Clinical manifestations and diagnosis of vasculitic neuropathies

INTRODUCTION — Vasculitis can affect any organ or tissue, including the peripheral nerves. When vasculitis affects the epineurial and endoneurial vessels supplying peripheral nerves, inflammation and subsequent critical ischemia result in nerve damage with potentially profound clinical sequelae.

Vasculitic neuropathy is usually only one feature of a systemic vasculitis that can involve the skin, lungs, kidneys, and other organs. Although many systemic vasculitides can cause neuropathy, those that affect either small- or medium-sized arteries are the most commonly implicated. Examples include the group of vasculitic disorders commonly associated with antineutrophil cytoplasmic autoantibodies (ANCA; ie, granulomatosis with polyangiitis [GPA], microscopic polyangiitis [MPA], and eosinophilic granulomatosis with polyangiitis [EGPA; Churg-Strauss]), polyarteritis nodosa (PAN), and mixed cryoglobulinemia.

In a minority of patients with vasculitic neuropathy, the peripheral nervous system is the only site of involvement. In this setting, the disorder is referred to as nonsystemic vasculitic neuropathy or isolated peripheral nervous system vasculitis [1-4].

This topic will review the clinical manifestations and diagnosis of systemic and nonsystemic vasculitic neuropathy. The treatment of nonvasculitic neuropathy is presented separately. (See "Treatment and prognosis of nonsystemic vasculitic neuropathy".)

PATHOGENESIS — Vasculitis is a heterogeneous group of disorders, and understanding of the initial pathogenetic events in specific vasculitides remains incomplete. (See "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis" and "Overview of cryoglobulins and cryoglobulinemia", section on 'Etiopathogenesis' and "Pathogenesis of giant cell arteritis" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Pathogenesis'.)

When the peripheral nervous system is involved by vasculitis, the two main pathways that lead to ischemic vasculitic nerve damage are immune complex deposition and cell-mediated immunity [5,6]:

●Immune complex deposition – Immune complex deposition within the vessel walls can cause complement deposition and release of proinflammatory cytokines. Persistent inflammation within the vessel wall causes vascular injury. Immune complex-mediated injury is relevant to the pathophysiology of mixed cryoglobulinemia and at least some cases of polyarteritis nodosa (PAN), particularly those associated with hepatitis B.

●Cell-mediated immunity – Cell-mediated immunity occurs when antigen-presenting cells (including perhaps, in some cases, endothelial cells) present relevant antigens to circulating T cells. These interactions result in the production of proinflammatory cytokines, cell adhesion molecules, and other inflammatory mediators that cause neutrophils and lymphocytes to adhere to and injure the blood vessel.

In addition to these two major pathways, other mechanisms such as neutrophil degranulation and release of toxic granules may also contribute to specific forms of vasculitis. Immune complex- and cell-mediated immunity pathways are not mutually exclusive, and the degree to which each is implicated in peripheral nerve injury likely varies across different vasculitides. As an example, in a study of nerve biopsy specimens from patients with hepatitis C virus-related mixed cryoglobulinemia, which is associated with prominent immune complex deposition, expression of messenger ribonucleic acid (mRNA) was markedly increased for various T-cell inflammatory mediators, including interferon gamma, tumor necrosis factor (TNF)-alpha, and macrophage inflammatory protein-1 alpha [7].

ETIOLOGY AND CLASSIFICATION — Neuropathies caused by vasculitis are a heterogeneous group of disorders that can be associated with a systemic vasculitis or, more rarely, a vasculitis that is confined to the peripheral nervous system. There are many different classification schemes to describe and group the various neuropathies from vasculitis, which include the International Chapel Hill Consensus Conference (CHCC) nomenclature system [8], the Peripheral Nerve Society Task Force classification system (table 1) [9], and classification based on the size of the involved vessel (ie, nerve large arteriole vasculitis versus nerve microvasculitis) [10].

Systemic vasculitides associated with neuropathy — Neuropathy from vasculitis can occur in association with both primary systemic vasculitides and with secondary systemic vasculitides related to various underlying diseases such as rheumatologic diseases or infection.

In general, neuropathy from vasculitis is usually observed as part of a systemic disease. As an example, in a review of 106 patients with vasculitis-associated neuropathy compiled at one center over a period of 28 years, 95 patients had systemic vasculitis compared with 11 who had vasculitis confined to the peripheral nervous system [4].

●Primary systemic vasculitides – The primary systemic vasculitides are generally classified according to the predominant size of the vessel involved (figure 1), although there is often some overlap in the size of the arteries involved with all of these diseases. (See "Overview of and approach to the vasculitides in adults", section on 'Major categories of vasculitis'.)

In general, the vasculitides that involve arterioles and small- and medium-sized arteries are more frequently associated with neuropathy compared with large-vessel disease (table 1). This is the case even though, at the level of the peripheral nervous system, the involved epineurial and endoneurial vessels are all considered small in caliber.

When peripheral neuropathy is present, neuropathic symptoms are often a major clinical feature that occurs in the early phases of disease and therefore carry important diagnostic value [11]. The primary systemic vasculitides most often complicated by vasculitic neuropathy include:

•Polyarteritis nodosa (PAN) – Neuropathy occurs in 50 to 75 percent of patients with PAN and is one of the most common clinical manifestations, along with skin and renal involvement. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Neurologic disease'.)

•Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides – Neuropathy is a common feature of most of the ANCA-associated vasculitides and is associated with more severe disease. The estimated incidence of peripheral nervous system involvement varies widely, in part due to the rarity of the diseases themselves [11]:

-Eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss) – 50 to 75 percent (see "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Neurologic')

-Granulomatosis with polyangiitis (GPA) – 11 to 67 percent (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Neurologic involvement')

-Microscopic polyangiitis (MPA) – 10 to 58 percent (see "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis", section on 'Neurologic involvement')

●Secondary systemic vasculitides – Vasculitic neuropathies can present in association with systemic rheumatic diseases, including:

•Systemic lupus erythematosus (SLE) – (See "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system", section on 'Peripheral neuropathies'.)

•Rheumatoid arthritis (RA) – 20 to 40 percent of patients with rheumatoid vasculitis. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Neurologic disease'.)

•Sjögren's disease – (See "Neurologic manifestations of Sjögren's disease", section on 'Peripheral nervous system disorders'.)

•Cryoglobulinemia – Peripheral neuropathy occurs in up to 60 percent of patients with mixed cryoglobulinemia syndrome, a secondary vasculitis caused by deposition of circulating cryoglobulins and often associated with hepatitis C, hepatitis B, or human immunodeficiency virus (HIV) infection. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis", section on 'Overview of typical findings'.)

Other major categories of secondary systemic vasculitis that can result in vasculitic neuropathy include malignancy, drugs, inflammatory bowel disease, and hypocomplementemic urticarial vasculitis syndrome. (See "Urticarial vasculitis", section on 'Other organ systems'.)

Nonsystemic vasculitic neuropathy — Nonsystemic vasculitic neuropathy accounts for a minority of those with vasculitic neuropathy [4,12]. This disorder is likely part of the spectrum of single-organ vasculitis (such as isolated vasculitis of the gallbladder or uterus).

Patients with vasculitis that is localized to the peripheral nervous system at presentation must be followed closely for signs of other organ involvement. Approximately 10 percent of patients initially diagnosed as having nonsystemic vasculitic neuropathy eventually develop vasculitis in other organs and are then diagnosed with a systemic disorder [10,13].

Of note, diabetic radiculoplexus neuropathy (also called diabetic amyotrophy, Bruns-Garland syndrome) and its variants are likely caused by ischemic injury from microvasculitis. While historically considered separately from nonsystemic vasculitic neuropathy, diabetic radiculoplexus neuropathy is now classified as a form of nonsystemic vasculitic neuropathy. (See "Epidemiology and classification of diabetic neuropathy" and "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)

CLINICAL FEATURES

Presenting neurologic symptoms — Vasculitic neuropathy typically presents acutely as a focal, painful neuropathy that progresses subacutely over days to weeks to involve other regions of the body with objective sensory or sensorimotor deficits on serial examinations (figure 2). A more acute course over days or a chronic relapsing course over weeks can also be seen. Vasculitic neuropathy is characteristically patchy, and therefore pain, numbness, and weakness are usually asymmetric.

Pain is a sensitive feature of vasculitic neuropathy and is present in more than 90 percent of patients [14]. The pain is typically of severe intensity and can start as a sharp achy pain that evolves to have more typical neuropathic features such as burning, tingling, and a warm/cold sensation [10].

In addition to pain, most patients also experience numbness or paresthesias in the affected nerve distributions, as well as weakness. While isolated sensory vasculitic neuropathy has been described, most patients have mixed sensorimotor neuropathy with sensory loss and weakness.

Patterns of nerve involvement — There are three primary patterns of vasculitic neuropathy, which include multiple mononeuropathy (also called mononeuritis multiplex), distal sensorimotor polyneuropathy, and plexopathy. Many patients have mixed, overlapping features, and asymmetry in neuropathy between limbs either on examination or by history is often the most useful clinical feature to elicit.

Multiple mononeuropathy — Vasculitic neuropathy classically presents as multiple mononeuropathy (also called mononeuritis multiplex), which refers to an anatomic pattern of peripheral neuropathy that affects two or more noncontiguous named nerves simultaneously or sequentially [15].

Nerves of the lower extremity are often affected first in vasculitic neuropathy, usually in the peroneal or tibial distribution, though the actual site of nerve infarction may be more proximal in the course of the sciatic nerve [10,16]. Peroneal neuropathy causes weakness of ankle dorsiflexion ("foot drop"), which patients may be unaware of if the weakness is mild. Weakness is more evident while observing the patient walking; patients with tibialis anterior weakness raise their knee on the affected side to avoid tripping over the weakened foot, leading to a "foot-slapping" gait. Having the patient walk on their heels can also bring out more subtle foot dorsiflexion weakness.

As time progresses, other peripheral nerves are affected, including ulnar (causing numbness in the fourth and fifth digits and/or hand weakness and atrophy (picture 1)); radial (causing wrist extension weakness (picture 2), or "wrist drop," and numbness on the dorsum of the hand and forearm); median (causing numbness in the palm and/or first three digits of the hand and thumb weakness); femoral (causing quadriceps weakness and numbness in the anteromedial thigh); and, more rarely, cranial nerves such as the trigeminal nerve (causing facial pain and numbness) or oculomotor nerves (causing diplopia). Nerve infarction often leads to muscle wasting (atrophy), which, in many cases, is permanent (picture 1).

The finding of multiple mononeuropathy is suggestive of but not specific for vasculitis. Other causes of mononeuropathy multiplex are reviewed below. (See 'Differential diagnosis' below.)

In many patients, by the time of evaluation, the confluence of sequential neuropathies causes clinical findings suggestive of a generalized axonal polyneuropathy with some asymmetry, rather than multiple mononeuropathy (figure 2). The focal nature of disease onset and progression may be evident only by history.

Distal sensorimotor polyneuropathy — In approximately 20 to 30 percent of patients, vasculitic neuropathy presents as a distal, seemingly symmetric sensorimotor polyneuropathy that is painful and progressive [10,17]. There is a length-dependent pattern of involvement of multiple somatic nerves, beginning distally (in the feet) and spreading proximally to involve the lower legs, fingers, and hands.

Although clinically the neuropathy may appear symmetric, electromyography (EMG) with nerve conduction velocity testing often reveals greater asymmetry to the process than appreciated on clinical examination.

Radiculopathy and/or plexopathy — While radiculopathies and plexopathies have been documented in association with systemic vasculitides such as polyarteritis nodosa (PAN) [18], this presentation is most characteristic of the microvasculitis syndrome of diabetic radiculoplexus neuropathy (now classified as a nonsystemic vasculitic neuropathy).

In its most typical form, patients present with the acute onset of unilateral sharp pain in the thigh that evolves to include the entire leg. Over the course of days to weeks, weakness occurs in the affected leg, not respecting individual nerve distribution (hence plexopathy) and usually severe enough to require a walking aid [19]. Examination clinically and by EMG often shows paraspinal denervation (suggesting radicular injury). There is frequent autonomic dysfunction and weight loss.

Over the course of months, the same syndrome spreads to the other leg in the majority of patients. Unlike other microvascular complications of diabetes, such as retinopathy or peripheral neuropathy, patients typically have had well-controlled diabetes for only a few years. (See "Diabetic amyotrophy and idiopathic lumbosacral radiculoplexus neuropathy".)

While initially described in diabetics, this same syndrome has been observed as a presentation of vasculitic neuropathy in nondiabetics and in the arms. (See "Brachial plexus syndromes", section on 'Diabetic-related brachial plexopathy'.)

Systemic features — Constitutional symptoms such as fever, malaise, and weight loss are present in most patients with systemic vasculitis. These symptoms are less common and milder in patients with nonsystemic vasculitic neuropathy, with weight loss and fever observed in approximately 30 and 10 to 15 percent of patients, respectively [13].

Specific organ involvement beyond the peripheral nerves may also provide a clue to the presence of an underlying disorder. As examples:

●Palpable purpura (picture 3) or skin ulcers are found in primary vasculitides associated with small- or medium-vessel vasculitis (eg, hypersensitivity vasculitis or granulomatosis with polyangiitis [GPA]). (See "Overview of and approach to the vasculitides in adults", section on 'Major categories of vasculitis'.)

●Respiratory tract involvement is consistent with some form of antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (eg, destructive upper airway lesions in GPA; asthma, allergic rhinitis, and/or nasal polyps in eosinophilic granulomatosis with polyangiitis [EGPA; Churg-Strauss]; and alveolar hemorrhage in all forms). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Respiratory tract involvement" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Asthma and lung disease'.)

●Intestinal angina may signal the presence of medium-vessel mesenteric vasculitis, as found in PAN. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Gastrointestinal disease'.)

Histopathology — Inflammation of blood vessel wall resulting in ischemic nerve injury causing axonal loss is the main histopathologic feature of vasculitic neuropathy (picture 4). The small epineurial arterioles are predominantly affected in most cases of vasculitic neuropathy [20]. Nonsystemic vasculitic neuropathy tends to affect smaller vessels (causing a microvasculitis).

The histopathologic findings depend on the stage of vasculitis. In active disease, there is lymphoplasmacytic infiltration of the vessel wall with signs of vascular damage such as fibrinoid necrosis, thrombosis, vascular/perivascular hemorrhage, leukocytoclasia, or loss/disruption of endothelium, internal elastic lamina, or smooth muscle cells in media (picture 5 and picture 6) [9]. In more chronic lesions, vascular findings indicative of chronicity such as intimal hyperplasia, medial fibrosis, or thrombosis with recanalization can be found. Note that epineurial perivascular inflammatory cell collection is nonspecific and found in multiple other diseases, including chronic inflammatory demyelinating polyneuropathy.

The histopathologic findings are typically not specific for a cause of vasculitis. Infrequently, more specific findings point to a cause such as eosinophilia in EGPA (picture 7) or granulomas in GPA. In addition to vascular inflammation and injury, the nerve parenchyma is typically injured as well. Infarction of the peripheral nerve is rarely found. More commonly, foci of Wallerian-type degeneration are distributed heterogeneously in location among the different nerve fascicles, indicative of variable vascular injury.

DIAGNOSTIC EVALUATION — The diagnostic evaluation of the patient with suspected vasculitic neuropathy includes a thorough medical history, physical examination, selected laboratory tests, and neurophysiologic testing with nerve conduction studies and electromyography (EMG). Nerve biopsy, which is often performed in conjunction with muscle biopsy, is generally performed when an associated systemic vasculitis is not suspected or when there is diagnostic uncertainty.

History — A thorough review of systems should include questions related to the other organs commonly involved by systemic vasculitis, particularly the eyes (redness, pain, visual loss); ears (hearing dysfunction, otalgia); nose (congestion, crusts, epistaxis); mouth (oral ulcers, gum inflammation); lungs (cough, hemoptysis); and skin (rash, livedo reticularis, ulcers). (See "Overview of and approach to the vasculitides in adults" and "Vasculitis in children: Incidence and classification".)

Examination — A thorough physical examination may detect findings compatible with an associated systemic disease (see 'Systemic vasculitides associated with neuropathy' above). Patients with vasculitic neuropathies may be unaware of focal nerve dysfunction, particularly if other organ manifestations such as arthritis, sinusitis, or skin ulcers dominate the clinical picture. Objective evidence of motor weakness, such as foot drop, wrist drop, or loss of deep tendon reflexes, should be sought.

Laboratory testing — The purpose of laboratory testing in cases of suspected vasculitic neuropathy is primarily to support or help exclude associated systemic conditions that may be suggested by the history and physical examination.

We perform the following basic laboratory tests in patients with suspected vasculitic neuropathy:

●Complete blood count and differential

●Serum creatinine and estimation of glomerular filtration rate

●Liver function tests

●Urinalysis, with microscopic examination of urinary sediment

●Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)

In patients without an established diagnosis of a systemic vasculitis, we also perform serologic assays to evaluate for underlying systemic rheumatic or infectious diseases:

●Antinuclear antibody (ANA) assay

●Antineutrophil cytoplasmic autoantibodies (ANCA), with testing for anti-proteinase 3 (anti-PR3) and anti-myeloperoxidase (anti-MPO) antibodies

●Antibodies to double-stranded deoxyribonucleic acid (dsDNA)

●Antibodies to extractable nuclear antigens (anti-Sm and anti-ribonucleoprotein [RNP])

●Anti-Ro/SSA, anti-La/SSB

●Antiphospholipid antibodies (lupus anticoagulant [LA], immunoglobulin G [IgG], and IgM anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2-glycoprotein [GP] I)

●Complement components (C3 and C4)

●Rheumatoid factor (RF)

●Serum cryoglobulins

●Serum and urine protein electrophoresis with immune electrophoresis

●Tests for hepatitis B virus, hepatitis C virus, and HIV infections

●Lyme disease assays

●Serum creatine kinase (CK)

The presence of ANA is nonspecific but compatible with the presence of a connective tissue disease, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), or Sjögren's disease. Patients with cryoglobulinemia and ANCA-associated vasculitides may also be ANA positive. If the ANA titer is high (eg, >1:160), further investigation is indicated to more precisely define the specific antibody responsible. (See "Measurement and clinical significance of antinuclear antibodies".)

The presence of autoantibodies to dsDNA, Sm antigen, or RNP is compatible with, but is not diagnostic of, SLE. The presence of antibodies to Ro/SSA or La/SSB antigens can be seen in patients with Sjögren's disease or in those with SLE. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP" and "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems".)

A positive ANCA test is seen in the majority of patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA), as well as in a substantial proportion of those with eosinophilic granulomatosis with polyangiitis (EGPA; Churg-Strauss). By contrast, patients with classic polyarteritis nodosa (PAN) are ANCA negative. However, ANCA positivity alone is not sufficient to make a diagnosis, and ANCA positivity without corresponding seropositivity of anti-PR3 or anti-MPO antibodies may not have pathologic significance. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

In mixed cryoglobulinemia, in which the precipitate is generally comprised of monoclonal IgM and polyclonal IgG components, the IgM invariably demonstrates RF activity (ie, reactivity to the Fc portion of IgG). As a result, all patients with mixed cryoglobulinemia are RF positive, often strikingly so. RF positivity is also observed in some patients with RA. (See "Overview of cryoglobulins and cryoglobulinemia".)

Electrodiagnostic studies — Nerve conduction studies and EMG (NCS/EMG) are usually performed in patients with suspected vasculitic neuropathy to complement the clinical history and examination, to exclude mimics such as chronic inflammatory demyelinating polyneuropathy (CIDP), and to help guide selection of a biopsy site, if necessary.

Electrodiagnostic testing in vasculitic neuropathy is consistent with axonal damage involving multiple individual nerves in an asymmetric fashion. More proximal axonal involvement at the level of nerve roots or of the cervical or lumbar nerve plexus can also occur. Findings suggestive of a demyelinating process, rather than an axonal process, are not consistent with vasculitic neuropathies and should prompt additional diagnostic evaluation. (See "Overview of polyneuropathy", section on 'Identifying the etiology'.)

The following electrodiagnostic features are typically noted in vasculitic neuropathy [3,21-23]:

●Nerve conduction studies in patients with vasculitic neuropathy reveal low-amplitude sensory nerve action potentials, low-amplitude compound muscle action potentials, and either normal or slightly slow nerve conduction velocities. (See "Overview of nerve conduction studies", section on 'Axonal degeneration'.)

●Electromyographic examination of affected muscle may show diffuse signs of denervation with fibrillations and positive sharp waves. (See "Overview of electromyography", section on 'Motor neuronopathies'.)

●The pattern of nerve involvement may be consistent with multiple mononeuropathies, distal sensorimotor polyneuropathy, or more rarely radiculopathy or plexopathy (figure 2). (See 'Patterns of nerve involvement' above.)

Additional testing in selected patients

Lumbar puncture — Lumbar puncture is not routinely required in all patients with suspected vasculitic neuropathy but should be considered in patients with atypical clinical features such as proximal signs and symptoms, electrodiagnostic evidence of proximal involvement or demyelinating features, or clinically suspected malignancy or meningeal infection [9].

Other tests in patients without systemic vasculitis — In patients without preliminary evidence of a systemic vasculitis, in whom a diagnosis of nonsystemic vasculitic neuropathy is being considered, it may be reasonable to perform additional selected tests before proceeding with nerve/muscle biopsy if there are other clinical clues to suggest a more systemic process. Examples may include lumbar puncture, paraneoplastic antibodies, porphyria screen, genetic testing for PMP22 deletion (hereditary neuropathy with liability to pressure palsies), transthyretin gene testing, chest computed tomography (CT), visceral angiography, and additional body imaging for malignancy. (See 'Lumbar puncture' above and 'Differential diagnosis' below.)

Nerve/muscle biopsy — Nerve biopsy is required to diagnose nonsystemic vasculitic neuropathy. If the neuropathy is presenting as part of an already known systemic vasculitis and the clinical features are typical of vasculitic neuropathy, then a biopsy is not necessary. However, if the neuropathy is the first manifestation of a suspected systemic vasculitis or when other investigations fail to diagnose vasculitis, then a nerve and muscle biopsy should be performed.

Biopsies are generally performed on superficial sensory nerves that are affected clinically or electrodiagnostically [9,24]. A combined nerve/muscle biopsy is often performed, as vasculitis can pathologically involve both nerve and adjacent muscle and combined tissue increases the diagnostic yield of finding definite vasculitis [25]. The sural nerve, a sensory nerve in the posterior calf, is a common nerve to biopsy in combination with the adjacent gastrocnemius muscle. Superficial peroneal nerve-peroneus brevis muscle is another common site for biopsy [26]. In the upper extremities, the superficial radial nerve can be biopsied.

Serial sections of the entire length of the biopsied nerve and muscle should be examined by an experienced neuropathologist. Even with appropriately targeted combined nerve/muscle biopsies, the sensitivity of biopsy for vasculitis is only approximately 60 percent [26,27]. Hallmark histopathologic findings of vasculitis include inflammation of blood vessel wall and evidence of vascular damage resulting in ischemic nerve injury and axonal loss. (See 'Histopathology' above.)

Because of the patchy nature of the disease, often all the findings of definite vasculitic neuropathy cannot be demonstrated in a biopsy sample. If the clinical history and pattern of nerve injury (axonal degeneration) are compelling, pathologic predictors can be used to reach a pathologic diagnosis of probable or possible vasculitic neuropathy. These predictors include vascular deposition of complement, IgM, or fibrinogen; myofiber necrosis or infarcts; and asymmetric/multifocal nerve fiber loss from axonal degeneration [9].

DIAGNOSIS

Neuropathy due to systemic vasculitis — Neuropathy due to a systemic vasculitis is most commonly a clinical diagnosis based on the presence of neuropathy with clinical features that are typical for vasculitic neuropathy in the setting of an established or newly diagnosed primary or secondary systemic vasculitis. Nerve/muscle biopsy is usually not required.

Typical clinical features of vasculitic neuropathy as defined by the Peripheral Nerve Society case definition include sensory or sensorimotor involvement; asymmetry and/or multifocality; lower limb predominance; distal predominance; pain; acute relapsing course; and electrodiagnostic evidence of an axonal, sensorimotor or sensory neuropathy [9]. Features that are not consistent with vasculitic neuropathy include purely motor signs and symptoms; entirely proximal signs and symptoms; lack of asymmetry by history, examination, or electrodiagnostic testing; and nonaxonal (demyelinating) features on electrodiagnostic testing. (See 'Clinical Features' above.)

In cases of diagnostic uncertainty, a biopsy of the nerve and muscle can help confirm the presence of a vasculitic neuropathy in a patient with known or suspected systemic vasculitis. (See 'Nerve/muscle biopsy' above.)

Nonsystemic vasculitic neuropathy — The diagnosis of nonsystemic vasculitic neuropathy largely depends on histopathologic evidence of vasculitis involving the peripheral nervous system and the exclusion of other known associated diseases. Nerve biopsy is required for diagnosis, except in cases of a diabetic radiculoplexus neuropathy phenotype.

The case definition proposed by the Peripheral Nerve Society for a diagnosis of nonsystemic vasculitic neuropathy required all of the following [9]:

●Nerve biopsy showing intramural inflammation accompanied by pathologic evidence of vascular wall damage. (See 'Histopathology' above.)

●Typical clinical features of vasculitic neuropathy (sensory or sensorimotor involvement; asymmetry and/or multifocality; lower limb predominance; distal predominance; pain; acute relapsing course; and electrodiagnostic evidence of an axonal, sensorimotor or sensory neuropathy). (See 'Clinical Features' above.)

●No atypical features (purely motor signs and symptoms; entirely proximal signs and symptoms; lack of asymmetry by history, examination, or electrodiagnostic testing; cerebrospinal fluid [CSF] pleocytosis; CSF protein >110 mg/dL).

●No evidence of another primary disease process that is known to be associated with vasculitic neuropathy or that can mimic vasculitis pathologically (eg, lymphoma, lymphomatoid granulomatosis, or amyloidosis). It is imperative that a full evaluation for other forms of vasculitis is performed in all patients suspected of having nonsystemic vasculitic neuropathy. (See 'Laboratory testing' above.)

As discussed above, all of the findings of definite vasculitic neuropathy may not be present on a biopsy sample because of the patchy nature of disease. In such cases, the clinician may rely on other pathologic findings that can be used as predictors to reach a diagnosis of probable or possible vasculitic neuropathy. (See 'Nerve/muscle biopsy' above.)

DIFFERENTIAL DIAGNOSIS — A variety of nonvasculitic etiologies must be considered in patients presenting with an acute to subacute asymmetric or multifocal neuropathy [28]. For some disorders, both vasculitic and nonvasculitic neuropathies can occur. In such cases, nerve biopsy may be needed as the presence of a vasculitic mechanism has implications for treatment strategy. Many of these neuropathies also feature pain as a prominent symptom.

Ischemic neuropathies:

●Livedoid vasculopathy [29] (see "Livedoid vasculopathy")

●Sickle cell anemia [30] (see "Overview of the clinical manifestations of sickle cell disease")

●Cholesterol emboli syndrome [31] (see "Embolism from atherosclerotic plaque: Atheroembolism (cholesterol crystal embolism)")

●Atrial myxoma [32] (see "Cardiac tumors")

Inflammatory/immune-mediated neuropathies:

●Sarcoidosis (occasionally associated with vasculitis) [33] (see "Neurologic sarcoidosis", section on 'Clinical features')

●Chronic inflammatory demyelinating polyneuropathy (CIDP), particularly the multifocal acquired demyelinating motor and sensory neuropathy (Lewis-Sumner syndrome) variant (see "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Asymmetric sensorimotor (multifocal)')

●Multifocal motor neuronopathy (see "Multifocal motor neuropathy")

●Multifocal variants of Guillain-Barré syndrome (see "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Variant forms of Guillain-Barré syndrome')

●Neuropathy associated with eosinophilic disorders (occasionally associated with vasculitis) (see "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Neurologic disease')

●Neuropathy associated with Crohn disease, ulcerative colitis, and celiac disease (occasionally associated with vasculitis) [34,35]

●Chronic graft-versus-host disease [36] (see "Clinical manifestations and diagnosis of chronic graft-versus-host disease")

Infectious/toxic neuropathies (occasionally or routinely associated with vasculitis):

●Leprosy (see "Leprosy: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Neuropathy')

●Lyme disease (see "Nervous system Lyme disease", section on 'Peripheral neuropathy')

●Viral (hepatitis C virus, hepatitis B virus, HIV, human T-cell lymphotropic virus type I, varicella-zoster virus, cytomegalovirus, parvovirus B19, Epstein-Barr virus, West Nile virus, measles), especially in immunocompromised patients

Drug-induced neuropathies (occasionally or routinely associated with vasculitis) (see "Overview of polyneuropathy", section on 'Toxic')

Genetic neuropathies:

●Hereditary neuropathy with liability to pressure palsies (see "Overview of hereditary neuropathies", section on 'Hereditary neuropathy with liability to pressure palsy')

●Hereditary neuralgic amyotrophy

●Charcot-Marie-Tooth neuropathies (see "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis")

●Porphyria (see "Porphyrias: An overview", section on 'Spectrum of neurovisceral manifestations')

●Familial amyloid neuropathy, including transthyretin amyloidosis (see "Overview of amyloidosis", section on 'Neurologic abnormalities')

●Tangier disease (see "Neuropathies associated with hereditary disorders", section on 'Tangier disease')

●Lysosomal diseases (see "Neuropathies associated with hereditary disorders", section on 'Lysosomal diseases')

●Mitochondrial disorders (see "Neuropathies associated with hereditary disorders", section on 'Mitochondrial disorders')

●Deficiency of adenosine deaminase 2 (causes an inflammatory vasculopathy that can include vasculitic neuropathy) [37]

Neuropathies related to neoplastic disease:

●Direct infiltration of nerves by tumor

●Paraneoplastic (vasculitic and nonvasculitic) (see "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle")

●Intravascular lymphoma or neurolymphomatosis (see "Intravascular large B cell lymphoma" and "Secondary central nervous system lymphoma: Clinical features and diagnosis", section on 'Neurolymphomatosis')

●Neoplastic meningitis (see "Clinical features and diagnosis of leptomeningeal disease from solid tumors")

●Primary immunoglobulin light chain (AL) amyloidosis (see "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis", section on 'Clinical presentation')

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

SUMMARY

●Pathogenesis – Vasculitic neuropathy results from inflammation of the epineurial and endoneurial vessels supplying peripheral nerves, resulting in ischemic nerve damage with potentially profound clinical sequelae. (See 'Introduction' above and 'Pathogenesis' above.)

●Classification – Neuropathies caused by vasculitis are a heterogeneous group of disorders that can be associated with a systemic vasculitis or, more rarely, a vasculitis that is confined to the peripheral nervous system. (See 'Etiology and classification' above.)

●Disease associations – The primary systemic vasculitides that involve arterioles and small- and medium-sized arteries are most frequently associated with neuropathy, including polyarteritis nodosa (PAN) and the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides. Vasculitic neuropathies are also common in association with secondary systemic vasculitis in patients with rheumatoid arthritis (RA) and other rheumatic diseases. (See 'Systemic vasculitides associated with neuropathy' above.)

Nonsystemic vasculitic neuropathy accounts for a minority of vasculitic neuropathy and is likely part of the spectrum of single-organ vasculitis. (See 'Nonsystemic vasculitic neuropathy' above.)

●Clinical presentation – Vasculitic neuropathy typically presents acutely as a focal, painful neuropathy that progresses over weeks to involve other regions of the body. Pain is a sensitive feature and is present in more than 90 percent of patients. The process is characteristically patchy, and therefore pain, numbness, and weakness are usually asymmetric. (See 'Presenting neurologic symptoms' above.)

Multiple mononeuropathy (also called mononeuritis multiplex) is the classic anatomic pattern of involvement of vasculitic neuropathy (figure 2). Less common patterns include distal, seemingly symmetric sensorimotor polyneuropathy; radiculopathy; and plexopathy. (See 'Patterns of nerve involvement' above.)

●Histopathology – The main histopathologic features of vasculitic neuropathy are intramural inflammation accompanied by evidence of vascular wall damage (picture 4). (See 'Histopathology' above.)

●Diagnosis – Systemic vasculitic neuropathy is usually diagnosed clinically based on the presence of neuropathy with clinical features that are typical for vasculitic neuropathy in the setting of an established or newly diagnosed primary or secondary systemic vasculitis. (See 'Neuropathy due to systemic vasculitis' above.)

The diagnosis of nonsystemic vasculitic neuropathy largely depends on histopathologic evidence of vasculitis involving the peripheral nervous system and the exclusion of other known associated diseases. Nerve biopsy is required for diagnosis. (See 'Nonsystemic vasculitic neuropathy' above.)

The diagnostic evaluation of a patient with suspected vasculitic neuropathy includes laboratory studies to support or exclude associated systemic vasculitic disorders, nerve conduction studies and electromyography (EMG), and nerve/muscle biopsy in selected patients. (See 'Diagnostic evaluation' above.)

●Differential diagnosis – A variety of nonvasculitic etiologies must be considered in patients presenting with an acute to subacute asymmetric or multifocal neuropathy. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Steven David Brass, MD, MPH, MBA, who contributed to an earlier version of this topic review.