608

Vasculitic Neuropathies
Nathaniel Beachy, MD1 Kelsey Satkowiak, MD1 Kelly Graham Gwathmey, MD2

1 Department of Neurology, University of Virginia, Charlottesville, Address for correspondence Kelly Graham Gwathmey, MD,
Virginia Department of Neurology, Virginia Commonwealth University, 1101
2 Department of Neurology, Virginia Commonwealth University, East Marshall Street, PO Box 980599, Richmond, VA 23298-0599
Richmond, Virginia (e-mail: kelly.gwathmey@vcuhealth.org).

Semin Neurol 2019;39:608–619.

Abstract Vasculitic neuropathies are disorders that result from inflammation in the peripheral
nerves’ vascular supply, resulting in ischemic injury. These disorders may be a result of
systemic inflammation or may be confined to the peripheral nervous system. Causative
Keywords etiologies include primary systemic vasculitis, vasculitis secondary to other conditions

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► vasculitic neuropathy
► vasculitis
► nonsystemic
vasculitic neuropathy
► microvasculitis
► nerve large arteriole
such as primary connective tissue disorders, infectious, paraneoplastic, and drug-
induced conditions, and nonsystemic vasculitic neuropathy. Early recognition and
treatment of these conditions is imperative to prevent substantial morbidity and
mortality. The goal of this review is to provide an organization of the vasculitic
neuropathies and an overview of principles of diagnosis and treatment for the clinical
neurologist.

Vasculitic neuropathies result when inflammation in the vasa
nervorum leads to ischemic injury of peripheral nerves. Such
ischemic injury may be a result of systemic inflammation or
may be confined to the peripheral nervous system (PNS). The
systemic inflammatory conditions that cause vasculitic neu-
ropathies include the primary systemic vasculitides (e.g.,
polyarteritis nodosa [PAN]) and other conditions such as
primary connective tissue disorders, infectious, paraneoplas-
tic, and drug-induced conditions that secondarily affect the
peripheral nerves.1 Early recognition and treatment of these
conditions is paramount to prevent substantial morbidity and
mortality. The goal of this review is to provide an organization
of the vasculitic neuropathies and an overview of principles of
diagnosis and treatment for the clinical neurologist.
Classification
Several proposed classification schemes for vasculitic neuro-
pathies exist, incorporating factors such as clinical presenta-
tion, size of affected vessels, and underlying mechanism of
injury. For the purpose of this review, we adopt the Peripheral
Nerve Society Task Force classification (►Table 1), which is
discussed later.2,3 It is important to note that the other most
widely used classification scheme is the International Chapel
Hill Consensus Conference classification.4,5 Some experts
classify the vasculitic neuropathies pathologically based on
size of the involved vessels.6 There are ongoing studies to
further delineate the optimal classification scheme.7
The Peripheral Nerve Society Task Force guidelines of
2010 propose three categories of vasculitic neuropathy:
primary systemic, secondary systemic, and nonsystemic/
localized.2 Primary systemic vasculitides include conditions
for which there is involvement of multiple organ systems
with no clear underlying autoimmune condition, connective
tissue disease, or other causative entity. Examples include
microscopic polyangiitis (MPA), eosinophilic granulomatosis
with polyangiitis (previously Churg-Strauss), granulomato-
sis with polyangiitis (previously Wegener’s granulomatosis),
Henoch-Schönlein purpura, PAN, giant cell arteritis, and
essential mixed cryoglobulinemia.2 The task force guidelines
subdivide the primary systemic vasculitides into predomi-
nantly large vessel vasculitis, predominantly medium vessel
vasculitis, and predominantly small vessel vasculitis. The
International Chapel Hill Consensus Conference guidelines of
2012, which categorizes systemic vasculitis based on caliber
of involved vessels and associated clinicopathologic features,
further subdivides the small vessel primary systemic vascu-
litides into those associated with vessel wall immune glo-
bulin deposition and those without (anti-neutrophilic
cytoplasmic antibody [ANCA]-associated).5
Secondary systemic vasculitides are associated with under-
lying connective tissue diseases or develop secondary to

Issue Theme Peripheral Neuropathies; Copyright © 2019 by Thieme Medical DOI https://doi.org/
Guest Editors, Michelle Kaku, MD, and Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0039-1688990.
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Tel: +1(212) 584-4662.

Table 1 Classification of vasculitides associated with neuropathy
I. Primary systemic vasculitides
1. Predominantly small vessel vasculitis
a. Microscopic polyangiitisa
b. Granulomatosis with polyangiitisa
c. Eosinophilic granulomatosis with polyangiitisa
d. Essential mixed cryoglobulinemia (non-HCV)
e. Henoch-Schönlein purpura
2. Predominantly medium vessel vasculitis
a. PAN
3. Predominantly large vessel vasculitis
a. Giant cell arteritis
II. Secondary systemic vasculitides associated with one of
the following
1. Connective tissue disorders
a. Rheumatoid arthritis
b. Systemic lupus erythematosus
c. Sjogren’s syndrome
d. Systemic sclerosis
e. Dermatomyositis
f. Mixed connective tissue disease
2. Sarcoidosis
3. Behçet’s disease
4. Infection (such as HBV, HCV, HIV, CMV, leprosy,
Lyme’s disease, HTLV-1)
5. Drugs
6. Malignancy
7. Inflammatory bowel disease
8. Hypocomplementemic urticarial vasculitis syndrome
III. Nonsystemic/localized vasculitis
1. Nonsystemic vasculitic neuropathy (includes nondia-
betic radiculoplexus neuropathy and some causes of
Wartenberg’s migrant sensory neuritis)
2. Diabetic radiculoplexus neuropathy
3. Localized cutaneous/neuropathic vasculitis
a. Cutaneous PAN
b. Others
Abbreviations: CMV, cytomegalovirus; HBV, hepatitis B virus; HCV,
hepatitis C virus; HIV, human immunodeficiency virus; HTLV, human
T-lymphotropic virus; PAN, polyarteritis nodosa.
Note: Reproduced with permission from Collins et al.2
a
Antineutrophil cytoplasmic antibody-associated vasculitides.
infection, malignancy, drugs, or other systemic inflammatory
conditions. These vasculitides are felt to be immune-
mediated.2,3 In contrast to systemic vasculitis, nonsystemic
vasculitis involves only peripheral nerves and may be thought
of as single-organ vasculitis under the International Chapel Hill
Consensus Conference classification.2,5,8 Subtypes of nonsys-
temic vasculitic neuropathy (NSVN) include Wartenberg
Vasculitic Neuropathies Beachy et al. 609
migratory sensory neuropathy, nondiabetic lumbosacral radi-
culoplexus neuropathies, and postsurgical inflammatory neu-
ropathies. Other localized vasculitides such as diabetic
lumbosacral radiculoplexus neuropathy (DLRPN) and parso-
nage Turner’s syndrome (i.e., neuralgic amyotrophy) are con-
sidered variants of the NSVN category.8
Some neurologists prefer classifying vasculitic neuropa-
thies by the size of the vessel involved: nerve large arteriole
or nerve microvasculitis. Nerve large arteriole vasculitis
affects primarily small arteries and large arterioles (75–
300 µm in diameter), and these are implicated in primary
and secondary systemic vasculitides.9–11 Nerve microvascu-
litis affects the smallest arterioles and capillaries (<40 µm in
diameter) and occurs most commonly with NSVN and other
localized vasculitides.6,9,11 Exceptions apply to each of these
categories, such as the microvasculitis seen in Sjögren’s
syndrome (SS), a secondary systemic vasculitis.
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Clinical Features
Vasculitic neuropathy presentations vary based on the dis-
tribution and severity of inflammation. Systemic vasculitic
neuropathies often present with involvement of several organ
systems, and the neuropathy may be overshadowed by pul-
monary, gastrointestinal, dermatologic, or urinary symptoms.
Constitutional symptoms such as weight loss, arthralgias,
myalgias, and fatigue are common at the time of presentation.
NSVN, in contrast, exclusively involves the PNS, and systemic
symptoms are mostly absent. Only a minority of these patients
present with vague constitutional symptoms.9
Vasculitic neuropathy characteristically presents as acute or
subacute onset of multiple, painful sensory or sensorimotor
mononeuropathies.12 Classically, these mononeuropathies
crescendo over weeks and may ultimately overlap, yielding an
appearance of a distal symmetrical or asymmetrical polyneuro-
pathy. All sensory modalities are typically involved, as purely
small fiber neuropathies are rarely vasculitic in nature. Infarc-
tion often affects the proximal nerve, such as the mid-sciatic and
other distal extremity nerves are less commonly affected.13,14
Cranial neuropathies are occasionally encountered in ANCA-
associated vasculitis.15–17 Progression is step-wise in two-thirds
of cases and slowly progressive in the remaining third.12 A
slowly progressive pattern is observed more frequently in the
elderly and in NSVN.1 Prognosis correlates with the extent of
systemic involvement, as untreated systemic vasculitis carries
the potential for organ failure and death.
Primary Systemic Vasculitis
Polyarteritis Nodosa
This small and medium vessel vasculitis lacks ANCA, and
presents with neuropathy 65 to 85% of the time.18,19 It can
also present with constitutional symptoms, skin involve-
ment (livedo reticularis, palpable purpura, digital gangrene),
abdominal pain, renal artery aneurysms, and hypertension.
Unlike many of the ANCA-associated vasculitides (AAV),
pulmonary arteries are spared.18,20 It is sometimes asso-
ciated with active hepatitis B.18
Seminars in Neurology Vol. 39 No. 5/2019
610 Vasculitic Neuropathies Beachy et al.
Granulomatosis with Polyangiitis (Previously
Wegner’s Granulomatosis)
Granulomatosis with polyangiitis is an AAV that presents most
commonly in the seventh decade, equally in men and women.
Patients can have localized ear, nose, and upper airway gran-
ulomatous inflammation, but often go on to develop lower
airway involvement with renal complications.19,21 About 20%
of cases have associated neuropathy, which is more common in
male patients who are older, have higher ANCA titers, and have
more widespread disease.19,22 Most of the time, the antibodies
are against the proteinase-3 (PR3) antigen, also called C-ANCA
(or cytoplasmic ANCA).22,23
Eosinophilic Granulomatosis with Polyangiitis
(Previously Churg-Strauss Syndrome)
This small vessel necrotizing AAV often presents with asthma
as the principal feature, which precedes any other systemic
manifestation.24 It presents in younger population with a
mean age at the time of diagnosis between 48 and
52 years.24–28 The American College of Rheumatology diag-
nosis requires that at least four of the following six criteria
are present: asthma, elevated peripheral blood eosinophils
greater than 10%, a mono- or polyneuropathy, fleeting
pulmonary infiltrates, paranasal sinus abnormalities, and
extravascular eosinophils.24,29 Development of neuropathy
occurs in around 50 to 70% of patients.24,30,31 Laboratory
workup can show positive ANCA, primarily to the myeloper-
oxidase (MPO) antigen (previously called P-ANCA [or peri-
nuclear ANCA]).26 Histopathology reveals a granulomatous
and necrotizing vasculitis with eosinophils.29
Microscopic Polyangiitis
Microscopic polyangiitis is a rare AAV that occurs in patients
around the median age of 60 years, somewhat more fre-
quently in males. A common presenting symptom is cough
due to high incidence of pulmonary involvement, but there
can also be renal involvement (necrotizing glomerulone-
phritis), and, of course, neuropathy.32–34 Prevalence of neu-
ropathy is variable but occurs anywhere from around 40 to
70% of patients.32,35,36 Laboratory workup can show either
MPO or PR3 ANCAs, with PR3 ANCAs present up to 75% of the
time.32 Skin lesions and gastrointestinal symptoms occur
frequently as well.32,33,37
Secondary Systemic Vasculitis
Rheumatoid Vasculitis
Rheumatoid vasculitis (RV) is usually a late presentation of
severe seropositive RA, and its incidence has declined in
recent past to approximately 3.9 per million.38 It involves the
small- and medium-sized arteries, small arterioles, capil-
laries, and venules.39 Vasculitic neuropathy is seen in 30 to
54% of patients with RV.40,41 The mortality rate of RV is high
at 25% over 5 years.40 Peripheral neuropathy of any etiology
is present in 57% of patients with RA.42 Etiologies other than
vasculitis include entrapment neuropathy or exposure to
various medications.43–45 Extensive autopsy of a patient who
died from RV revealed necrotizing vasculitis of small arteries
Seminars in Neurology Vol. 39 No. 5/2019
and large arterioles with ischemic nerve injury beginning in
the mid-sciatic nerve, suggesting vascular watershed areas
may be the initial site of nerve infarction.13
Sjögren’s Syndrome
Nerve large arteriole vasculitis and microvasculitis are seen in
SS. Incidence of neuropathy ranges from 2 to 64% in various
studies.46 Presentations are diverse and include trigeminal
sensory neuropathy, distal sensorimotor neuropathy, small or
large fiber sensory neuronopathy, and autonomic neuropathy.
Vasculitic neuropathy is less common and represents 13% of
neuropathies in SS.47,48 Recently, antibodies to calponin-3, a
protein expressed in dorsal root ganglion perineuronal satellite
cells, have been identified in 11% of patients with SS compared
with 2% of controls, and are expressed most frequently in
patients with concurrent neuropathy.49 Anti-calponin-3 shows
promise both in diagnostic utility and in implicating DRG
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perineuronal satellite cells as targets in the pathway of SS.
Viral Infections and Cryoglobulinemia
Mechanistically, infectious vasculitis can occur through forma-
tion of immune complexes, direct vascular invasion, molecular
mimicry, toxin formation, or altered immune regulation.50,51
Only cytomegalovirus (CMV) and varicella zoster virus (VZV)
are known to directly invade endothelial cells.52,53 Vasculitic
neuropathy, however, is strongly associated with viral infec-
tions that persist and replicate for long periods of time such as
HIV, HBV, HCV, and parvovirus B19.50,54–56
Hepatitis B and Polyarteritis Nodosa
One to five percent of patients with HBV will develop PAN,
typically within the first 9 months of acute hepatitis.57,58
Conversely, 10 to 50% of patients with PAN are found to have
circulating hepatitis B surface antigen (HBsAg).57,59,60 PAN
presents similarly with or without concurrent HBV infection,
although neuropathy is more common and cutaneous man-
ifestations less common in those with HBV.
Hepatitis C and Mixed Cryoglobulinemia
Chronic HCV infection can lead to the development of
cryoglobulins, which are monoclonal or polyclonal proteins
that precipitate at temperatures below 4°C. While most
patients are asymptomatic, many develop cryoglobulinemic
vasculitis (CV) through immune complex-mediated activa-
tion of the complement cascade. As many as 65% of HCV-
related CV develops clinically significant peripheral neuro-
pathy, typically distal symmetric or asymmetric polyneuro-
pathy, or a multiple mononeuropathy.61–66 Laboratory
evaluation typically reveals cryoglobulins, low C4, and high
RF.54 HCV is also associated with PAN, sometimes without
cryoglobulinemia. PAN-type vasculitic neuropathy is seen in
19% of patients with HCV vasculitis and presents more
acutely and with a multiple mononeuropathy pattern.62
HIV and Cytomegalovirus
HIV is a rare cause of vasculitic neuropathy. Systemic vascu-
litic neuropathy is now seen in less than 1% of patients
infected with HIV and is most often seen in patients with

CD4 counts of 200 to 500 cells/microliter.67 When CD4 count
drops below 50 cells/microliter, vasculitic neuropathy asso-
ciated with CMV may be seen.68 Additionally, patients with
HIV are more prone to other infectious causes of vasculitic
neuropathy such as HBV, HCV, and HTLV-1. Peripheral neu-
ropathy due to HIV-associated vasculitis is typically self-
limited and resolves with appropriate treatment of HIV.69
Paraneoplastic Vasculitis
Paraneoplastic vasculitic neuropathy is most commonly asso-
ciated with small cell lung cancer (SCLC) and lymphoma, but
has also been associated with colon, kidney, bile duct, stomach,
pancreas, liver, prostate, endometrial, and tongue cancers.70–74
Common presentations include painful sensorimotor neuro-
pathy and multiple mononeuropathy, and symptoms are
usually confined to the PNS.73,75 Antineuronal nuclear anti-
gen-2 (anti-Hu) antibodies are strongly associated with SCLC,
but in many cases an antibody is not found.71,76,77 Prognosis is
typically poor, but treatment of either the underlying malig-
nancy or vasculitis can sometimes improve outcome.78 One
retrospective study suggested a possible association between
vasculitic neuropathy and malignancy, as 6 of 40 patients with
biopsy-proven vasculitic neuropathy developed a malignancy
within 2 years of the onset of neuropathy.75
Drug-Induced Vasculitis
Vasculitic neuropathy has been described with several drugs.
Minocycline, a tetracycline derivative for acne vulgaris, has
long been associated with drug-induced lupus and cutaneous
PAN. Several cases of vasculitic neuropathy have been
reported, some consistent with drug-induced lupus79 or
PAN,80 and others without signs of other autoimmune con-
ditions.79,81,82 The presentation is typically multiple mono-
neuropathies. The length of exposure to minocycline varies
and can be as short as 2 weeks or as long as 4 years.81,82
Treatment consists of discontinuation of the drug and
administration of corticosteroids or additional immunosup-
pressive agents.
Anti-programmed death 1 (PD-1) antibodies, such as
pembrolizumab and nivolumab, function as immune check-
point inhibitors and are increasingly being used for treat-
ment of both solid-organ and hematological malignancies.83
There have been two reported cases of vasculitic neuropathy
associated with these checkpoint inhibitors, both treated
with corticosteroids in addition to drug cessation.83,84
Cocaine is known to trigger AAV as well as pseudovascu-
litis.85–89 The latter may present clinically as vasculitis and
include ANCA; however, it characteristically lacks biopsy
findings consistent with vasculitis.89 As in other cases of
drug-induced vasculitic neuropathy, corticosteroids and
immunosuppressive agents may be used.
Nonsystemic Vasculitic Neuropathy
Nonsystemic vasculitic neuropathy is an underrecognized
single-organ vasculitis affecting only the peripheral nerves.
As such, diagnosis with a peripheral nerve biopsy is manda-
tory. Some consider it a microvasculitis, affecting epineural
Vasculitic Neuropathies Beachy et al. 611
vessels under 40 µm in diameter,6 though this distinction is
not absolute and epineural large arterioles 80 to 90 µm in
diameter may be affected.8,90–92
NSVN differs from SVN in that it is confined to the PNS
and secondarily affects muscles, progresses more slowly, and
is not typically fatal if left untreated.9,11,93 However, 10% of
patients will progress to SVN.1,11,94 Constitutional symp-
toms are less common and tend to be mild. Approximately
28% of patients have weight loss, and fevers are seen in 13%.8
Only 5 to 10% present acutely with a rapidly progressive
course, with most patients progressing slowly over the
course of years.8,12,95–97 NSVN carries a predilection for
the common fibular nerve, involved in 91% of patients,
though multiple nerves are often involved by the time a
neurologist is sought.8
Similar to SVN, common presentations of NSVN include
multiple mononeuropathy, asymmetric polyneuropathy, and
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distal symmetric polyneuropathy. Interestingly, 20% of patients
will have no pain at all.8 New definitions for multiple mono-
neuropathy and asymmetric polyneuropathy have recently
been proposed, as the lack of standard definition has led to
wide variability between studies.8 Under these new defini-
tions, multiple mononeuropathy (proposed new term “multi-
focal neuropathy”) consists of simultaneous or sequential
involvement of two or more individual peripheral or cranial
nerves. Asymmetry is defined as having any of the following
characteristics: difference of at least 1 grade in strength or
reflexes between homologous groups or interside difference of
at least 50% in perceived intensity in any sensory modality.
Subtypes and variants of NSVN include Wartenberg
migratory sensory neuropathy, postsurgical inflammatory
neuropathy, DLRPN, diabetic thoracic radiculoneuropathy,
diabetic cervical radiculoplexus neuropathy, and neuralgic
amyotrophy. Several good reviews have been written on
these topics.8,14
Diagnosis
Peripheral neuropathy may be the presenting complaint of
patients with underlying systemic vasculitis, a treatable con-
dition that carries potential for substantial morbidity and
mortality if left untreated. Therefore, vasculitis should remain
high on the differential etiologic diagnosis of peripheral
neuropathy. Features of neuropathy that raise suspicion for
vasculitis and increase the yield of nerve biopsy include acute
onset,98,99 asymmetric or multifocal pattern,75,98–100 positive
ANCAs,101 elevated erythrocyte sedimentation rate (ESR),
elevated C-reactive protein (CRP),98,102 elevated β2-microglo-
bulin,98 and increased vascular endothelial growth factor
(VEGF).103–105 However, vasculitis should also be considered
in slowly progressive neuropathies, especially if they are
painful.105 A general approach to the diagnosis of vasculitic
neuropathy includes a series of routine laboratories, EMG, and
nerve biopsy with additional workup tailored to the clinical
presentation as outlined in ►Fig. 1.
According to consensus recommendations, routine workup
of suspected vasculitic neuropathy includes the following
laboratory studies: complete blood count with differential,
Seminars in Neurology Vol. 39 No. 5/2019
612 Vasculitic Neuropathies Beachy et al.
Fig. 1 Diagnostic algorithm for vasculitic neuropathies. ANA, antinuclear antibodies; ANCA, antineutrophilic cytoplasmic antibodies; CBC,
complete blood count; CMP, comprehensive blood count; CXR, chest X-ray; ESR, erythrocyte sedimentation rate; HBsAg, hepatitis B surface
antigen; HCV, hepatitis C virus; RF, rheumatoid factor.
chemistry panel, urinalysis, hemoglobin A1c, ESR, CRP, anti-
nuclear antibodies (ANA), rheumatoid factor (RF), ANCA,
serum protein electrophoresis (SPEP), complement (C3, C4,
total), cryoglobulins, HBsAg, anti-HCV antibodies, and chest X-
ray.2,14,106 It is particularly important to recognize or eliminate
systemic vasculitis as an etiology. ANCAs and elevated ESR
greater than 100 mm/hour are suggestive of SVN.107 However,
only 30% of cases of NSVN will have a truly normal ESR, so an
elevated ESR does not exclude NSVN.96 Leukocytosis, anemia,
RF, ANA, and decreased complement are suggestive of SVN, but
also nonspecific.105
Recently, serum neurofilament light chains (sNfL)108 and
elevated VEGF103,104 have been shown to predict vasculitic
neuropathy. In particular, sNfL predicted vasculitic neuro-
pathy with a sensitivity of 82% and specificity of 100%, and
appeared to correlate with disease activity.108
Distinctive patterns on electrodiagnostic testing may
further support a clinical diagnosis of vasculitic neuropathy.
The most common pattern is multiple mononeuropathy fol-
lowed by asymmetric axonal sensorimotor polyneuropathy.75
Additionally, electrodiagnostic studies may identify sites for
Seminars in Neurology Vol. 39 No. 5/2019
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nerve and muscle biopsy and identify areas of asymptomatic
involvement. The recommended electrodiagnostic approach
includes a wide sampling of distal and proximal nerves with
side-to-side comparisons looking for asymmetry. Many vas-
culitic neuropathy patients have multiple acute or subacute
axonal mononeuropathies which may over time coalesce to
result in a distal symmetric or asymmetric pattern. Occasion-
ally, “pseudo-conduction block” is observed in motor nerve
conduction studies due to focal axonal conduction failure.
Subsequent Wallerian degeneration results in resolution of
the block, leading to a low amplitude motor response support-
ing significant axonal loss.109
The sural, superficial radial, and superficial fibular sensory
nerves are the most commonly biopsied nerves, but any
clinically affected sensory nerve is suitable for biopsy. Adjunc-
tive muscle biopsy, such as peroneus brevis with superficial
fibular sensory nerve, improves diagnostic yield as muscle is
often an easier tissue in which to see evidence of vasculi-
tis.1,14,92,106,110,111 Among patients with a clinical phenotype
that raises suspicion of vasculitis, the diagnostic yield is only
20 to 50%.112–117 In patients with other clinical features to

Fig. 2 Nerve large arteriole vasculitis. A paraffin-embedded, hema-
toxylin and eosin stained section reveals a perineurial arteriole with
intramural lymphocytic invasion and fibrinoid necrosis (upper right
portion of vessel).
support vasculitis such as positive ANCAs, elevated inflamma-
tory markers, and classic clinical presentation, the yield is
increased.118 The diagnostic yield of combined superficial
fibular nerve and peroneus brevis muscle biopsy is likely
greater than nerve biopsy alone.110,111,118 The sensitivity for
this combined biopsy ranges from 55 to 86%,12,96,111 and the
pooled sensitivity for superficial fibular nerve/peroneus brevis
muscle biopsy was 64% compared with 56% for sural nerve
alone in one series.118
Biopsy of nerve large arteriole vasculitis reveals fibrinoid
necrosis of the tunica media and intima of epineurial and
perineurial vessels ranging from 75 to 300 µm in diameter
(►Fig. 2).9,10 Microvasculitis is seen in small arterioles,
capillaries, and venules typically less than 40 µm in diameter,
and is characterized by inflammation of the vessel wall with
fragmentation and necrosis of the tunica media (►Fig. 3).11
Fig. 3 Microvasculitis. An Epon-embedded, toluidine blue-stained,
semi-thin section reveals a single capillary surrounded by perivascular
lymphocytes (lower left) and extensive loss of large myelinated fibers
in the adjacent nerve.
Vasculitic Neuropathies Beachy et al. 613
In both SVN and NSVN, typical findings include axonopathy
with Wallerian degeneration, hemosiderin-laden macro-
phages, perineurial thickening, neovascularization, immune
deposits of IgM, complement proteins, and fibrinogen in
epineurial vessel walls.2,13,14,107,119–122
Treatment
Systemic Vasculitic Neuropathy
Both primary and secondary systemic vasculitis can be life
threatening, and treatment should begin quickly once diag-
nosed due to the high untreated mortality rate.2,123 Prior to
development of current therapies, primary systemic vasculi-
tides had a 5-year survival of only approximately 10%.123 This
has improved drastically with current treatments. For SVN,
treatment is aimed at gaining control of inflammation with
induction therapy. Once remission is achieved, a maintenance
therapy is continued for 18 to 24 months (►Table 2).123,124
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Corticosteroids are the standard induction therapy, with a
prednisone dose of 1 mg/kg day, but if symptoms are very
severe, 1 g of IV methylprednisolone can be given over 3 to
5 days followed by daily oral therapy.1,125 Higher doses are
usually continued for 6 to 8 weeks, at which time they can be
tapered.1,11 Cyclophosphamide can be added as an induction
agent for severe cases, usually of granulomatosis with poly-
angiitis and microscopic polyangiitis.11,126 Patients require
approximately 3 to 12 months of induction cyclophospha-
mide before remission is achieved and they are switched to
maintenance therapy.11,127,128 Rituximab more recently has
proven to be as effective as cyclophosphamide for induction
in AAVs.129–132 Methotrexate is another option for induction
in patients with milder symptoms from GPA and MPA.127,133
Maintenance therapy usually involves substituting cyclo-
phosphamide for azathioprine or methotrexate.11,128,134
Maintenance therapy should be continued at a standard
dose for 18 to 24 months before a taper is attempted.2,11
Other options for refractory symptoms or progression of
disease include plasma exchange and IVIG infusions.135–138
Response to therapy is discussed below.
Nonsystemic Vasculitic Neuropathy
In NSVN, when appropriate, monotherapy with corticoster-
oids is usually the first step; however, several studies have
indicated that combination therapy is more effective than
corticosteroids alone.97,126 Indications for a second immuno-
suppressant include rapidly progressive NSVN or progression
of symptoms while on corticosteroid monotherapy.2 Research
is ongoing to identify molecular targets for treatment in NSVN.
A recent study shows that CD52 is expressed in some nerve
biopsies of patients with NSVN, providing a potential pharma-
cologic treatment target in the future with alemtuzumab.139
Virus-Associated Vasculitic Neuropathies
Historically, for HCV-related cryoglobulinemia with vasculitis,
the first-line treatments were antiviral drugs.140,141 This
includes interferon-α plus ribavirin and, in cases of HCV
genotype 1, a protease inhibitor.141 In 2014, the FDA approved
a combination of two direct-acting antiviral agents (ledipasvir
Seminars in Neurology Vol. 39 No. 5/2019
614 Vasculitic Neuropathies Beachy et al.

Table 2 Treatment approach for vasculitic neuropathies

Therapy Drug Dosing Side effects Laboratory monitoring

Induction Corticosteroids
Cyclophosphamide
(especially severe cases
of GPA and MPA)
Rituximab (for AAV)
1 mg/kg/d PO prednisone
or 1 g IV methylpredniso-
lone over 3–5 d followed by
daily PO therapy 6–8 wk
with taper
2 mg/kg/d PO or 15 mg/kg
vs. 0.6–0.7 g/m IV pulse
therapy q 2–3 wk
(3–12 mo of induction
dosing)
375 mg/m2 once a week for
4 wk
Weight gain, hyperglyce- Glucose, blood pressure
mia, agitation/insomnia,
muscle atrophy, GI upset,
osteonecrosis, or delayed
bone growth
Bone marrow suppression, CBC weekly at first,
hemorrhagic cystitis, renal function,
gonadal toxicity, opportu- urinalysis for hematuria
nistic infections, renal
impairment, increased risk
of malignancy
(lymphoma, leukemia,
non-melanomatous skin
cancer, bladder)
Hypotension, fever, GI Hepatitis panel prior to
upset, dyspnea, angioe- use, CBC

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dema, headache, urticaria,
pulmonary disease, and
infection (PML)
Methotrexate 7.5–15 mg/wk; gradually Bone marrow suppression, CBC, LFTs
(mild GPA and MPA) titrated up to 20–25 mg/wk liver toxicity, GI toxicity,
rash, interstitial
pneumonitis uncommonly
Maintenance Azathioprine 50 mg/d, increased by Bone marrow suppression, CBC and LFTs weekly
50 mg every 3–5 d to a goal acute hypersensitivity x1 mo, monthly x6 mo,
of 2 mg/kg/d reaction, liver toxicity, then q3 mo
pancreatitis, increased risk
of infection, and
malignancy
Methotrexate Continued 18–24 mo after See above See above
induction with weekly folic
acid
Refractory IVIG (treatment refrac- 2 g/kg divided over 2–5 d Anaphylactic reaction, IgA prior to use
disease tory SVN, or relapse of aseptic meningitis, HA,
GPA/MPA) flulike symptoms, renal
insufficiency, neutropenia,
rash, hyperviscosity
syndrome
Plasma exchange (SVN No standardized approach, Bleeding, infection, PT INR/PTT, CBC
with severe glomerulo- typically 3–5 sessions cardiovascular/fluid shifts,
nephritis or alveolar hypocalcemia
hemorrhage)

Abbreviations: AAV, ANCA-associated vasculitis; CBC, complete blood count; GI, gastrointestinal; GPA, granulomatosis with polyangiitis; IV,
intravenous; IVIG, intravenous immune globulins; LFTs, liver function tests; MPA, microscopic polyangiitis; PML, progressive multifocal
leukoencephalopathy; PO, per os; PT, prothrombin; PTT, partial thromboplastin time; SVN, systemic vasculitic neuropathy.

and sofosbuvir) for the treatment of HCV genotype 1 infec-
tions, and other interferon-free regimens have followed.142
More recently, the addition of immunomodulatory therapies
for moderate to severe disease, such as plasma exchange or
rituximab, has been found to assist in quicker and longer
lasting improvement of skin, joint, kidney, or peripheral nerve
fiber injury.141,143–147 Antivirals plus rituximab may be the
initial treatment of choice for advanced disease based on
emerging evidence.63,147,148
Chronic HBV infections causing vasculitis should be trea-
ted with first-line antiviral therapies, which include nucleo-
tide/nucleoside analogs such as entecavir or tenofovir, and
pegylated interferon-alfa. For PAN induced by hepatitis B
infection, there are some data suggesting a benefit with
corticosteroids and plasma exchange for 1 to 2 weeks before
initiating antiviral therapy.149,150
Neuropathy from HIV-associated vasculitis tends to be
acute, and once remission is obtained, does not often recur.56
Treatment approach should include initiating antiretroviral
drugs, corticosteroids, and plasma exchange.56,118
Response to Treatment
There are numerous ways to assess treatment response in this
group of patients. Physical examination can objectively identify
changes in strength, sensory loss, or deep tendon reflexes.2,11
There are also scored scales such as the Neuropathy Impairment

Seminars in Neurology Vol. 39 No. 5/2019


Score or disability scales (such as the Overall Neuropathy
Limitations Scale) that can be used to evaluate weakness,
reflexes, and sensory loss.2,11 Several serum tests are available
for physicians to monitor patients as well. Trending markers of
inflammation such as ESR or CRP can be useful to identify
response to treatment.1,2 Additionally, an acute rise in, or
persistently elevated, ANCA titer has been associated with an
increased likelihood of relapse in AAV.151,152
Symptomatic Therapy
Neuropathic pain can be extremely disabling in patients with
vasculitic neuropathy. Several classes of drugs are commonly
used to treat these symptoms including antidepressants, antic-
onvulsants, and, less commonly, opioids. In 2006, the Eur-
opean Federation of Neurological Societies produced the first
guidelines on treatment of neuropathic pain, and since that
time there have been many randomized controlled trials.153
In terms of antidepressants, tricyclic antidepressants
(TCAs) have been found to improve symptoms of painful
peripheral neuropathy.154,155 One subgroup of the vasculitic
neuropathies that does not benefit from TCA therapy is HIV-
associated neuropathy.155 Serotonin norepinephrine reup-
take inhibitors (SNRIs) have also proven beneficial, with
duloxetine and venlafaxine being the most highly stu-
died.155–158 SNRIs tend to have fewer side effects when
compared with TCAs, which may make them a good option
depending on patient comorbidities. As far as anticonvul-
sants, the gabapentinoid class is the first line for neuropathic
pain, namely gabapentin and pregabalin.159,160
Opioids do show some benefit in neuropathic pain but
tend to be thought of as a second or third line therapy.154,156
Tramadol, for example, has µ-receptor agonist and norepi-
nephrine and serotonin reuptake inhibitor activity. Other
patches and creams such as lidocaine or capsaicin can also be
useful second line options.
Conclusion
The etiologies of peripheral nerve vasculitis are diverse and
may be the result of systemic vasculitis or secondary to
connective tissue disease, viral infections, drug-related, or
paraneoplastic disorders. NSVN is a separate category in which
vasculitis is isolated to the PNS. Early recognition of the
vasculitic neuropathies is of utmost importance, as delay in
diagnosis, especially in the systemic vasculitides, can result in
significant disability and death. Initial induction treatment for
vasculitic neuropathies is usually corticosteroids, often with
cyclophosphamide, rituximab, or methotrexate. Other immu-
nosuppressants and immunomodulatory therapies have been
used for the maintenance phase of treatment.
Conflict of Interest
None.
Acknowledgment
The authors would like to thank Dr. James Mandell for
providing ►Figs. 2 and 3.
Vasculitic Neuropathies Beachy et al. 615
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