Review

Isolated of the peripheral

M.P. Collins, M.I. Periquet

Department of Neurology, Medical College ABSTRACT combination therapy to be more effec- of Wisconsin, Milwaukee, Wisconsin, USA. Vasculitis restricted to the peripheral tive than prednisone alone. Although Michael P. Collins, MD, Ass. Professor; nervous system (PNS), referred to as most patients have a good outcome, M. Isabel Periquet, MD, Ass. Professor. nonsystemic vasculitic neuropathy more than 30% relapse and 60% have Please address correspondence and (NSVN), has been described in many residual pain. Many nosologic, path- reprint requests to: reports since 1985 but remains a poorly ogenic, diagnostic, and therapeutic Michael P. Collins, MD, Department of understood and perhaps under-recog- questions remain unanswered. Neurology, Medical College of Wisconsin, nized condition. There are no uniform 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, USA. diagnostic criteria. Classifi cation is Introduction E-mail: [email protected] complicated by the occurrence of vas- The vasculitides comprise a broad Received on March 6, 2008; accepted in culitic neuropathies in many systemic spectrum of diseases which exhibit, revised form on April 1, 2008. vasculitides affecting small-to-me- as their primary feature, infl ammation Clin Exp Rheumatol 2008; 26 (Suppl. 49): dium-sized vessels and such clinical and destruction of vessel walls, with S118-S130. variants as nonsystemic skin/ secondary ischemic injury to the in- © CopyrightCopyright CLINICAL AND vasculitis and diabetic/non-diabetic volved tissues (1). They are generally EXPERIMENTAL RHEUMATOLOGY 2008.2008. lumbosacral radiculoplexus neuropa- classifi ed based on sizes of involved thy. Most patients present with pain- vessels and histopathologic and clini- Key words: Vasculitis, peripheral ful, stepwise progressive, distal-pre- cal features. Two classifi cation systems nervous system diseases, pathology, dominant, asymmetric or multifocal, have gained wide acceptance. In 1990, diagnosis, classifi cation, therapeutics, sensory-motor defi cits evolving over the American College of Rheumatology prognosis. months-to-years. NSVN is identical to (ACR) proposed classifi cation criteria but less severe than systemic vascu- for seven forms of vasculitis designed litis-associated neuropathies (SVNs). to discriminate between patients with All vasculitic neuropathies are ax- pre-established diagnoses (2), and in onal by electrodiagnostic/pathologic 1994, the Chapel Hill Consensus Con- criteria. Laboratory testing is unre- ference (CHCC) published defi nitions markable except for mildly elevated for ten type of vasculitis (3). Signifi cant erythrocyte sedimentation rate (ESR) discordance results when these two sys- in 50%. Highly elevated ESRs, leuko- tems are applied to the same cohorts of cytosis, rheumatoid factors, and anti- patients (4). For this reason, a consen- neutrophil cytoplasmic antibodies sus methodology for classifi cation of (ANCAs) raise concern for underlying ANCA-associated vasculitides (AAV) . Without a specifi c and (PAN) was clinical/laboratory marker, the condi- recently proposed, which incorporates tion depends on nerve biopsy for di- both the ACR classifi cation criteria and agnosis. Biopsies showing necrotizing CHCC defi nitions (5). vasculitis are about 50% sensitive, Except for cutaneous leukocytoclastic mandating reliance on “suspicious” angiitis, these systems do not address changes in many patients. Vasculitic the nonsystemic or localized vascu- lesions predominate in smaller epineu- litides. Localized vasculitis affects ves- rial vessels and are milder than those sels in a single tissue or organ, without in SVNs. The disorder is often accom- clinical evidence of more widespread panied by subclinical involvement of involvement (6, 7). Anatomically re- adjacent muscles and skin. NSVN has stricted vasculitis has been described the potential to spontaneously relapse in almost all organs, including the CNS and remit but neurologic defi cits ac- (8), skin (9), kidneys (10), eyes (11), cumulate. No randomized controlled muscles (12), heart (13), lungs (14), trials have been performed, but one GI tract (15), and genital tract (16). In Competing interests: none declared. retrospective cohort survey showed these disorders, progression to systemic

S-118 Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet REVIEW disease is unusual and excision can be B-associated PAN, 60% with micro- Some patients with a vasculitic neurop- curative. A recent study comparing lo- scopic polyangiitis (MPA) diagnosed athy exhibit no clinical evidence of sys- calized with systemic PAN showed that post-CHCC, 65-70% with Churg-Strauss temic involvement despite long-term the pathologic process was less destruc- syndrome (CSS), and 15% with Wegen- follow-up, indicative of another local- tive to the vascular wall in the localized er’s granulomatosis (WG) (18-21). On ized vasculitis. Isolated PNS vasculi- variant (17). the other hand, vasculitic neuropathies tis was fi rst reported by Kernohan and Systemic vasculitides involving small- are vanishingly rare in large-vessel Woltman in 1938 (22). The concept was to-medium-sized vessels often affect vasculitides such as giant cellcell a arteritisrteritis revitalized and established as a distinct the PNS. For example, neuropathies (Table I). A proposed classifi cation of clinicopathologic entity by Kissel et al. occur in 60% of patients with PAN di- vasculitides associated with vasculitic in 1985 and Dyck et al. in 1987 (23, agnosed pre-CHCC, 80% with hepatitis neuropathy is found in Table II. 24). Dyck coined the term nonsystemic

Table I. Prevalence of vasculitic neuropathy types.

Series NSVN PAN*/ RV CSS UCTD WG SLE Cancer SS EMC Other MPA** /HCV

Kissel, 1985 (23) 7 3 0 0 5 0 1 0 0 0 0 Harati, 1986 (62) 21 2 2 0 4 0 0 3 0 0 Scl-1 Dyck, 1987 (24) 20 32 2 4 0 1 1 0 3 0 Scl-1, HIV-1 Said, 1988 (25) 25 26 26 6 6 0 1 1 2 0 Scl-1. HIV-3, Sarcoid-1, GCA-1, PM-1 Panegyres, 1990 (84) 7 0 5 3 0 1 0 0 1 0 MGUS-1 Hawke, 1991 & (54) McCombe, 1987 (148) 2 11 7 3 8 1 3 1 1 0 0 Midroni, 1995 (60) 4 3 8 3 10 0 2 0 1 0 HV-1 Nicolai, 1995 (149) 2 2 1 4 7 0 0 0 0 3 HIV-1 Singhal, 1995 (150) 7 6 0 2 0 1 4 0 0 0 0 Ohkoshi, 1996 (151) 1 6 1 3 0 0 2 0 0 0 0 Collins, 2000 (52) 11 6 8 0 0 2 1 2 0 0 MGUS-3, VZV-1, HV-2 Sanchez, 2001 (152) 5 12 0 3 0 2 2 1 0 0 Sarcoid-1 Vital, 2006 & Vital, 35 28 9 17 0 4 1 0 3 6 Skin/nerve-5, HIV-4, 2006 (32, 153) § Sarcoid-2, Eos-2, DM-2, EBV-1 Bennett, 2007 (37) † 22 10 3 3 2 3 0 3 2 2 HIV-2, Scl-1 Mathew, 2007 (34) 11 27 12 22 6 14 4 4 0 4 HSP-1, meningioma-1 Oka, 2007 (35) 8 13 3 6 0 0 1 0 3 0 0 Zivkovic, 2007 (36) 9 4 6 0 1 2 4 4 1 2 DM-4, Scl-1, Sarcoid-1, MCTD-1 Total (percent) 197 191 93 79 49 31 27 19 17 17 HIV-11 (1.4) (26) (25) (12) (10) (6.4) (4.0) (3.5) (2.5) (2.2) (2.2) DM-6 (.8) MGUS-4 (.5) Scl-5 (.7) Sarcoid-5 (.7) Nerve/skin-5 (.7) HV-3 (.4) Eos-2 (.3) HSP-1 (.1) GCA-1 (.1) PM-1 (.1) VZV-1 (.1) MCTD-1 (.1) EBV-1 (.1) Meningioma-1 (.1)

CSS: Churg Strauss Syndrome; DM: diabetes mellitus; EBV: Epstein-Barr virus; EMC: essential mixed cryoglobulinemia; Eos: hypereosinophilia with- out lung involvement; GCA: giant cell arteritis; HCV: virus; HIV: human immunodefi ciency virus; HSP: Henoch Schonlein ; HV: hypersensitivity vasculitis; MCTD: mixed connective tissue disease; MGUS: monoclonal gammopathy of undetermined signifi cance; MPA: microscopic polyarteritis, NSVN: nonsystemic vasculitic neuropathy; PAN: polyarteritis nodosa; PM: polymyositis; RV: rheumatoid vasculitis; sarcoid: sarcoidosis; Scl: scleroderma; SLE: systemic erythematosus; SS: Sjögren’s syndrome; UCTD: undifferentiated connective tissue disease; VZV: varicella zoster virus, WG: Wegener’s granulomatosis. *Includes cases of -associated PAN **MPA combined with PAN because these disorders were not distinguished in vasculitic neuropathy series prior to 1997 §Drs. Claude and Anne Vital provided additional clinicopathologic information on the 216 patients in their series, which was used to classify patients by clinical diagnosis and pathologic category (using criteria from Collins et al., 2003). †Diagnoses from poster presentation on July 15, 2007 at the meeting of the Peripheral Nerve Society and confi rmed by Dr. David L. Bennett in e-mail communication on December 15, 2007.

S-119 REVIEW Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet vasculitic neuropathy, which is now the Table II. Proposed classifi cation of vasculitides associated with neuropathy. accepted name for the disorder. Some 1. Primary systemic vasculitides investigators have argued that NSVN is a. Predominantly large vessel vasculitis a mild form of systemic vasculitis with i. Giant cell arteritis clinical involvement predominating in b. Predominantly medium vessel vasculitis the PNS (25), whereas others have con- i. Polyarteritis nodosa c. Predominantly small vessel vasculitis cluded that the disease is a unique, or- i. Granulomatous gan-specifi c vasculitis (24, 26). In sup- Churg Strauss Syndrome* port of this theory, some patients with Wegener’s granulomatosis* isolated vasculitic neuropathy have ii. Non-Granulomatous Microscopic polyarteritis* remained free of systemic involvement Essential mixed cryoglobulinemia (non-HCV) over decades of follow-up (24, 27). Henoch Schönlein Purpura Moreover, the PNS is relatively resist- ant to ischemia and thus should not be 2. Secondary systemic vasculitides particularly susceptible to a systemic a. Vasculitis secondary to connective tissue diseases i. ischemic process (28). ii. Systemic lupus erythematosus Since this topic was last reviewed in iii. Sjögren’s syndrome 2004 (29), many additional patients iv. Scleroderma v. with NSVN have been reported or vi. Mixed connective tissue disease identifi ed in the pre-existing literature, b. Sarcoidosis-related vasculitis including two detailed retrospective co- c. Behçet’s disease horts (30,31), articles/abstracts provid- d. -related vasculitis (such as HBV, HCV, HIV, CMV, leprosy, , HTLV-I) ing more limited information on many e. Drug-induced vasculitis patients (32-37), and several smaller f. Malignancy-related vasculitis series or case reports (38-47). Other g. Vasculitis associated with infl ammatory bowel disease case reports are not considered due to inadequate or absent pathologic fi nd- 3. Nonsystemic/localized vasculitis ings, insuffi cient clinical information, a. Nonsystemic vasculitic neuropathy or evidence of an underlying systemic b. Diabetes mellitus-related vasculitis i. Diabetic radiculoplexus neuropathy (proximal-predominant) disease. Table III itemizes clinicopatho- ii. Diabetic multifocal neuropathy (distal-predominant) logic attributes of the seven largest se- c. Non-diabetic lumbosacral radiculoplexus neuropathy ries of NSVN. Diagnostic criteria vary d. Localized cutaneous/neuropathic vasculitis between studies, but our criteria are as i. Cutaneous polyarteritis nodosa follows: ii. Others 1. Clinical and electrodiagnostic evi- *ANCA-associated vasculitides. dence of an axonal neuropathy; CMV: cytomegalovirus; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immuno- 2. Nerve or muscle biopsy diagnostic defi ciency virus; HTLV: human T-lymphotropic virus. of or suspicious for vasculitis; 3. No clinical, laboratory, or pathologic and a publication from the Neuropathy women outnumber men by a factor of evidence of tissue involvement be- Association® noted NSVN to have an 5:4 (177 women; 143 men). In reports yond or muscles; annual incidence of 5 cases per million for which these attributes are not ex- 4. No identifi ed etiology (including in- (49), but neither of these assertions plicitly excluded, weight loss occurs in fections or drugs); and were referenced. On the other hand, ~30% of patients and fevers in ~15%. 5. No systemic disease potentially pre- there is abundant data on the relative Although some patients present with disposing to vasculitis (e.g., connec- frequency of different types of vascu- acute mononeuropathies or multiple tive tissue disease, diabetes mellitus, litic neuropathy compiled from series mononeuropathies, most exhibit a more malignancy, mixed cryoglobuline- dedicated to such patients. An updated subacutely or chronically progressive, mia, and sarcoidosis). compilation of diagnoses from series sometimes stepwise clinical course and with a wide spectrum of patients is slowly accrue multifocal/asymmetric Epidemiology found in Table I. damage to multiple peripheral nerves. No study has determined the incidence Accordingly, the diagnosis is typically or prevalence of NSVN or, for that Clinical features delayed for months. The median dur- matter, any other type of vasculitic Combining data from the 2004 review ation of symptoms before diagnosis neuropathy. One review article on im- of NSVN with more recently ascer- ranged from 5-7.5 months in four series mune-mediated neuropathies stated tained series and case reports, the mean (26, 31, 50, 51), but patients reported that PNS vasculitis has an annual in- age of onset is 59.5 years (standard de- by Kararizou et al. were symptomatic cidence of 0.6-1.2 per 100,000 (48), viation 15.3; range 13-88). Reported for a median of 60 months, suggesting

S-120 Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet REVIEW

Table III. Nonsystemic vasculitic neuropathy cohorts: clinicopathologic characteristics.

Dyck Said Davies Collins Kararizou Sugiura Bennett 1987 (24) 1988 (25), 1996 (26) 2003 (51) 2005 (30) 2006 (31) 2007 (37) 1996 (141)

Number of patients 20 32 25 48 22 23 22 Age (mean ± SD, years) 62.4 ± 12.3 61 ± 14 61 ± 13.2 61.8 ± 14.5 54.1 ± 14.5 58.4 ± 14.5 59 ± 12.7 Gender (women: men) 13:7 18:14 13:12 30:18 10:12 9:14 13:8 Constitutional symptoms exclusionary No No Yes No No Yes No Selected for absence of systemic spread on FU Yes No Yes No No FU No FU No FU Median duration of symptoms before diagnosis (months) ? ? 6 5 60 7.5 23.5 Median duration of FU after diagnosis (months) ? 60 33.5 63 No FU No FU No FU Pain (% of patients) ? 19/32 ? 46/48 19/22 17/23 19/22 (75) (98) (86) (74) (86) Cranial nerve involvement (% of patients) ? ? ? 4/48 2/22 0/23 2/22 (8) (9) (0) (9) Pure sensory (% of patients) 2/20 ? ? 6/48 ? 3/23 4/22 (10) (13) (13) (18) Asymmetric fi ndings (% of patients) 16/20 24/32 17/25 47/48* 13/22 § 18/23 18/22 (80) (75) (68) (98) (59) (78) (82) Mean modifi ed Rankin score ? ? ? 3.25 3.2 2.7 ? ESR elevation (% of patients) 10/19 19/32 10/16 31/48 4/22 7/23 6/21 (53) (59) (63) (65) (18) (30) (29) Defi nite vasculitis in nerve (% of patients) 5/20 13/32 19/25 26/48 22/22 11/23 8/22 (25) (41) (76) (54) (100) (48) (36) Defi nite vasculitis in muscle (% of patients) NA 26/32 NA 3/19 NA NA 2/7 (81) (16) (29) Spread of vasculitis to non-neuromuscular organs 0† 11/32 0† 3/48 No FU No FU No FU (% of patients) (34) (6) Relapse rate (% of total patients) ? 7/32 9/25 18/48 No FU No FU No FU (31) (36) (38) Overall mortality (% of patients) 3/20 10/32 1/25 10/48 No FU No FU No FU (15) (31) (4) (21) 5-year survival (% of patients) ? 85 ? 87 No FU No FU No FU

*Mild asymmetries not discounted; §Mild asymmetries discounted; †Absence of spread during FU a selection criterion; ESR: erythrocyte sedimentation rate; SD: standard deviation; FU: follow-up. that some patients in this series might patterns was as follows: Asymmetric In the upper limbs, the ulnar nerve is have had an alternate condition (30). polyneuropathy 85%, multifocal neu- more vulnerable than the median, radi- Neurological defi cits (weakness and ropathy 13%, and distal symmetric al, and more proximal nerves. Vasculitis sensory loss) are almost always distally polyneuropathy 2%. However, cumula- is an axonopathy and thus tends to af- accentuated, but proximal involve- tive incidences from all reported series fect mixed (sensory-motor) and purely ment is not uncommon. In the largest and cases with available data are quite sensory cutaneous nerves. Hence, most reported cohort, assembled by work- different: Multifocal neuropathy 45%, patients with NSVN exhibit mixed mo- ers at Ohio State University (OSU), asymmetric polyneuropathy 30%, and tor and sensory defi cits, but 15% have examination revealed proximal lower distal symmetric polyneuropathy 25%. purely sensory signs and symptoms limb weakness in 60% of patients and The necessary inference is that many (24, 31, 37, 50, 51). Vasculitis-related proximal upper limb weakness in 40% investigators use a more inclusive defi - sensory loss typically involves all mo- (51). The three most common clini- nition of multifocal neuropathy and dalities with occasional large fi ber pre- cal patterns are multifocal neuropathy discount minor asymmetries. dominance. Eighty percent of reported (multiple mononeuropathy), asym- The most commonly affected nerves in patients have had pain. At presentation, metric polyneuropathy (“overlapping” NSVN are a diffuse admixture of lower most patients are still independent in multifocal neuropathy), and distal limb nerves derived from the lumbosac- activities of daily living. Approximately symmetric polyneuropathy. In the OSU ral plexus. The most frequently involved 50% can walk without assistance, 35% series, wherein no asymmetries were individual nerve is the common pero- require walking aids, and 15% are non- discounted, the frequency of these neal or peroneal division of the sciatic. ambulatory (26, 30, 31, 51).

S-121 REVIEW Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet

The clinical presentation of NSVN is Table IV. Differential diagnosis of acute/subacute multifocal or asymmetric neuropathy. similar to that of a SVN (23, 24, 52). • Vasculitic Neuropathies (see Table II) Sugiura et al. compared 23 patients with NSVN to 40 with MPA-associat- • Other Infl ammatory Conditions ed neuropathy and found no signifi cant ° Sarcoidosis ° Multifocal acquired demyelinating sensory and motor neuropathy (Lewis-Sumner syndrome) differences in gender, initial symptoms, ° Neuralgic amyotrophy, brachial or lumbosacral rate of progression, clinical pattern, ° Multifocal variants of Guillain-Barre syndrome presence and distribution of weakness ° Hypereosinophilic syndrome Graft versus host disease or sensory loss, functional involve- ° ° Hashimoto thyroiditis ment, pain, and cranial nerve involve- ment, but as a group, the MPA cohort • Infectious neuropathies ° Leprosy was more disabled (31). A cohort of ° Lyme disease patients with CSS-related neuropathy ° Human immunodefi ciency virus/cytomegalovirus reported by the same group was also ° Human T-lymphotropic virus-I Varicella Zoster Virus more severely affected (53). Bennett et ° ° Septicemia al. compared 22 patients with NSVN to 31 with various SVNs (37). The groups • Genetic neuropathies ° Hereditary neuropathy with liability to pressure palsies were similar in gender, pain, clinical ° Hereditary neuralgic amyotrophy pattern, and cranial nerve involvement, ° Porphyria but patients with NSVN were sympto- ° Tangier disease matic for a longer period of time prior • Neuropathies related to malignancy to diagnosis than those with SVN (mean ° Direct neoplastic infi ltration 23.5 versus 8.5 months), suggestive of ° Multifocal peripheral nervous system mass lesions ° Lymphomatoid granulomatosis slower progression. Median duration of ° Primary amyloidosis symptoms was also longer in a cohort • Other of patients with NSVN ascertained in ° Sensory perineuritis Sydney than in a SVN cohort reported ° Cholesterol emboli syndrome by the same center (26, 54) but not for ° Atrial myxoma cohorts reported by OSU (52). In sum- ° Intraneural hemorrhage (e.g., hemophilia, leukemia, idiopathic thrombocytic purpura) mary, NSVN is clinically identical to a SVN except for reduced severity and – profi le as one suggestive of vasculitis. nerves reveal low-amplitude or absent possibly – more indolent progression. This mandates characterization of the responses, normal or mildly prolonged neuropathy’s tempo (acute, subacute, distal latencies, normal or mildly re- Differential diagnosis chronic), clinical course (steadily or duced conduction velocities, and nor- For patients with pathologic evidence stepwise progressive, stable, improv- mal or mildly prolonged F-wave laten- of defi nite/probable vasculitic neuro- ing, relapsing), functional involvement cies. Although persistent, ischemia- pathy, the differential diagnosis in- (sensory-motor, pure sensory, pure induced, demyelinating partial motor cludes all conditions associated with motor), anatomic pattern (distal sym- conduction blocks are rarely seen, vasculitis of the PNS, including but not metric, distal and proximal symmetric, “pseudo”-conduction blocks occur limited to the primary systemic vascu- asymmetric, multifocal, unilateral) and more commonly (10-25% of patients), litides, certain connective tissue dis- inferred pathology (axonal, demyeli- refl ective of active axonal degeneration eases (especially rheumatoid arthritis), nating). Painful, stepwise progressive, (24, 29). EMG reveals fi brillation po- hepatitis B, HIV infection, hepatitis C, distal-predominant, asymmetric/multi- tentials and motor unit potential drop- other causes of mixed cryoglobuline- focal, axonal, sensory-motor neuropa- out consistent with axon loss in most mia, sarcoidosis, cancers, and – rarely thies are particularly concerning for clinically affected muscles. – other or drugs. Cancers vasculitis, even with a clinical course of If suffi ciently extensive, most electro- are a suffi ciently rare cause of vascu- several years. Conversely, pure motor diagnostic studies show evidence of litic neuropathy to preclude the need or indolently progressive, sensory-pre- a multifocal/asymmetric, distally ac- for an extensive malignancy workup dominant, distal, symmetric polyneuro- centuated process. That said, even the in all patients. Prior to biopsy, it is also pathies are rarely vasculitic (47). most compulsive electrodiagnostician important to consider other causes of rarely has the time and necessary pa- an asymmetric/multifocal neuropathy, Electrodiagnosis tient compliance to perform multiple many of which are listed in Table IV. Electrodiagnostic studies in patients nerve conductions and examine a full with NSVN almost always reveal evi- complement of muscles in all four Diagnosis dence of a primary axonal, sensory- limbs, as would be required to diag- The fi rst and most important diagnos- motor process (36). Thus, sensory and nose “multiple mononeuropathy” by tic step is to identify the neuropathic motor nerve conductions of involved electrodiagnostic criteria alone. More

S-122 Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet REVIEW commonly, extensive but non-exhaus- rheumatoid factors, leukocytosis, and defi nite NSVN? With one exception tive testing of three or four limbs is ANCAs were more prevalent in MPA- (62), all pathologic studies of NSVN performed, assessing for asymmetries associated neuropathy than NSVN, and SVN have revealed changes in- and other non-length-dependent fea- whereas ANA, DNA antibodies, RNP dicative of a primary axonal process. tures that, when combined with the antibodies, SSA/SSB antibodies, and Axons are more vulnerable to ischemia patient’s signs and symptoms, supports elevated CSF protein were not (31). In than Schwann cells, perineurial cells, a diagnosis of multifocal/asymmetric the United Kingdom, anemia, elevated and fi broblasts (28). Affected fascicles polyneuropathy. ESR, and ANCAs were associated with are characterized by decreased myeli- SVN but not ANA, rheumatoid factors, nated nerve fi ber density, conspicuous Laboratory elevated CSF protein, or CSF pleocyto- Wallerian degeneration, regenerating The laboratory evaluation of a pa- sis (37). Therefore, the best laboratory axonal clusters, and infrequent sec- tient with suspected vasculitic neu- predictors of an underlying systemic ondary demyelination/remyelination ropathy is designed to assess for (1) vasculitis in a patient with vasculitic (31, 63). Axon loss tends to be centro- non-neurologic organ dysfunction; (2) neuropathy are elevated CRP, elevated fascicular in distribution in proximal measures of systemic infl ammation; ESR, ANCAs, and perhaps rheumatoid watershed areas (e.g., bi- and (3) specifi c causes of a multifo- factors. furcation in distal thigh) but becomes cal neuropathy or vasculitis. With the multifocal in distal parts of the nerve aforementioned differential diagnosis Pathology due to intermingling of descending fi b- in mind, potentially useful laboratory In the absence of a specifi c labora- ers (28, 63, 64). tests include CBC, eosinophil count, tory marker or clinical profi le, nerve or Cellular infi ltrates in NSVN are perivas- metabolic panel, urinalysis, two-hour nerve/muscle biopsy is required in all cular and predominate in the epineuri- glucose tolerance test, ESR, C-reac- patients with suspected NSVN to con- um (24, 31, 65, 66). They are composed tive protein, ANA, ENA, rheumatoid fi rm, corroborate, or refute the clinical primarily of T cells and macrophages, factor, C3, C4, ANCAs, serum protein diagnosis. The most commonly biopsied with T cells generally outnumbering electrophoresis, ACE, cryoglobulins, nerves are the sural and superfi cial per- macrophages by a factor of 2 to 3 (31, hepatitis B surface antigen, hepatitis C oneal. A peroneus brevis muscle biopsy 67, 68). B cells are uncommon (2-3% antibodies, Lyme antibodies, HIV anti- is always obtained concomitant with a of infl ammatory cells) (31,67), and NK bodies, and HTLV-I antibodies. Malig- superfi cial peroneal nerve biopsy (52). cells and polymorphonuclear leuko- nancy screening should be performed Sural nerve biopsies are also sometimes cytes rare (67, 68). Epineurial T cells if indicated by other clinical features, combined with muscle biopsies (e.g., are almost always CD4+ or CD8+, but laboratory fi ndings, or risk factors. gastrocnemius, quadriceps, or anterior CD4+/CD8+ ratios vary from study to No paraneoplastic antibodies are spe- tibialis) (37, 58, 59). For patients in study (29). Only 1% of T cells express cifi cally associated with cancer-related whom the sural or superfi cial peroneal the γδ T-cell receptor (65). vasculitic neuropathy (55). nerves are not involved by clinical or The vasculitic lesions themselves are al- Pooling data from all published series electrodiagnostic criteria, the superfi cial most always located in the epineurium, and case reports, ESR is elevated in radial, lateral antebrachial cutaneous, with infrequent perineurial and rare en- 50% of patients with NSVN, typically intermediate femoral cutaneous, and doneurial involvement (24, 26, 31, 32). to a mild degree. The incidence of other saphenous nerves can be biopsied. Some investigators classify NSVN laboratory abnormalities is ANA 25%, Diagnosis of pathologically defi nite as a microvasculitis that preferential- anemia 25%, leukocytosis 15%, rheu- vasculitic neuropathy requires nerve ly involves epineurial microvessels matoid factor 10%, decreased comple- biopsy evidence of infl ammation with- (venules, capillaries, and small arteri- ment 5%, CSF pleocytosis 5%, elevated in the vessel wall and signs of vascu- oles with few layers of smooth muscle CSF protein 30%, and CSF oligoclonal lar damage such as fi brinoid necrosis, and no internal elastic lamina)(32,69). bands 10%. Mean CSF protein ranges endothelial disruption or degeneration, “Small arterioles” are variably defi ned from 44 to 56 mg/dL. ANCAs are dis- fragmentation/loss of the internal elas- as having diameters less than 40 μm or tinctly uncommon in NSVN, occurring tic lamina, degeneration of vascular 70μm (69-71). Larger arterioles have in 3% (3/90) of reported patients (37, smooth muscle cells, hemorrhage, or diameters up to 100 μm. Arterial ves- 38, 56, 57). Three studies compared acute thrombosis (60, 61). Some neu- sels with diameters greater than 100 laboratory fi ndings in patients with romuscular pathologists diagnose defi - μm are conventionally referred to as NSVN to those in patients with SVN. nite but inactive vasculitis in biopsies small arteries (72). All endoneurial In the OSU study, elevated ESR, leu- revealing perivascular infl ammation and perineurial vessels are microscopic kocytosis, and rheumatoid factors oc- and markers of more chronic vascular (<40μm), whereas most epineurial ves- curred with increased frequency in injury such as hyperplasia/fi brosis of sels are larger in size (50-300μm) (28). SVN than NSVN, but not ANA, ane- the vessel wall or chronic thrombosis Therefore, PNS microvasculitis should mia, decreased complement, CSF pleo- with recanalization (26, 59). predominate in the endoneurium, but cytosis, or increased CSF protein (52). What are the usual nerve biopsy fi nd- endoneurial vasculitis is rare (24, 52, In Japan, elevated CRP, elevated ESR, ings in patients with pathologically 54, 73). In the only quantitative studies,

S-123 REVIEW Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet diameters of involved epineurial ves- injury neuroma, endoneurial purpura, vs. 19/45 SVN) and Bennett et al. sels in NSVN were 88±31 μm and enlarged axons fi lled with organelles, (13/22 NSVN vs. 9/31 SVN) (24, 37). 98±87μm, confi rming that NSVN has a and epineurial vascular deposits of im- These observations suggest that vascu- predilection for smaller epineurial ves- munoglobulin or complement (32, 52, lar pathology in NSVN is milder and sels but not in the defi ned ranges for 59, 60, 63, 79, 81-83). In one cohort less necrotizing than in SVN, consist- microvasculitis (30, 31). survey of patients undergoing super- ent with the recent pathologic study Another unsettled question concerns fi cial peroneal nerve/peroneus brevis comparing other forms of localized the pathologic defi nition of microvas- muscle biopsy for possible vasculitic vasculitis with systemic PAN (17). culitis. Some groups require only trans- neuropathy, pathologic fi ndings signif- The yield of muscle biopsy for vascu- mural infi ltration of microvessels by icantly associated with defi nite vascu- litis in NSVN is highly variable, rang- mononuclear infl ammatory cells with- litis were Wallerian degeneration, pre- ing from 16-100%, with a mean of out associated vascular damage (32, dominantly axonal pathology, asym- ~50%(25, 32, 37, 51, 84-86). Recent 70, 71, 74) under the theory that small metric nerve fi ber loss, and myofi ber studies suggest that adjacent skin is vessels do not readily undergo fi brinoid necrosis/regeneration (52). also subclinically involved in NSVN. necrosis (69). However, necrosis of en- The true sensitivity of nerve biopsy for In one report, a non-lesional skin bi- doneurial microvessels does occur (73, vasculitic neuropathy is unknowable opsy of the distal leg in a patient with 75, 76), and affected microvessels in due to the lack of a reliable reference NSVN revealed leukocytoclastic vas- the kidneys and lungs in patients with standard short of autopsy. However, in culitis (46). In another report, distal leg AAV are frequently necrotic (77, 78). patients with non-diagnostic biopsies, skin biopsies in three patients demon- Moreover, a pathologic fi nding of PNS clinically probable vasculitic neuropathy strated perivascular T cells and macro- microvasculitis without vascular dam- can be diagnosed by recourse to clinical phages in dermal vessels (43). As a fur- age might bbee a nnonspecifionspecifi c fi nnding,ding, ooc-c- and pathologic criteria (52). The sensi- ther indication of NSVN’s propensity curring with undetermined frequency in tivity of a defi nite biopsy for vasculitis to involve skin, 3/48 NSVN patients in such disorders as chronic infl ammatory is then estimated as [(number of defi nite the OSU cohort developed cutaneous demyelinating polyradiculoneuropathy, cases) ÷ (number of defi nite cases plus vasculitis during long-term follow-up, paraneoplastic sensory neuronopathy, number of probable cases)] x100%. Uti- and in the Vital series, 5/119 patients motor neuron disease, Buerger disease, lizing this error-prone method, a superfi - had isolated nerve/skin vasculitis (32, cholesterol emboli syndrome, and lo- cial peroneal or sural nerve biopsy fi nd- 51). By analogy, the dermatology lit- cal trauma (60, 70, 71, 74). For these ing of defi nite vasculitis is about 50% erature is replete with reports of cuta- reasons, until better evidence becomes sensitive for NSVN (Table V). neous polyarteritis nodosa (cPAN) ac- available, the diagnosis of microvascu- In the Vital et al. series, the fraction of companied by neuropathy (see below). litis should be reserved for cases with NSVN patients with “probable” vascu- Hence, NSVN can be associated with vascular damage. To enhance the iden- litis (including those in their microvas- regional involvement of both muscles tifi cation of microvascular injury, Dyck culitis cohort) was 21/35, contrasting and skin. and colleagues immunostain their bi- with only 4/26 for MPA-associated opsies with antibodies against anti-hu- vasculitic neuropathy (i.e., 4 probable, Clinical variants man smooth-muscle actin, assessing 22 defi nite), a signifi cant difference In addition to the “classic” form of for fragmentation, loss, or destruction (32). A similar over-representation of NSVN detailed above, several syn- of vascular smooth muscle cells (79). patients with “probable” NSVN was dromes may represent clinical vari- To increase the sensitivity of nerve reported by Dyck et al. (15/20 NSVN ants. The fi rst is vasculitis restricted to or nerve/muscle biopsy for vasculi- tis, most workers describe pathologic Table V. Estimated sensitivity of nerve biopsy for nonsystemic vasculitic neuropathy. changes “suggestive” or “suspicious” for “probable” vasculitic neuropathy in Nerve Biopsied Reference Defi nite biopsies Probable/Possible Estimated sensitivity specimens lacking diagnostic fi ndings biopsies of defi nite biopsy (26, 32, 52, 59, 60, 80). Pathologic Superfi cial peroneal Abgrall (85) 2 1 2/3 (67%) criteria for probable vasculitis are non- Collins (51) 11 8 11/19 (58%) uniform, but most require perivascular Vital (32) 14 21 14/35 (40%) or vascular infl ammation and one or Total 27 30 27/57 (47%) more alterations supportive of active or Sural Dyck (24) 5 15 5/20 (25%) healed vasculitis, including Wallerian Davies (26) 19 6 19/25 (76%) degeneration, asymmetric fi ber loss, Garces-Sanchez (50) 6 2 6/8 (75%) thickening of vessel walls, luminal nar- Collins (51) 14 16 14/30 (47%) rowing or obliteration, thrombosis with Sugiura (31) 11 12 11/23 (48%) recanalization, epineurial neovascu- Mathew (34) 7 4 7/11 (64%) larization, hemosiderin deposits, focal Bennett (37) 8 14 8/22 (36%) Total 70 69 70/139 (50%) perineurial degeneration or thickening,

S-124 Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet REVIEW nerves and skin (87). The best charac- spread contralaterally in 80-90%. Most and then spread to adjacent segments terized entity in this group is cPAN (9, patients lose weight. Upper limb in- (proximal-predominant 36; distal- 88, 89). Cutaneous PAN affects small- volvement occurs in ~10%. Laboratory predominant 21). They were initially to-medium-sized arteries in the deep workup is notable only mildly elevated unilateral in 50/57 but became bilat- dermis and panniculus, which undergo ESR in ~20% and elevated CSF protein eral in 51/57. Weight loss occurred in fi brinoid necrosis typical of PAN. The in 85% (mean 90 mg/dL). The condi- 74% and sensory symptoms in 86%. characteristic skin lesions are recur- tion is self-limited. Symptoms worsen 10% had an associated cervical radicu- rent, painful nodules in the lower legs over a period of one week to three years loplexus neuropathy. Mean CSF pro- that often ulcerate. Other skin mani- (median four months) and then slowly tein was 66.5 mg/dL. ESR was above festations include livedo racemosa, improve over one-to-42 months (me- 40 mm/hour in 9%. Electrodiagnostic gangrene, urticaria, and bullae. The dian 15 months). Most patients are left studies showed evidence of an axonal course of the disease is prolonged but with some residual weakness, especial- lumbosacral polyradiculoneuropathy, benign, featuring multiple episodes of ly distally. There is a 10-15% relapse with maximal involvement of the L5- reactivation and resolution. Although rate. Nerve biopsies reveal T-cell pre- S1 myotome. Nerve biopsies revealed other organs are not involved, there dominant perivascular/vascular infl am- perivascular lymphocytic infi ltrates in is commonly an associated multifocal mation involving epineurial and, to a the epineurium and, to a lesser extent, or distal symmetric neuropathy in the lesser extent, endoneurial microvessels, perineurium and endoneurium, with lower limbs, mimicking the distribu- accompanied changes suggestive of predominant microvessel involvement. tion of the skin lesions. Pooling data vasculitis, including asymmetric fi ber Microvasculitis (with vessel damage) from many reports, 40-45% of patients loss, neovascularization, hemosiderin, occurred in 15%, but fi brinoid necrosis have neuropathic signs and symp- focal perineural thickening, injury neu- was rare. Additional features suspicious toms (9, 88-94), and 50% have EMG roma, and complement deposition in for vasculitis were seen in up to 70% evidence of neuropathy (9, 89, 91, 93). vessel walls, but necrotizing vasculitis of biopsies. Thus, the fi ndings were Five patients underwent muscle biop- is rarely seen (80, 99, 102-104). These suggestive of a largely non-necrotiz- sies in one series, all of which revealed fi ndings support the hypothesis that dia- ing microvasculitis. After a median of necrotizing vasculitis (88). Thus, this is betic amyotrophy is a PNS microvascu- 35.5 months, all patients had improved, a localized, PAN-type vasculitis predi- litis and thus a variant of NSVN, char- but 90% were still weak, 55% still had lected for skin, arteries, and muscles in acterized by predominant microvascu- pain, and 17% had relapsed. This entity the lower limbs. lar involvement, severe pain, weight appears to be another variant of NSVN, A second variant is diabetic lumbosac- loss, primary lower limb involvement, defi ned by more prevalent weight loss, ral radiculoplexus neuropathy. Patients and self-limited course. proximal lower limb weakness, and with diabetes mellitus are not immune An analogous syndrome is “non-dia- microvascular involvement. to developing a NSVN-like, multifo- betic lumbosacral radiculoplexus neu- cal, distally accentuated vasculitic ropathy,” which must be distinguished Natural history neuropathy (76). They may even be from the rarely reported acute, painful, The natural history of untreated NSVN so predisposed, but the relative risk of idiopathic, monophasic lumbosacral is largely unknown because nearly all vasculitic neuropathy in diabetics com- plexopathy syndrome that occurs as reported patients have been treated pared to non-diabetics has never been a regionally displaced variant of the with immunosuppressive agents, with investigated. A clinically distinct vas- more prevalent neuralgic amyotrophy rare exceptions (22, 27, 34, 40, 113- culitic syndrome occurs in 1% of dia- involving the brachial plexus (105- 115). Based on these exceptional cases betics (especially older men with type 107). Unlike this entity, non-diabetic and reported patients’ clinical courses 2 diabetes) and goes by such names lumbosacral radiculoplexus is a pro- prior to treatment, we know that NSVN as diabetic amyotrophy, diabetic lum- gressive condition. The only cohort can: (1) Slowly progress for up to 40 bosacral radiculoplexus neuropathy, (n=57) was assembled by investiga- years; (2) Slowly progress for several Bruns-Garland syndrome, and proximal tors at the Mayo Clinic (79, 108), but years and then stabilize or subacutely diabetic neuropathy (80, 95-102). Most additional patients matching this pro- accelerate; (3) Follow a monophasic patients fi rst develop acute pain in their fi le have been reported (109-112). In course with complete or near-com- hip/thigh or, less commonly, lower leg the Mayo Clinic cohort, median age plete recovery for up to three years; (4) or entire lower limb. Weakness ensues of onset was 69.5 years (range 27- Progress in a fulminant, Guillain-Bar- days-to-weeks after the onset of pain. 86). There was no gender preference. ré syndrome-like fashion, producing Early on, proximal lower limb mus- All patients experienced severe, acute severe quadriparesis over weeks-to- cles are more commonly affected than pain and developed weakness after an months; and (5) Spontaneously relapse distal muscles, but weakness routinely unspecifi ed delay. Pain/weakness typi- and remit, with inter-attack intervals spreads to other segments of the same cally progressed over days-to-months ranging up to fi ve years or even “dec- limb, involving more than one myo- (median duration of symptoms prior ades” (116). The relative frequency and tome and peripheral nerve. Pain and to diagnosis 7.0 months), commenced severity of these various natural evolu- weakness usually begin unilaterally and in the proximal or distal lower limb, tions are unknown.

S-125 REVIEW Nonsystemic vasculitic neuropathy / M.P. Collins & M.I. Periquet

Pathogenesis of the upregulated immune genes were matrix metalloproteinase (MMP)-1 The preponderance of data supports the indicative of T cell and/or macrophage (68, 127), MMP-2 and MMP-9 (86, hypothesis that NSVN and, for that mat- activation (124). These observations 127, 133, 134), receptor for advanced ter, almost all SVNs are autoimmune support a pathogenic model wherein glycation end-products (130), nuclear disorders primarily mediated by cellu- disease-specifi c, autoreactive T cells factor κβ (126, 130, 135), various cel- lar cytotoxicity. A cell-mediated patho- are recruited to the PNS and activated lular adhesion molecules (122, 126, genesis is supported by multiple lines by self-glycolipid antigens presented 136), various oxidative and hypoxic of evidence. First, all pathologic studies by macrophages and Schwann cells stress-induced proteins (35, 127, 130), demonstrate a marked predominance of abetted by requisite stimulatory/co- and components of the plasminogen ac- T cells and macrophages in epineurial stimulatory molecules, then maturing tivator system (127). infi ltrates in sural nerve biopsies of pa- into cytotoxic T lymphocytes that dam- tients with NSVN (31,67,68,117). Sec- age target cells in epineurial vessels, Treatment ond, many of the T cells are activated with periodic re-stimulation of effector Treatment recommendations for prima- and express markers characteristic of T cells by ICOS-L-expressing macro- ry systemic vasculitides are grounded cytotoxic T lymphocytes (61, 68, 118). phages in the epineurium. on comparisons with natural history Third, markers of antigen presenting In addition to mononuclear cells, controls; retrospective cohort surveys; cells are upregulated in the epineu- epineurial vessel walls often contain randomized, controlled, open trials; and rium and, to a lesser extent, endoneu- deposits of immunoglobulin and com- a few randomized, controlled, blinded rium. Specifi cally, mannose receptors plement in sural nerve biopsies from trials (137-139). Over the past 15 years, are massively expressed on epineurial patients with NSVN. Combining data treatment has evolved from the “stand- perivascular cells (probably activated from four studies, epineurial vascular ard” Fauci protocol of continuous oral macrophages) (119); MHC class II deposits of IgM are present in 47% of cyclophosphamide (CYC) and high- molecules – which present peptide an- biopsies, IgG in 46%, C3 in 72%, and dose prednisone to a more individual- tigens to CD4+ T cells – are inconsist- any immunoglobulin or C3 in 87% (26, ized, less toxic approach tailored to the ently upregulated on epineurial T cells, 30, 67, 84). Epineurial vascular depos- patient’s age, extent and severity of dis- macrophages, Schwann cells, endothe- its of complement terminal membrane ease, and risk factors. Although “stand- lial cells, and perineurial cells (67, 117, attack complex (MAC) are found in ard” combination therapy was highly 120, 121); and CD1a/CD1b molecules ~80% of patients with NSVN and SVN effective in inducing remission in WG, are expressed on some Schwann cells (67). Thus, immune complex deposi- it converted the disease into a chronic, and epineurial macrophages (119, 122). tion or in situ formation might represent relapsing disorder associated with sig- Unlike MHC II, CD1 molecules present another mechanism of vascular dam- nifi cant disease-and treatment-related lipid antigens to CD1-restricted T cells. age in NSVN, but immune deposits are morbidity (140). Current treatment Fourth, co-stimulatory molecule CD86, found only in heavily infi ltrated vessels strategies seek to minimize exposure to which interacts with CD28 on naïve (30,67), raising concern for nonspecifi c CYC by use of non-CYC-based main- and resting T cells, is upregulated on accumulation in damaged vessels and tenance regimens or by replacement of endothelial cells in NSVN (122). Fifth, complement activation by necrosis. The CYC in the induction phase for patients co-stimulatory molecule ICOS (induci- rarity of B cells and polymorphonuclear with non-severe disease. ble costimulator) is signifi cantly upreg- leukocytes also argues against immune Concerning NSVN, no randomized con- ulated on epineurial T cells in patients complex deposition as a primary mecha- trolled trials of therapy have appeared. with various vasculitic neuropathies nism. The near-complete absence of cir- In fact, there is no controlled data what- (123). ICOS is expressed preferen- culating ANCAs in patients with NSVN soever on treatment of this condition, tially by activated, memory CD4+ and suggests that ANCAs are not pivotal to apart from one class III retrospective CD8+ cells, modulating their effector the pathogenesis of NSVN (56). cohort survey reported by investiga- function. There is a corresponding up- Many other infl ammatory mediators tors at OSU (51). This study analyzed regulation of ICOS-ligand (ICOS-L) are upregulated in sural nerve speci- treatment responses and long-term out- on macrophages in areas where ICOS- mens from patients with vasculitic neu- comes (median follow-up 63 months) in expressing T cells are found, implying ropathy (systemic and nonsystemic), 48 patients with NSVN. Twenty-eight that macrophages act as antigen pre- including pro-infl ammatory cytokines were initially treated with corticoster- senting cells to re-stimulate memory (66, 125-127), cytokines implicated in oids alone, and 20 received combina- T cells and sustain the effector phase type 1 (Th1) helper T-cell responses tion therapy (CYC in 18). Combination of the chronic immune response. Sixth, (128), chemokines and chemokine therapy was signifi cantly more effec- CD58 – an adhesion/co-stimulatory receptors involved in T cell and mac- tive than monotherapy molecule interacting with CD2 on T rophage migration (128), IL-6 (mixed in inducing sustained remission (95% cells – is upregulated on Schwann cells results) (66, 125, 128-130), Th2 cy- vs. 61%) and improving disability and endothelial cells (122). Seventh, in tokines (mixed results) (125, 128), al- (85% vs. 57%), with additional trends a DNA microarray analysis of three pa- lograft infl ammatory factor-1 (131), ni- towards reduced relapse rate (29% vs. tients with vasculitic neuropathy, many tric oxide (68, 127), COX-2 (68, 132), 59%), chronic pain (44% vs. 71%), and

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Table VI. Neurologic outcomes in survivors of nonsystemic and systemic vasculitic neuro- Conclusion pathies. Despite an ever increasing number “Final” disability NSVN (26, 51) SVN (52, 54, 154, 155) of clinical and pathogenic studies on No or essentially no symptoms 17% 8% NSVN, the disease is still poorly un- Mild symptoms, no restrictions 43% 32% derstood, vaguely defi ned, and perhaps Mildly to moderately impaired; ambulatory 21% 34% under-recognized. It is a pleomorphic without assistance condition that shares pathologic fea- Ambulatory with assistance, dependent in some ADLs 16% 21% tures with the primary systemic necro- Non-ambulatory 3% 5% tizing vasculitides but is milder in se- ADLs: activities of daily living; NSVN: nonsystemic vasculitic neuropathy; SVN: systemic vasculitis- verity, more restricted in anatomic dis- associated neuropathies. tribution, and possibly more likely to involve microvessels. Although NSVN 5-year mortality. No patient treated Mortality rates for NSVN were 4% and is sometimes truly confi ned to the PNS, with CYC for greater than six months 15% in two cohorts selected for absence the same clinical picture occurs with relapsed, whereas patients treated with of spread to non-neurologic tissues subclinical involvement of adjacent CYC for one-to-six months had a 54% during follow-up (24, 26) and 21% and tissues such as skin and muscles, sug- relapse rate, but CYC was discontinued 31% in two cohorts not excluding such gesting that the triggering antigen may in 40% because of adverse effects. patients (51, 141). Five-year survival not be neural-specifi c. There are no other controlled trials with in the latter two studies was 85% and Many important nosologic, pathogenic, which to compare these results, but 87%. By comparison, 5-year survival diagnostic, and therapeutic questions they are congruent with data reported in modern systemic vasculitis cohorts remain unanswered. At the most funda- in one other NSVN series, wherein dis- averages ~75% (142-147). An unex- mental level, what is the primary cause? ability scores improved in 10/11 (91%) pected fi nding in the OSU NSVN co- Does NSVN share pathogenic mecha- patients administered combination hort was the high relapse rate. 46% of nisms with such systemic vasculitides therapy ( plus CYC, aza- patients relapsed following a sustained as MPA and PAN? Is it truly a cell- thioprine, or methotrexate) versus 6/11 treatment response (51). Relapse was mediated process, or do the observed (55%) treated with corticosteroids alone defi ned as new signs or symptoms of mononuclear cell infi ltrates have a non- (26). Recently, Mathew et al. reported weakness, sensory loss, or neuropathic specifi c bystander or regulatory func- treatment responses in 10 patients with pain (not nonspecifinonspecifi c symptomssymptoms suchsuch tion (65, 118)? Are diabetic/non-diabet- NSVN followed for greater than one as malaise and fever) (34). Relapses ic radiculoplexus neuropathy variants year (34). Seven received prednisolone occurred 6-47 months after onset of of NSVN or distinct diseases? Is NSVN alone, two CYC and prednisolone, and treatment (median 15 months) and pathogenically related to cPAN and lo- one no treatment. All 10 improved and ranged in number from one-to-four. calized skin/muscle vasculitis? What is achieved a “good” outcome, but 2/7 in Ten relapsing patients had discontin- the natural history of the disease? What the prednisolone group relapsed versus ued therapy, but eight were still tak- are the best clinical predictors of sys- 0/2 in the CYC group. This limited data ing prednisone. No patient relapsed on temic spread? What is the optimal treat- suggests that patients with progressive CYC. All relapses but one responded ment regimen? How should clinically NSVN should be treated with pred- to re-treatment with corticosteroids, suspected patients with non-diagnostic nisone and CYC, probably in accord CYC, and/or IVIg. Combining data nerve biopsies be managed? Of note, with protocols established for the pri- from all NSVN series and case reports a Guideline Group has been commis- mary systemic vasculitides, whereby with 12 months or more of follow-up, sioned by the Peripheral Nerve Society CYC is replaced with a less toxic main- the relapse rate per treated patient is to address some of these questions, but tenance drug after three-to-six months, 32% (29, 34, 38, 44). prospective, multi-center collaborations assuming the neuropathy has remitted Data from Japan suggests that NSVN will be needed to signifi cantly advance (progression of neuropathic defi cits is a less severe neuropathy than those our knowledge of the condition. arrested and early signs of improve- encountered in MPA and CSS (31, 53). ment). Patients with stable-to-improv- Indeed, the fi nal outcome in long-term References ing symptoms might be observed, given survivors is reasonably good, with 60% 1. JENNETTE JC, FALK RJ: The role of pathol- ogy in the diagnosis of systemic vasculitis. NSVN’s potential to spontaneously re- of patients having no or mild symptoms Clin Exp Rheumatol 22007;007; 2255 ((Suppl.Suppl. 444):4): mit. Responses to IVIg and plasma ex- and no signifi cant functional limita- S52-S56. change have been reported in individual tions, but 60% report some degree of 2. HUNDER GG, AREND WP, BLOCH DA et al.: The American College of Rheumatology patients (43, 44). chronic pain (26, 51). No study has 1990 criteria for the classifi cation of vas- compared fi nal disability in patients culitis. Introduction. Arthritis Rheum 1990; Outcome with NSVN and SVN, but data com- 33: 1065-7. Although no direct comparisons have piled from several series (Table VI) 3. 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