Skin Denervation and Cutaneous Vasculitis in Eosinophilia-Associated Neuropathy

ORIGINAL CONTRIBUTION Skin Denervation and Cutaneous Vasculitis in Eosinophilia-Associated Neuropathy

Chi-Chao Chao, MD; Sung-Tsang Hsieh, MD, PhD; Chia-Tung Shun, MD; Song-Chou Hsieh, MD, PhD

Background: Eosinophilia is frequently associated with Main Outcome Measures: Quantitation of epider- peripheral neuropathy, and neuropathic pain is a major mal innervation, immunopathological findings of the cu- presentation. Little is known about the involvement of taneous vasculature, and motor disability grade. sensory nerve terminals and the vasculature in the skin of patients with eosinophilia. Results: Six patients fulfilled the criteria of Churg- Strauss syndrome, and the other 6 patients were catego- Objectives: To investigate the skin innervation and the rized as having primary eosinophilia. All of the 12 pa- pathological abnormalities of the cutaneous vasculature tients had mononeuropathy multiplex or polyneuropathy and their clinical significance in eosinophilia-associated with sensory symptoms as the initial manifestation. In- neuropathy. traepidermal nerve fiber densities were reduced in 10 patients (83.3%), being significantly lower than in the con- Design: Case series. trols (mean±SD, 2.12±2.30 vs 10.56±3.69 fibers/mm, respectively; PϽ.001) and negatively correlated with the Setting: National Taiwan University Hospital, Taipei, Taiwan. disability grade (P=.003). Nine patients (75.0%), including all of the 6 patients with Churg-Strauss syndrome, Patients: Twelve patients with neuropathy and con- had cutaneous vasculitis, and two-thirds of the 9 pa- comitant eosinophilia (with an eosinophilic ratio of white tients had perivascular infiltration of eosinophils. blood cell classification Ͼ10% or absolute eosinophil count of Ͼ1000/µL). Conclusion: Skin denervation with cutaneous vasculitis is a major manifestation of eosinophilia-associated Interventions: Clinical assessments of neurological defi- neuropathy. cits, laboratory tests, nerve conduction studies, and a skin biopsy specimen 3 mm in diameter taken from the distal leg without active skin lesions. Arch Neurol. 2007;64(7):959-965

OSINOPHILIA IS FREQUENTLY tion of T cells and macrophages, suggest- associated with inflamma- ing the nature of the immune-mediated tory and autoimmune dis- vasculopathy.6,7 orders, eg, necrotizing vasculitis in Churg-Strauss 1 See also pages 935, syndromeE (CSS). Scattered reports have 966, and 974 Author Affiliations: indicated the frequent association of Departments of Neurology eosinophilia with various types of neu- (Drs Chao and S.-T. Hsieh), ropathies based on nerve biopsies.2,3 Tra- Skin innervation is reduced in inflam- Pathology (Dr Shun), and ditionally, the demonstration of eosino- matory neuropathies such as Guillain- Internal Medicine philic vasculitis in tissues depends on Barre´ syndrome, chronic inflammatory (Dr S.-C. Hsieh), National nerve or muscle biopsies.4,5 We recently demyelinating polyneuropathy, and au- Taiwan University Hospital, and demonstrated the feasibility of using skin toantibody-related neuropathy.8-10 Skin Departments of Anatomy and denervation has been demonstrated in Cell Biology (Dr S.-T. Hsieh) biopsies to investigate cutaneous vasculi- and Forensic Medicine tis in addition to exploring skin innerva- systemic inflammatory diseases includ- 6 (Dr Shun), National Taiwan tion ; in vasculitic neuropathy and sys- ing vasculitis and systemic lupus ery- 7,11 University College of Medicine, temic lupus erythematosus, there was thematosus. In lupus, the degree of Taipei, Taiwan. significant dermal vasculitis with infiltra- skin denervation is related to the extent

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 of cutaneous vasculitis.7 These findings raise the possi- the patients following established methods.9 Studied nerves bility that skin innervation is altered in eosinophilia. included sural, peroneal, tibial, median, and ulnar (motor Eosinophilic syndrome is associated with neuropa- and sensory) nerves. Abnormal results in nerve conduction thies of diverse manifestations, ranging from focal to sys- studies were defined as having reduced amplitude of com- temic neuropathies. In patients with CSS, sensory symp- pound motor action potentials or sensory action potentials, prolonged distal latencies, or slowing of nerve conduction toms and neuropathic pain are major initial symptoms, velocity. accounting for 50% of presentations.4 Among different subtypes of neuropathies, the effects of eosinophilia on SKIN BIOPSY AND small fibers have received less attention, and to our knowl- IMMUNOHISTOCHEMISTRY OF THE SKIN edge, skin innervation has not been extensively evalu- ated in eosinophilia-associated neuropathy before. After informed consent was obtained, a skin biopsy specimen In this study, we investigated the following: (1) whether 3 mm in diameter was taken from the distal lateral leg 10 cm eosinophilia could be demonstrated in cutaneous tis- proximal to the lateral malleolar process. No active skin lesion sues; (2) whether there was associated dermal vasculi- was noted at the site of biopsy in any patient. If the sensory tis; and (3) whether skin innervation was altered in eo- symptoms were discrepant between the right and left legs, the sinophilia-associated neuropathy. side with the more severe symptoms was sampled. The sampled skin tissue was fixed in 4% paraformaldehyde overnight. Sec- tions 50 µm thick and perpendicular to the dermis were cut METHODS on a sliding microtome, quenched with 1% hydrogen perox- ide in methanol, and blocked with 5% normal goat serum. SUBJECTS Sections were incubated with rabbit antiserum to protein gene product 9.5 (1:1000; UltraClone, Isle of Wight, England) The criteria of eosinophilia-associated neuropathy included overnight. Protein gene product 9.5 is a ubiquitin carboxyl- the following: (1) clinical evidence of symptomatic periph- terminal hydrolase that labels myelinated and unmyelinated eral neuropathy; (2) eosinophilia according to an elevated nerve fibers in the peripheral nervous system. Sections were Ͼ ratio of white blood cell classification ( 10%) or the abso- then incubated with biotinylated goat antirabbit IgG (Vector Ͼ lute eosinophil count ( 1000/µL); and (3) the absence of Laboratories, Burlingame, California) for 1 hour and avidin- diabetes mellitus, renal impairment, malignancies, and spe- biotin complex (Vector Laboratories) for another hour. The cific autoimmune diseases including systemic lupus ery- reaction product was demonstrated using chromogen SG thematosus, rheumatoid arthritis, Sjo¨gren syndrome, and (Vector Laboratories). scleroderma. Patients fulfilling these criteria were recruited from National Taiwan University Hospital, Taipei, Taiwan, QUANTITATION OF from January 1, 1997, to December 31, 2005. In addition to detailed neurological examinations, patients EPIDERMAL INNERVATION also had laboratory tests carried out, including plasma glu- Epidermal innervation was quantified according to estab- cose level, functional tests of the liver and kidney, and levels 9 of antinuclear antibody, rheumatoid factor, anti-Sjo¨gren syn- lished criteria in a coded fashion. Observers were blinded to the clinical information. Protein gene product 9.5–positive nerves drome A antigen, anti-Sjo¨gren syndrome B antigen, anti- ϫ Smith antigen, antiscleroderma antigen (Scl-70), C3 and C4 in the epidermis of each skin section were counted at 40 mag- complement, and cryoglobulin. Possible malignancies were ex- nification with a BX40 microscope (Olympus, Tokyo, Japan). cluded by examining tumor markers (carcinoembryonic anti- Each individual nerve with branching points after crossing the gen and carbohydrate antigen 19-9), abdominal echo, and chest basement membrane was counted as a single nerve. Epider- radiography results. Parasite infections were screened by stool mal nerves splitting below the basement membrane were counted ovum examinations. If patients had a history of asthma, chest as 2 nerves. The length of the epidermis along the upper mar- radiography and computed tomography were performed to de- gin of the stratum corneum in each skin section was measured termine whether there was pulmonary infiltration. A diagno- using Image-Pro PLUS (Media Cybernetics, Silver Spring, Mary- sis of CSS followed the definition of the American College of land). Intraepidermal nerve fiber (IENF) density was hence de- Rheumatology subcommittee.12 In this article, if patients with rived and expressed as the number of fibers per millimeter of eosinophilia-associated neuropathy did not have CSS, malig- epidermal length. In the distal leg, the mean±SD (fifth percen- nancies, or parasitic infections, this subtype of eosinophilia was tile) normative values of IENF densities from our laboratory classified as primary eosinophilia. were 11.16±3.70 (5.88) fibers/mm for subjects younger than 60 years and 7.64±3.08 (2.50) fibers/mm for subjects aged 60 The ability of ambulation was assessed by a disability grade 7 from 0 to 6: grade 0 indicated normal neurological status; grade years or older. 1, minor signs or symptoms capable of running; grades 2 and 3, ambulation without and with assistance, respectively; grade PATHOLOGICAL ASSESSMENT OF VASCULITIS 4, wheelchair bound or bed bound; grade 5, requiring mechani- IN SKIN BIOPSY SPECIMENS cal ventilation; and grade 6, death.13 This study was reviewed and approved by the ethics com- Biopsy specimens of the skin for evaluating vasculitis were fixed mittee of National Taiwan University Hospital. Informed con- in 4% paraformaldehyde, embedded in paraffin, and stained with sent was obtained from each patient before the investigations. hematoxylin-eosin as described previously.6,7 Both perivascu- For comparison, age- and sex-matched subjects in the control lar inflammation and vascular injury (extravasation of red blood group were retrieved from a previously described cohort.14 cells, fibrinoid necrosis, or disruption of vascular wall integrity by leukocytes) were required to definitely diagnose vas- NERVE CONDUCTION STUDIES culitis. The vasculature in the skin belongs to the small vessels; this type of vessel is less likely to undergo fibrinoid necrosis, Nerve conduction studies were performed with a Viking IV which is usually seen in medium-sized vessels.15 The disrup- Electromyographer (Nicolet, Madison, Wisconsin) in all of tion of vascular integrity, such as the discontinuity of the vas-

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Eosinophilsa Disability Gradeb Case No./ Differential, Absolute, Systemic Pattern of Motor Sensory Sex/Age, y Diagnosis % /µL Involvement Neuropathy Weakness Symptoms Treatment Initial Follow-up 1/F/54 CSS 49.0 11 662 Asthma, MM UL, left distal; Left foot, Steroid 3 2 sinusitis LL, bilateral distal neuropathic pain 2/M/59 CSS 44.0 8932 Asthma, MM LL, right distal Right leg, Steroid 2 1 lung neuropathic pain 3/F/50 CSS 63.0 10 345 Asthma, MM UL, right distal; Bilateral feet, Steroid, 32 skin LL, bilateral distal paresthesia cyclophosphamide 4/M/46 CSS 14.5 1382 Asthma, PN LL, bilateral distal Bilateral feet, Steroid, 32 lung, skin neuropathic cyclophosphamide pain 5/F/40 CSS 40.0 3800 Asthma, GI, MM LL, bilateral distal Left foot, Steroid 2 1 skin and proximal neuropathic pain 6/F/71 CSS 71.8 15 624 Asthma, MM LL, left distal and Bilateral feet, Steroid 2 1 lung, GI proximal paresthesia 7/M/39 Primary 23.2 4485 NA MM UL, bilateral distal Bilateral hands, None 4 2 eosinophilia and proximal; paresthesia LL, bilateral distal and proximal 8/M/36 Primary 18.5 1391 NA PN LL, bilateral distal Bilateral feet, Steroid, PE 2 1 eosinophilia and proximal paresthesia 9/M/56 Primary 25.0 3250 NA MM LL, bilateral distal Right foot, Steroid 3 1 eosinophilia and proximal neuropathic pain 10/M/53 Primary 26.8 3409 NA MM UL, right distal and Right leg, Steroid, PE 3 1 eosinophilia proximal, left neuropathic distal; LL, right pain distal and proximal 11/M/50 Primary 13.6 2577 Urticaria MM UL, bilateral distal; Bilateral hands, Steroid 3 1 eosinophilia LL, right paresthesia proximal, left distal and proximal 12/M/27 Primary 24.0 3211 NA MM LL, bilateral distal Bilateral feet, Steroid 2 1 eosinophilia neuropathic pain

Abbreviations: CSS, Churg-Strauss syndrome; GI, gastrointestinal tract; LL, lower limb; MM, mononeuropathy multiplex; NA, not applicable; PE, plasma exchange; PN, polyneuropathy; UL, upper limb. aDifferential indicates the differential count of eosinophils according to leukocyte classification; absolute, absolute eosinophil count. bThe disability grade is according to the definition described in the “Methods” section.

cular wall by infiltrating leukocytes or the extravasation of RESULTS red blood cells, permits the diagnosis of vascular injury.16 Immunohistochemistry analysis was performed using the avidin-biotin-peroxidase complex technique as described CLINICAL PRESENTATION AND earlier. Cell surface antigens were examined using the fol- LABORATORY DATA lowing monoclonal antibodies: T cells with CD3 (1:100; Ventana Medical System, Tucson, Arizona), B cells with CD20 (1:100; Dako, Glostrup, Denmark), and macrophages There were 12 patients with eosinophilia-associated neu- 4,6 with CD68 (1:200; Dako). Sections were then incubated ropathy (8 men and 4 women; mean±SD age, with biotinylated horse antimouse IgG (Vector Laboratories) 47.92±11.65 years; age range, 27-71 years). The clini- for 1 hour and the avidin-biotin complex (Vector Laborato- cal presentations of these patients are listed in Table 1. ries) for another hour. The reaction product was shown by the chromogen 3,3Ј-diaminobenzidine (Sigma-Aldrich Co, Six patients (2 men and 4 women) fulfilled the criteria St Louis, Missouri) and counterstained with hematoxylin. of CSS. In addition to eosinophilia and peripheral neu- The skin pathological abnormalities and phenotypes of cel- ropathy, all of these 6 patients had adult-onset asthma lular infiltration were examined by 1 of us (C.-T.S.) in a (age at onset, 31-68 years) with involvement of the skin, blinded fashion. lung, gastrointestinal system, and paranasal sinus. The

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Pattern of RBC Perivascular Perivascular IENF Density, Case No. Diagnosis Neuropathy Extravasation Inflammation Vasculitisa Eosinophils Fibers/mm 1 CSS MM ϩϩDefinite − 0 2 CSS MM ϩϩDefinite ϩ 3.00 3 CSS MM ϩϩDefinite ϩ 0 4 CSS PN ϩϩDefinite − 1.38 5 CSS MM ϩϩDefinite ϩ 3.44 6 CSS MM ϩϩDefinite ϩ 5.98 7 Primary eosinophilia MM − ϩ Borderline − 0 8 Primary eosinophilia PN − − NA − 6.39 9 Primary eosinophilia MM − − NA − 2.57 10 Primary eosinophilia MM ϩϩDefinite ϩ 0.19 11 Primary eosinophilia MM ϩϩDefinite − 0 12 Primary eosinophilia MM ϩϩDefinite ϩ 2.49 Patients with 75.0 83.3 75.0 50.0 83.3 abnormality, %

Abbreviations: CSS, Churg-Strauss syndrome; IENF, intraepidermal nerve fiber; MM, mononeuropathy multiplex; NA, not applicable; PN, polyneuropathy; RBC, red blood cell; ϩ, positive; −, negative. a Definite vasculitis indicates the presence of both RBC extravasation and perivascular inflammation; borderline vasculitis, the presence of either RBC extravasation or perivascular inflammation.

other 6 patients (all men), apart from 1 patient with re- DERMAL VASCULITIS IN current urticaria before the onset of neuropathy, were free EOSINOPHILIA-ASSOCIATED NEUROPATHY from allergic diseases, parasitic infections, autoimmune diseases, and tumors. Dermal vasculitis in the regions with no active skin le- All of the 12 patients presented with sensory and sion was demonstrated in all of the 6 patients with CSS motor impairment of acute or subacute onset. Mono- and in the 3 patients with primary eosinophilia (Table 2). neuropathy multiplex was the major form of the neu- Additionally, in these 9 cases, perivascular infiltration of ropathy in 10 patients, whereas the other 2 patients had eosinophils was noted in 4 of the 6 patients with CSS and symmetrical sensorimotor polyneuropathy. In all of the in 2 of those 3 patients with primary eosinophilia patients, the initial neurological symptoms were pares- (Figure 1A). In addition to eosinophilic infiltration, most thesia with various distributions: in the unilateral lower infiltrating cells were positive for the marker of macro- limb (5 cases), simultaneously in bilateral hands (2 phages and T cells but not for that of B cells (Figure 1B-D). cases), and in bilateral feet (5 cases). Neuropathic pain was present in 7 patients (4 with CSS and 3 with pri- SKIN DENERVATION IN mary eosinophilia). Most patients had mild motor diffi- EOSINOPHILIA-ASSOCIATED NEUROPATHY culties (disability grade 2 in 5 cases, grade 3 in 6 cases, and grade 4 in 1 case). There was no correlation be- In most patients with eosinophilia-associated neuropa- tween the eosinophil counts and disability. In nerve thy, the abundance of epidermal nerves was markedly re- conduction studies, 6 patients had motor abnormalities duced compared with that in the skin of control sub- in the upper and lower limbs and 6 had motor abnor- jects (Table 2); in 4 patients, the epidermis was even malities in the lower limbs only; all of the patients had completely denervated (Figure 2). Compared with age- sensory abnormalities in the lower limbs. Eleven pa- and sex-matched control subjects (8 men and 4 women; tients received immunomodulation therapy including mean±SD age, 49.00±11.47 years; age range, 31-72 years), corticosteroids, cyclophosphamide, and plasma ex- the IENF densities in patients with eosinophilia- change, and all of the patients showed remission of eo- associated neuropathy were significantly lower sinophilia and significant improvement in ambulation (mean±SD, 10.56±3.69 vs 2.12±2.30 fibers/mm, respec- (of at least 1 disability grade). One patient with primary tively; PϽ.001) (Figure 3A), and the IENF densities eosinophilia experienced spontaneous remission in were reduced in 10 patients (83.3%). The IENF densi- motor weakness (from an initial grade of 4 to a fol- ties in these patients were negatively correlated with the low-up grade of 2). The neuropathy exhibited a remis- disability scores (P=.003) (Figure 3B). sion-relapse course in 3 patients with CSS; the other 9 patients had a monophasic course. In summary, there were no obvious differences in neurological manifesta- COMMENT tions between the CSS and primary eosinophilia groups, and the responses to immunomodulating The major findings with eosinophilia-associated neu- therapy were similar in both groups. ropathy in this study include the following: (1) marked

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C D

150 µm

Figure 1. Cutaneous vasculitis in eosinophilia-associated neuropathy. Paraffin-embedded sections were stained with hematoxylin-eosin (A) and analyzed immunohistochemically for macrophages with CD68 (B), for T cells with CD3 (C), and for B cells with CD20 (D), then counterstained with hematoxylin (A-C, original magnification ϫ100). A, Perivascular infiltration of eosinophils (arrows) surrounds a small dermal vessel (inset). The vascular wall of this representative vessel in the deep dermis and subcutaneous fascia becomes disrupted by infiltration of leukocytes (including eosinophils) with marked perivascular eosinophils (arrowhead in inset). B-D, Perivascular infiltrating cells (brown-black) include macrophages (inset in B) and T cells (inset in C) but not B cells.

skin denervation; (2) dermal vasculitis with eosino- vides direct evidence that small-diameter sensory nerves philic infiltration; and (3) correlated motor disability with are susceptible in eosinophilia-associated neuropathy. skin denervation. The pathogenesis of eosinophilia-associated neuropa- Many organ systems can be damaged by sustained over- thy includes vasculitic injury and eosinophilic neuro- activation of eosinophils,1 and the involvement of the pe- toxicity.3,4,20 Traditionally, vasculitis was diagnosed based ripheral nerves occurs in approximately 50% of patients on nerve or muscle biopsies in eosinophilia4,5 and other with eosinophilia.17,18 The presence of paresthesia or neu- inflammatory diseases, such as primary Sjo¨gren syn- ropathic pain in eosinophilia-associated neuropathy raises drome, lumbosacral plexopathies of the diabetic and non- the possibility of small-fiber involvement.4,17,19 Previ- diabetic types, and rheumatoid arthritis.21-23 The cuta- ously, this issue could only be examined with nerve bi- neous vasculature provides an opportunity for evaluation opsies to demonstrate a loss of unmyelinated nerve fi- of vasculitis. In a previous study of 9 CSS cases with ac- bers.4 Because unmyelinated autonomic nerves are also tive skin lesions and neuropathy, vasculitis was noted in present in sural nerves, our study using skin biopsies pro- the skin biopsies.19 In our series with no active skin le-

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50 µm

Figure 2. Skin denervation in eosinophilia-associated neuropathy. Skin sections were immunostained with anti–protein gene product 9.5 antiserum. A, In a normal subject, the epidermis is innervated by protein gene product 9.5–positive nerves with a varicose appearance (arrows). Asterisks indicate dense subepidermal nerve plexuses and dermal nerves (original magnification ϫ400). B, In this representative patient with eosinophilia, epidermal nerves are depleted and there are occasional dermal nerves (asterisk).

vascular eosinophilic infiltration was demonstrated in two- A thirds of the patients in both subgroups. These findings

20 suggest that cutaneous vasculitis indeed also occurs in clinically inactive skin tissues with eosinophilia. 18 The correlation of skin denervation and motor dis- 16 ability grade suggests that the concomitant injury to large 14 and small fibers in eosinophilia-associated neuropathy

12 and skin denervation in eosinophilia reflect generalized neurological deficits. This finding extends previous ob- 10 servations exploring the clinical significance of skin de- 8 nervation. For example, skin denervation was found to 6 be correlated with the disability grade in Guillain-Barre´ IENF Density, Fibers/mm IENF Density, 9 4 syndrome. In systemic lupus erythematosus, skin de- 7 2 nervation was related to disease activities. Taken to- gether, these findings provide therapeutic implications 0 for clinical management. First, skin biopsy is a less in- Patients With Eosinophilia Control Subjects vasive procedure to diagnose eosinophilia-related neuropathy compared with traditional nerve and muscle bi- B opsies. In addition, skin biopsy has the benefit of exploring 6 the effects on nerve terminals, which are among the parts of the nerves most vulnerable to vasculitis. Second, skin 5 innervation may be an indicator for assessing the immu- nological derangements on neurological disabilities. This 4 information is important for designing therapeutic plan- ning or modifying current regimens because different lev- 3 els of strategies are available, from immunomodulating to immunosuppression. Further studies applying this tech- Disability Grade 2 nique are required to test these implications for manag-

1 ing eosinophilia-associated neuropathy, such as different degrees of immunosuppression for different degrees

0 of skin denervation.

0 1 2 3 4 5 6 7 8 9 IENF Density, Fibers/mm Accepted for Publication: October 13, 2006. Correspondence: Song-Chou Hsieh, MD, PhD, Depart- Figure 3. Skin denervation and motor disability in eosinophilia-associated ment of Internal Medicine, National Taiwan University neuropathy. A, Comparison of intraepidermal nerve fiber (IENF) densities Hospital, 7 Chung-Shan S Rd, Taipei 10002, Taiwan between patients with eosinophilia and age- and sex-matched control subjects. Horizontal lines indicate mean. B, Correlation between IENF density ([email protected]). and disability grade. Solid line indicates regression line; dashed lines, 95% Author Contributions: Dr S.-T. Hsieh had full access to confidence intervals. all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analy- sions, cutaneous vasculitis was present in 9 patients sis. Study concept and design: Chao, S.-T. Hsieh, and S.-C. (75.0%), including all of the patients with CSS and half Hsieh. Acquisition of data: Chao, S.-T. Hsieh, Shun, and of those with primary eosinophilia. Additionally, peri- S.-C. Hsieh. Analysis and interpretation of data: Chao, S.-T.

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©2007 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/03/2021 Hsieh, and S.-C. Hsieh. Drafting of the manuscript: Chao, tion in Guillain-Barre syndrome: pathology and clinical correlations. Brain. 2003; S.-T. Hsieh, Shun, and S.-C. Hsieh. Statistical analysis: 126(pt 2):386-397. 10. Lombardi R, Erne B, Lauria G, et al. IgM deposits on skin nerves in anti-myelin- Chao, S.-T. Hsieh, and S.-C. Hsieh. Obtained funding: S.-T. associated glycoprotein neuropathy. Ann Neurol. 2005;57(2):180-187. Hsieh and S.-C. Hsieh. Administrative, technical, and ma- 11. Gøransson LG, Tjensvoll AB, Herigstad A, Mellgren SI, Omdal R. Small- terial support: S.-T. Hsieh, Shun, and S.-C. Hsieh. Study diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol. supervision: S.-T. Hsieh. 2006;63(3):401-404. 12. Bloch DA, Michel BA, Hunder GG, et al. The American College of Rheumatology Financial Disclosure: None reported. 1990 criteria for the classification of vasculitis: patients and methods. Arthritis Funding/Support: This work was supported by grants Rheum. 1990;33(8):1068-1073. NSC93-2320-B-002-005 from the National Science Coun- 13. Hughes RA, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial predniso- cil and 94-N06 from National Taiwan University, Tai- lone in acute polyneuropathy. Lancet. 1978;2(8093):750-753. pei, Taiwan. 14. Pan CL, Lin YH, Lin WM, Tai TY, Hsieh ST. Degeneration of nociceptive nerve terminals in human peripheral neuropathy. Neuroreport. 2001;12(4):787-792. 15. Dyck PJ, Engelstad J, Norell J, Dyck PJ. Microvasculitis in non-diabetic lumbosacral radiculoplexus neuropathy (LSRPN): similarity to the diabetic variety REFERENCES (DLSRPN). J Neuropathol Exp Neurol. 2000;59(6):525-538. 16. Collins MP,Mendell JR, Periquet MI, et al. Superficial peroneal nerve/peroneus brevis 1. Rothenberg ME. Eosinophilia. N Engl J Med. 1998;338(22):1592-1600. muscle biopsy in vasculitic neuropathy. Neurology. 2000;55(5):636-643. 2. Monaco S, Lucci B, Laperchia N, et al. Polyneuropathy in hypereosinophilic 17. Moore PM, Harley JB, Fauci AS. Neurologic dysfunction in the idiopathic hy- syndrome. Neurology. 1988;38(3):494-496. pereosinophilic syndrome. Ann Intern Med. 1985;102(1):109-114. 3. Nagashima T, Cao B, Takeuchi N, et al. Clinicopathological studies of peripheral 18. Sehgal M, Swanson JW, DeRemee RA, Colby TV. Neurologic manifestations of neuropathy in Churg-Strauss syndrome. Neuropathology. 2002;22(4):299- Churg-Strauss syndrome. Mayo Clin Proc. 1995;70(4):337-341. 307. 19. Kawakami T, Soma Y, Kawasaki K, Kawase A, Mizoguchi M. Initial cutaneous 4. Hattori N, Ichimura M, Nagamatsu M, et al. Clinicopathological features of Churg- manifestations consistent with mononeuropathy multiplex in Churg-Strauss Strauss syndrome-associated neuropathy. Brain. 1999;122:427-439. syndrome. Arch Dermatol. 2005;141(7):873-878. 5. Vital A, Vital C, Viallard JF, Ragnaud JM, Canron MH, Lagueny A. Neuro- 20. Sunohara N, Furukawa S, Nishio T, Mukoyama M, Satoyoshi E. Neurotoxicity of hu- muscular biopsy in Churg-Strauss syndrome: 24 cases. J Neuropathol Exp Neurol. man eosinophils towards peripheral nerves. J Neurol Sci. 1989;92(1):1-7. 2006;65(2):187-192. 21. Ramos-Casals M, Anaya JM, Garcia-Carrasco M, et al. Cutaneous vasculitis in 6. Lee JE, Shun CT, Hsieh SC, Hsieh ST. Skin denervation in vasculitic neuropathy. primary Sjogren syndrome: classification and clinical significance of 52 patients. Arch Neurol. 2005;62(10):1570-1573. Medicine (Baltimore). 2004;83(2):96-106. 7. Tseng MT, Hsieh SC, Shun CT, et al. Skin denervation and cutaneous vasculitis 22. Dyck PJ, Windebank AJ. Diabetic and nondiabetic lumbosacral radiculoplexus in systemic lupus erythematosus. Brain. 2006;129(pt 4):977-985. neuropathies: new insights into pathophysiology and treatment. Muscle Nerve. 8. Chiang MC, Lin YH, Pan CL, Tseng TJ, Lin WM, Hsieh ST. Cutaneous innerva- 2002;25(4):477-491. tion in chronic inflammatory demyelinating polyneuropathy. Neurology. 2002; 23. Pue´chal X, Said G, Hilliquin P, et al. Peripheral neuropathy with necrotizing vas- 59(7):1094-1098. culitis in rheumatoid arthritis: a clinicopathologic and prognostic study of thirty- 9. Pan CL, Tseng TJ, Lin YH, Chiang MC, Lin WM, Hsieh ST. Cutaneous innerva- two patients. Arthritis Rheum. 1995;38(11):1618-1629.

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