost equal besides gender – which may have influenced the results [32]. Instrumentation and methods of measurement were the same. Therefore, more information is needed about ultrasonic time course and changes according to therapy. The pathophysiological aspects of

CSA and fascicle enlargement should be compared to histopathological findings. Furthermore, inclusion of NSVN patients, and ultrasonic visualization of vascularity – as a possible option for monitoring disease activity in nerve inflammation [33,34] – could further elucidate the role of PNUS in VN. The obvious advantages of nerve ultrasound are its easy applicability, good interrater reliability, and its non-invasiveness. Patients with vasculitic neuropathy show focal nerve enlargement in PNUS, which is not as pronounced as in demyelinating polyneuropathy. In contrast, other non-immune mediated axonal neuropathies do not show significant nerve enlargement. Furthermore, in vasculitic neuropathies CSA of the sural nerve seems to be significantly increased. Generalized nerve enlargement does not occur. Therefore, PNUS can be a useful addition to nerve conduction studies in case of asymmetric axonal damage of unknown origin. In addition, it could be used to define an affected nerve to be suitable for biopsy. Abbreviations ANA antinuclear antibodies ANCA anti-neutrophil cell antibodies c-ANCA cytoplasmatic ANCA p-ANCA perinuclear ANCA Anti-CCP anti-cyclic citrullinated peptide antibodies Anti-dsDNA anti-double stranded DNA antibodies CIDP chronic inflammatory demyelinating polyneuropathy CIP critical illness polyneuropathy CMAP compound muscle action potential CMT Charcot-Marie-Tooth CSA cross-sectional area CV conduction velocity ESR erythrocyte sedimentation rate GBS Guillain-Barré syndrome ICC intraclass correlation coefficient MADSAM multifocal acquired demyelinating sensory and motor neuropathy MMN multifocal motor neuropathy NCS nerve conduction studies PNP polyneuropathy PNUS peripheral nerve ultrasound RF rheumatoid factor SNAP sensory nerve action potential SVN systemic vasculitis neuropathy VN vasculitic neuropathy

A. Grimm et al. / Journal of the Neurological Sciences 347 (2014) 44–49

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Table 5 Ultrasonic measurements in comparison to demyelinating and axonal neuropathies. Mean CSA in mm2

Vasculitic neuropathies

Demyelinating neuropathies (CIDP, MMN, MADSAM)

Axonal neuropathies (diabetes, alcohol, critical illness)

N Mean age in years ± SD Disease duration in month +- SD Gender m:w Mean Height in cm Mean Weight in kg Enlargement in motor nerves of arms and legs Median nerve, proximal Median nerve, middle Median nerve, distal Ulnar nerve, proximal Ulnar nerve, distal Fibular nerve Tibial nerve, proximal Tibial nerve, distal Sural nerve Vagal nerve C6 in mm

14 62.0 ± 15.0 28.2 ± 25.2 5:9 168.8 ± 3.6 64.1 ± 10.6 2.9 ± 1.9 11.0 ± 2.5 11.6 ± 2.5 8.4 ± 0.4 8.5 ± 2.1 7.1 ± 1.8 10.7 ± 2.4 31.9 ± 5.7 11.9 ± 2.6 3.3 ± 1.4 2.0 ± 0.4 3.1 ± 0.6

22 56.1 ± 12.2 21.1 ± 23.0 20:2 175.9 ± 8.6 71.0 ± 8.3 5.4 ± 2.3 20.0 ± 11.3 19.6 ± 2.1 15.5 ± 1.7 14.9 ± 2.2 10.3 ± 1.5 12.0 ± 1.8 38.3 ± 13.9 15.4 ± 5.3 3.6 ± 0.7 4.7 ± 1.7 4.4 ± 0.4

26 63.8 ± 13.2 14.7 ± 20.7 17:9 175.2 ± 8.9 73.5 ± 15.5 1.9 ± 2.0 10.5 ± 0.3 10.6 ± 0.3 8.2 ± 0.01 8.4 ± 0.2 6.7 ± 0.1 9.2 ± 0.4 28.3 ± 6.9 9.5 ± 0.3 2.0 ± 0.9 2.7 ± 0.7 3.8 ± 0.9

ANOVA

p= p= p= p= p= pb p= p= p= p= p= p= p= pb p= pb p=

0.128 0.231 0.002 0.057 0.163 0.001 0.013 0.048 0.038 0.012 0.001 0.031 0.033 0.001 0.015 0.001 0.021

Abbreviations: C6 = cervical root 6, CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; CSA = cross-sectional area; MADSAM = multifocal acquired demyelinating sensory and motor neuropathy; MMN = multifocal motor neuropathy; mm2 = square millimeter; n = number; SD = standard deviation. Significance was set p b 0.05. Significant differences are shown in bold print.

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Ultrasound of the peripheral nerves in systemic vasculitic neuropathies.

Ultrasound of the peripheral nerves (PNUS) can be used to visualize nerve pathologies in polyneuropathies (PNP). The aim of this study was to investig...
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