Clinicopathologic study of 43 patients with sural nerve vasculitis

Clinicopathologic Study of 43 Patients With Sural Nerve Vasculitis RICHARD A. PRAYSON, MD AND DAVID J. SEDLOCK, MD Vasculitis is a relatively uncommon finding in sural nerve biopsy specimens and is associated with significant morbidity. This study retrospectively reviewed the clinicopathologic features of 43 patients (44 sural nerve biopsy specimens) with sural nerve vasculitis, defined as infiltration of vessel walls by inflammatory cells. These biopsy specimens were obtained over a 19-year period, during which 1503 nerve specimens were reviewed. The study group comprised 29 females and 14 males, ranging in age from 19 to 94 years (mean, 72.5 years) at the time of biopsy. The most frequent clinical presentations included paresthesias in 19 patients (61%), pain in 17 patients (57%), weakness in 10 patients (32%), and weight loss in 9 patients (29%). Histologically, 26 of 44 biopsy specimens (59%) demonstrated necrotizing vasculitis. The remaining 18 biopsy specimens demonstrated a nonnecrotizing lymphocytic vasculitis. Eosinophils were identified in 4 biopsy specimens, intravascular thrombi in 10 (22%) specimens, and granulomatous inflammation in 1 specimen. In 39 biopsy specimens (89%), multiple vessels were involved by vasculitis. Epineurial vessels were the most common target of vasculitis, (n ⴝ 42; 95%). Evidence of vascular wall scarring, indicative of healed vasculitis, was observed in 13 biopsy specimens (30%). All biopsy specimens showed

evidence of axonopathy, with mild axonal loss noted in 14 specimens (32%), moderate loss in 18 specimens (41%), and severe loss in 12 specimens (27%). Concomitant muscle biopsy was performed in 31 patients. Fifteen muscle biopsy specimens demonstrated evidence of vasculitis (48%), which was necrotizing in 11 cases. All muscle biopsy specimens demonstrated features of neurogenic atrophy. Twenty-five out of 32 patients were known to have been treated with steroids and demonstrated some degree of clinical improvement. In conclusion, sural nerve vasculitis is a relatively uncommon pathological finding (prevalence of 2.9% in this study). In most cases, multiple vessels were involved. Concomitant vasculitis was also identified in about half of the muscle biopsy specimens obtained at the time of nerve biopsy. In most patients, the vasculitis appeared to be at least partially responsive to immunosuppressive therapy. HUM PATHOL 34:484-490. © 2003 Elsevier Inc. All rights reserved. Key words: nerve, sural nerve, vasculitis, axonopathy, skeletal muscle. Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Vasculitis is a pathological condition characterized by inflammation within vessel walls. Peripheral nerve vasculitis is a rare finding in sural nerve biopsy specimens in which the disease often targets the vasa nervorum. The patient’s clinical presentation depends on the extent and pattern of nerve involvement. Vasculitic neuropathy may occur in the setting of systemic vasculitis, most commonly polyarteritis nodosa,1-5 or may be confined to be peripheral nervous system.6-11 This study examined the clinical and pathologic findings in 43 patients with biopsy-proven sural nerve vasculitis, encountered during a 19-year period at 1 institution.

were presumed to have chronic inflammatory polyradiculoneuropathy (CIPD) based on biopsy and clinical findings were excluded from the study. All peripheral nerve biopsy specimens were stained with hematoxylin and eosin, luxol fast blue, Masson trichrome, and Congo red. When available, 1-␮-thick toluidine blue– stained sections and teased nerve preparations were examined (n ⫽ 20). Electron micrographs were also reviewed when available (n ⫽ 21). Vasculitis was classified as necrotizing or nonnecrotizing. Necrotizing vasculitis was characterized by fibrinoid necrosis of the vessel wall associated with acute inflammation. The distribution of disease was assessed in terms of location, (epineurial, perineurial, endoneurial, or multiple site involvement), as well as number of affected vessels (1 or ⬎1). The presence of eosinophils, granulomatous inflammation, scarring, or fibrin thrombi was also recorded when present. The degree of myelinated axonal loss was assessed and graded as mild (⬍25 axonal loss), moderate (25% to 50% axonal loss), or severe (⬎50% axonal loss). The pattern of neural injury (axonopathy or demyelinative neuropathy) was also noted. Concomitant muscle biopsy was performed on 31 patients. Histological materials from these cases were reviewed for evidence of vasculitis and neurogenic atrophy (angular atrophic esterase positive myofibers, group atrophy, and fiber type grouping). Stains for hematoxylin and eosin, adenosine triphosphatase at pH 4.6 and 9.8, nicotinamide adenine dinucleotide (reduced form), cytochrome C oxidase, Gomori trichrome, and esterase were reviewed in all cases. In all cases, medical records were reviewed to ascertain clinical information, including the patient’s age at biopsy, gender, clinical presentation, treatment, response to therapy, evidence of multiorgan involvement by vasculitis, coexistent diseases, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level.

MATERIALS AND METHODS A retrospective search of the surgical pathology files from 1980 to 1999 revealed 1,503 sural nerve biopsy specimens; 44 (2.9%) of these were diagnosed with vasculitis and compose the study group. Cases encountered later than 1999 were not included for study because of their relatively short follow-up intervals. All available histological materials were examined in each case to confirm the diagnoses. Patients who

From the Department of Anatomic Pathology, The Cleveland Clinic Foundation, Cleveland, Ohio. Accepted for publication December 19, 2002. Address correspondence to Richard A. Prayson, MD, Department of Anatomic Pathology (L25), Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195. © 2003 Elsevier Inc. All rights reserved. 0046-8177/03/3405-0012$30.00/0 doi:10.1016/S0046-8177(03)00076-5

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TABLE 1. Summary of Clinical Features of Sural Nerve Vasculitis Mean age, range Number of females (N ⫽ 43) Most common clinical presentations Paresthesias Pain Weakness Weight loss Fever Skin lesions Treatments Prednisone Prednisone ⫹ other immunosuppressive agents Biopsy evidence of multiorgan involvement (excluding skeletal muscle) Coexistent disease Hypertension Diabetes mellitus Peptic ulcer disease Rheumatoid arthritis Pulmonary fibrosis Westergren sedimentation rate, mean (range) C-reactive protein, mean (range) Response to therapy No clinical improvement Mild clinical improvement Marked clinical improvement Lost to follow-up

received prednisone in conjunction with another immunosuppressive agent. Follow-up intervals for the group ranged from 4 to 287 months (median, 67 months). Of the 29 patients in whom information was available regarding response to treatment, clinical improvement was noted in 25, assessed as mild in 19 and marked in 6. Four patients were thought to have no significant clinical improvement during the follow-up interval. In 4 patients there was no information on response to the administered therapy. Three patients were known to have died within 2 years of biopsy. The cause of death was related to acute pancreatitis in 1 patient and was not known in the other 2 patients.

72.5 years, 19–94 years 29 (67%) 61% (n ⫽ 19) 55% (n ⫽ 17) 32% (n ⫽ 10) 29% (n ⫽ 9) 16% (n ⫽ 5) 5% (n ⫽ 2) 5 (16%) 26 (81%)

Histopathology 5 (16%)

Table 2 summarizes the histopathologic features in the patient group. One patient underwent 2 sural nerve biopsy procedures. Histologically, all biopsy specimens demonstrated evidence of vasculitis, defined by infiltration of the vessel wall by inflammatory cells. In 26 patients (59%), the vasculitic process was classified as necrotizing (Fig 1), and in the remaining 18 patients (41%), it was classified as nonnecrotizing (Fig 2). There was no obvious correlation between vasculitis type (necrotizing vs nonnecrotizing) and clinical presentation and follow-up. In 39 patients (89%), more than 1 vessel demonstrated evidence of vasculitis in the biopsy specimen evaluated. In the remaining 5 patients (11%), only a single vessel was involved by vasculitis,

8 (25%) 7 (22%) 4 (13%) 3 (9%) 2 (5%) 65.9 mm/hr (3–121mm/hr) 8.8 8.8 mg/dL (0.3–25.4mg/dL) 4 (13%) 19 (59%) 6 (19%) 4 (13%)

RESULTS Clinical Features Table 1 summarizes the clinical features of the 43 patients with sural nerve vasculitis who compose the study group. These patients included 29 females (67%) and 14 males ranging in age from 19 to 94 years (mean, 72.5 years) at the time of sural nerve biopsy. Clinical findings and symptoms at time of presentation included paresthesias in 19 patients (61%), pain in 17 patients (55%), weakness in 10 patients (32%), weight loss in 9 patients (29%), fever in 5 patients (16%), and skin lesions, likely representing cutaneous involvement by vasculitis, in 2 patients (5%). One patient each presented with muscle wasting, dysphagia, vertigo, night sweats, dry mouth, and cellulitis. Known information regarding past medical history included 8 patients with hypertension (25%), 7 patients (22%) with diabetes mellitus, 4 patients with peptic ulcer disease (13%), 3 patients with rheumatoid arthritis (9%), and 2 patients with pulmonary fibrosis (5%). One patient each was known to have hepatitis B, Sjo¨ gren’s syndrome, hyperthyroidism, and epilepsy. An ESR, as determined by the Westergren method and obtained within 1 week of the biopsy, was known in 28 patients. ESR ranged from 3 to 121 mm/hr (mean, 65.9 mm/hr). A CRP level was known in 17 patients and ranged from 0.3 to 25.4 mg/dL (mean, 8.8 mg/dLl). Clinical information regarding treatment and follow-up was available in 33 patients. Five patients received prednisone alone, and the remaining 28 patients

TABLE 2. Summary of Histopathologic Features of Sural Nerve Vasculitis (N ⫽ 44) Necrotizing vasculitis Nonnecrotizing vasculitis Axonal loss Mild Moderate Severe Number of vessels involved ⬎1 Epineurial Perineurial Endoneurial 1 Epineurial Perineurial Eosinophils present Granulomatous inflammation Vascular wall scarring Fibrin thrombi Dystrophic calcification Predominant pattern of neural injury Pure axonopathy Axonopathy ⬎ demyelinative neuropathy Muscle biopsy specimens (n ⫽ 31) Vasculitis present Necrotizing Nonnecrotizing Neurogenic atrophy present Angulated esterase positive fibers Grouped atrophy Fiber type grouping

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26 (59%) 18 (41%) 14 (32%) 18 (41%) 12 (27%) 39 (89%) 38 11 7 5 (11%) 4 1 4 (9%) 1 (2%) 13 (30%) 10 (22%) 1 (2%) 37 (84%), 23 with necrotizing vasculitis 7 (16%), 3 with necrotizing vasculitis 15 (48%) 11 4 31 (100%) 30 (97%) 14 (45%) 14 (45%)

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(84%) (Fig 5), including 23% with necrotizing vasculitis. A mixture of axonopathic and demyelinative changes with a predominance of axonopathic changes was observed in 7 biopsy specimens (16%), including 3 specimens with necrotizing vasculitis. Thirty-one patients underwent skeletal muscle biopsy at the time of sural nerve biopsy. Vasculitis was identified in 15 of these biopsy specimens (48%). In 11 specimens, necrotizing vasculitis was identified (Fig 6), and in 4 specimens, only nonnecrotizing vasculitis was observed. Changes consistent with neurogenic atrophy, likely related to peripheral nerve involvement by vasculitis, were observed in all 31 muscle biopsy specimens. Angular atrophic esterase positive muscle fibers, indicative of acute denervation atrophy, were noted in 30 biopsy specimens (97%). Group atrophy and fiber type grouping, indicative of a more chronic neurogenic process, was observed in 14 specimens each. Additional findings in the muscle biopsy specimens included evidence of target or targetoid fibers in 10 specimens (32%), occasional regenerating muscle fibers in 10 specimens (32%), and scattered degenerating muscle fibers in 7 specimens (23%). Three biopsy specimens (10%) demonstrated a type II muscle fiber atrophy

FIGURE 1. Necrotizing vasculitis in an epineurial artery with marked acute and chronic inflammation and fibrinoid necrosis of the wall. (Hematoxylin and eosin; original magnification ⫻100.)

although in 3 of these cases perivascular chronic inflammation was observed to involve other vessels. Epineurial involvement by vasculitis was observed in 42 biopsy specimens (95%). Perineurial vessel involvement by vasculitis was observed in 12 biopsy specimens (27%), and endoneurial vascular involvement was noted in 7 biopsy specimens (16%). In all patients who had endoneurial vascular involvement, more than 1 vessel was involved, including at least 1 epineurial vessel. Eosinophils were identified in association with the vasculitis in 4 biopsy specimens (9%), and nonnecrotizing granulomatous inflammation was seen in 1 biopsy specimen (2%). Platelet fibrin thrombi were observed in 10 biopsy specimens (22%). Healed arteritis, as evidenced by vascular wall scarring and fibrosis, was observed in 13 biopsy specimens (30%) (Fig 3). Dystrophic mineralization of arterial walls was observed in 1 biopsy specimen (2%). Axonal loss was evident in all biopsy specimens and was graded as mild in 14 specimens (32%), moderate in 18 specimens (41%) (Fig 4), and marked in 12 specimens (27%). The predominant pattern of neural injury appeared to be axonopathic in 37 biopsy specimens

FIGURE 2. Nonnecrotizing vasculitis in an endoneurial vessel. (Hematoxylin and eosin; original magnification ⫻200.)

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FIGURE 3. Perivascular fibrosis and scarring with chronic inflammation marking healing vasculitis. (Hematoxylin and eosin; original magnification ⫻100.)

(10%), and 2 specimens (6%) exhibited moth-eaten fibers. Biopsy evidence of vasculitis in other organs (excluding skeletal muscle) was found in 5 patients. Affected organs included periorbital soft tissue and lacrimal glands in 2 patients, kidney in 1 patient, salivary gland in 1 patient, and bone marrow in 1 patient. DISCUSSION There are a variety of pathologies that affect the peripheral nervous system in which inflammation is a prominent finding. This includes varying entities such as Guillain-Barre´ syndrome, chronic inflammatory polyradiculoneuropathy, sarcoidosis, infectious diseases, and paraneoplastic neuropathies.12 In most of these entities, the inflammatory cell infiltrates are seen within the nerve itself or in the perineurium, often centered around blood vessels. Occasionally, particularly with infectious processes, infiltration of vessel walls by inflammatory cells is noted, generally constituting a nonnecrotizing pattern of injury. The prevalence of true vasculitic neuropathy, outside the setting of the

aforementioned conditions, is markedly low. In the current series, out of slightly more than 1500 sural nerve biopsy specimens reviewed over a 19-year period, only 44 specimens (2.9%) demonstrated evidence of vasculitic neuropathy. In another study, of 1559 peripheral nerve biopsy specimens evaluated, only 25 (1.6%) had evidence of vasculitis. 7 Although a significant percentage of cases of vasculitic neuropathy are associated with multiorgan involvement by systemic vasculitis, some cases of vasculitis appear to be confined to the peripheral nervous system. Besides symptoms related to other organ involvement by systemic vasculitis, the most common manifestations of peripheral nerve disease are similar to those reported in the current series and include paresthesias, pain, muscle weakness or wasting, and weight loss. In patients with systemic vasculitis, a polyneuropathic picture is most common, in contrast to patients with vasculitis confined to the peripheral nerve and/or accompanying muscle, who most often exhibit a mononeuritis multiplex presentation.13 There clearly is an association of peripheral nerve vasculitis and connective tissue disease.14 The incidence of peripheral nerve involvement in the setting of rheumatoid arthritis is variable and ranges anywhere from 1% to as high as 50%.15-17 The higher figure is probably a more accurate reflection of the incidence of vasculitic neuropathy in the setting of rheumatoid arthritis, making it 1 of the more common forms of systemic vasculitis. The histopathologic findings may overlap with that of polyarteritis nodosa and include necrotizing vasculitis that preferentially involves vessels in the epineurial region.9,18-20 Involvement of the peripheral nervous system by vasculitis in the setting of systemic lupus erythematosus may be observed in approximately 10% of patients.12,21,22 Most patients present with evidence of a distal and symmetrical polyneuropathy.23 In addition to inflammatory changes, including vasculitis, patients with lupus are prone to develop atherosclerotic changes and thrombosis of vessels. Involvement of the peripheral nervous system in Sjo¨ gren’s syndrome has been estimated to occur in approximately 10% of patients and most commonly takes the form of a sensory ganglionitis, autonomic neuropathy, or polyneuropathy.24,25 Similar to lupus and rheumatoid arthritis, both necrotizing and nonnecrotizing vasculitis may be present, particularly involving epineurial vessels.9,26,27 Only a minority of patients in the current series (n ⫽ 4) had known diagnosis of 1 of these collagen vascular disorders. In the current series, the most common etiology for the sural nerve vasculitis was polyarteritis nodosa. In most of the biopsy specimens in the study, a necrotizing pattern of vasculitis was observed. Polyarteritis nodosa is marked by the presence of necrotizing vasculitis involving medium-sized arterial vessels. Similar to the other previously described connective tissue disorders, medium-sized arterial vessels in the epineurium are the primary target—a finding corroborated in this study. As is typical of many of the biopsy specimens, multiple

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FIGURE 4. Cross-section of a nerve fascicle demonstrating moderate axonal loss. (Toluidine blue; original magnification ⫻200.)

vessels are involved. Frequently, vessels that exhibit temporally different stages of the disease process are evident; that is, one can encounter vessels that demonstrate fibrinoid necrosis with acute inflammation adjacent to vessels with scarring and organizing thrombi. Beside vasculitis, the histopathologic manifestations of polyarteritis nodosa include ischemic or infarctive changes and hemorrhage. The former typically manifests itself by axonal degeneration that is sometimes geographic in distribution. Less commonly, Churg-Strauss syndrome, a disorder marked by asthma and peripheral blood eosinophilia, may involve the peripheral nervous system. Chumbley et al 28 reported evidence of peripheral neuropathy in 19 of 30 patients with Churg-Strauss syndrome. Other than the somewhat variable presence of eosinophils associated with the vasculitis, the histopathologic findings may be identical to those in pol-

yarteritis nodosa. Likewise, necrotizing vasculitis may be encountered, involving peripheral nervous system in the setting of Wegener’s granulomatosus.29 Wegener’s granulomatosus is associated with a necrotizing granulomatous vasculitis involving multiple organ systems, particularly the respiratory tract and kidney. Less than 5% of patients demonstrate evidence of peripheral neuropathy.29 Although most of the patients in this series demonstrated a necrotizing vasculitis, likely consistent with polyarteritis nodosa, in a minority of patients only a nonnecrotizing pattern of vasculitis was identified. In many of these cases, there is no evidence of chronic changes, such as vessel wall scarring or thrombosis, that indicate a chronic ongoing process. Similar to necrotizing vasculitis, the most frequently targeted vessels include both arteries and, more commonly, veins in the epineurial region. A subset of these cases may represent

FIGURE 5. Axonal degeneration in a nerve with necrotizing vasculitis. (Teased nerve preparation; original magnification ⫻400.)

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FIGURE 6. Necrotizing vasculitis in a muscle. (Hematoxylin and eosin; original magnification ⫻100.)

polyarteritis nodosa. Involvement of smaller-caliber vessels in some of these cases raises the diagnostic possibility of microscopic polyangiitis or microscopic polyarteritis.30,31 Microscopic polyangiitis is a necrotizing systemic vasculitis that can affect medium-sized arterial vessels, similar to polyarteritis nodosa, but often targets smaller-caliber vessels, including veins and capillaries. The disorder is associated with few or no immune deposits.31,32 Peripheral neuropathy may be present in 10% to 28% of affected individuals.31 Well-documented examples of vasculitis localized to the peripheral nerves have been reported. Most affected patients present with either multiple mononeuropathy or frequently distal sensory or motor neuropathy.8 In contrast to other forms of vasculitic neuropathy, localized vasculitis tends to involve smallercaliber arterial vessels and more frequently endoneurial versus epineurial vessels. Evidence of endoneurial involvement by vasculitis was observed in only 7 cases in the current series, and in all of these cases was accompanied by involvement of either epineurial or perineurial vessels. The exact frequency and prevalence of this disorder is somewhat uncertain;

on long-term follow-up, some of these patients develop evidence of systemic disease. Davies et al7 have suggested that patients who present with vasculitis confined to the peripheral nerves appear to have a better prognosis and response to immunosuppressive therapy than patients with systemic vasculitis. Biopsy still remains the gold standard by which diagnosis of vasculitis is confirmed. A search for noninvasive markers for vasculitis has not proven terribly successful. Markers of systemic inflammation, such as ESR and CRP, are nonspecific. Some patients may be relatively normal. Subsets of vasculitis may be associated with specific antibodies, that is, Wegener’s granulomatosus and antineutrophil cytoplasmic antibody. Even with the biopsy, the significance of a vasculitic pattern of injury may be difficult to discern without correlation from the clinical presentation, given the various other disease processes that may result in a vasculitic pattern of injury. Care should be taken to not misconstrue perivascular inflammation (perivasculitis) as representing true vasculitis. Certainly, vasculitis may be present in a subset of these patients; however, in many of these cases, the inflammation is a marker of another disease process or in some cases appears to not be associated with any particular disease entity. Of the 31 patients who had a concomitant muscle biopsy performed in the current series, vasculitis was identified in approximately half. Because vasculitis is often a focal process, it is generally felt that biopsy specimens from multiple organ systems will increase the diagnostic yield. In 16 of these patients, vasculitis was not identified in the concomitant muscle biopsy and was observed only in the nerve biopsy specimen. In such patients, biopsy of the muscle alone would have been nondiagnostic. The size of the biopsy specimen may affect the ability to make a diagnosis. This is particularly true when dealing with small-needle biopsies of skeletal muscle, where one is evaluating limited tissue and consequently a limited number of vessels. Larger, open biopsy procedures generate sample sizes more appropriate for the evaluation of vasculitis. Although the vasculitis was observed in about half of the muscle biopsy specimens, indirect evidence of peripheral nerve vasculitis in the form of neurogenic atrophy was observed in all specimens. Unfortunately, these findings of denervation atrophy are nonspecific and are only generally indicative of peripheral nerve disease. The underlying pathogenesis of vasculitis in most cases remains elusive and appears somewhat heterogeneous. Various mechanisms, including cell-mediated injury, humeral mechanisms, and immune complex– mediated injury, all may play roles in various scenarios. Nevertheless, most cases of vasculitic neuropathy appear to represent systemic disease. The variable responsiveness to immunosuppressive therapy further betrays the underlying heterogeneity of the patient group. Acknowledgment. The authors give special thanks to Ms. Denise Egleton for her help in preparing this manuscript.

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