Vasculitis is an immune-mediated disorder directed against blood vessels, which results in ischemia to end organs supplied by the affected blood vessels.^1–5 The vasculitides can be distinguished and classified based on at least three nosologic categories. They can be differentiated based on the caliber of vessel involved (i.e., small, medium, or large vessel). They can be distinguished on whether the disorder is primary [e.g., polyarteritis nodosa (PAN), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GAN, formerly known as Wegener granulomatosis), and Churg–Strauss syndrome (CSS)] or secondary to other systemic disorders (e.g., connective tissue disease, malignancy, infection, or drug reaction). Furthermore, the vasculitides can be separated based on whether they are systemic or isolated to the peripheral nervous system (PNS), and if associated with antineutrophil cytoplasmic antibodies (ANCAs) (Table 15-1).^2,3 Vasculitis is much more common in adults but can develop in children.⁶

PNS vasculitis can present as (1) a mononeuropathy or multiple mononeuropathies, (2) overlapping mononeuropathies, or (3) distal symmetric polyneuropathies (Fig. 15-1).^3–8 In the first pattern, patients may present with just a mononeuropathy, but usually multiple nerves eventually become affected over time, giving a distinct asymmetric pattern of involvement in the distribution of individual nerves. With the second pattern, different nerves on both sides of the body are affected but to varying degrees, leading to a generalized, yet asymmetric, pattern of involvement. Finally, with gradual progression, somewhat uniform and generalized involvement of peripheral nerves results in what looks like a distal symmetric polyneuropathy. Approximately 60–70% of patients present with mononeuropathy or multiple mononeuropathies (multifocal neuropathy or mononeuropathy multiplex pattern), while 30–40% of patients present as a distal symmetric polyneuropathy.⁷ There is a large differential diagnosis of patients with a multiple mononeuropathy (Table 15-2). For this reason, multifocal neuropathy, multiple mononeuropathies, or mononeuropathy multiplex are preferable terminologies to mononeuritis multiplex because the latter term implies a histologically defined disorder rather than a clinically defined syndrome.

Patients usually complain of burning or tingling pain in the distribution of the affected nerve(s). On examination, weakness and sensory loss are evident as well. Rare patients have purely sensory symptoms and signs.⁹ Muscle stretch reflexes may be normal or diminished, depending on whether or not the involved nerve innervating is in a reflex arc. For example, involvement of the sciatic nerve would lead to a diminished ankle jerk, but a median nerve infarct would not result in a loss of a biceps or triceps reflex.

Most patients have elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP).^2,10 Some vasculitides are associated with ANCAs, antinuclear antibodies (ANAs), cryoglobulins, rheumatoid factor, leukocytosis, and anemia. ANCAs are of particular importance as they are 85% sensitive and 99% specific for vasculitis.¹¹ The ANCAs are subclassified as cytoplasmic (cANCA) or perinuclear (pANCA) based on their immunofluorescence staining pattern and antigenic target; cANCAs are directed against proteinase 3 (PR3), while pANCAs target myeloperoxidase (MPO). PR3/cANCA is associated with granulomatosis with polyangiitis, while MPO/pANCA is typically associated with MPA, CSS, and less commonly PAN. MPO/pANCA has also been seen in minocycline-induced vasculitis.

Affected nerves may appear enlarged and hypoechoic with ultrasound.^12–14 MR imaging may also be useful to identify nerve lesions.^15,16 Motor and sensory nerve conduction studies demonstrate unobtainable potentials or reduced amplitudes.^{3,7,8,17–20} In particular, it is important to look for side-to-side asymmetries in amplitudes that reflect the multifocal nature of the pathology. Distal latencies are normal or slightly prolonged, while conduction velocities are normal or only mildly reduced. Conduction block or pseudoconduction block may be demonstrated in some affected nerves.^21–24 The presence of conduction block or temporal dispersion in a patient with a multifocal neuropathy pattern should suggest a disorder such as the multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy variant of chronic inflammatory demyelinating polyneuropathy (CIDP). The needle electromyography (EMG) reveals denervation changes in affected muscle groups. Again, the EMG abnormalities are often also asymmetric.

The sural, superficial peroneal (sensory branch), and superficial radial sensory nerves are the most common nerves that are biopsied.^1,4,5,25 Suspected vasculitis is one of the few clinical situations in which we routinely perform nerve biopsy. We usually biopsy the superficial peroneal nerve, if it is involved clinically and by nerve conduction studies (NCS). This is because the peroneus brevis muscle can also be biopsied from the same incision site, and the diagnostic yield is increased when the nerve and muscle both are biopsied (Fig. 15-2).^5,25–27 Diagnostic criteria for pathologically definite vasculitis include transmural inflammatory cell infiltration and fibrinoid necrosis of the vessel wall (Fig. 15-3).^{1,4,7,19,28–31} Supportive features of acute vasculitis also include loss or fragmentation of internal elastic lamina and loss/fragmentation/separation of smooth muscles in the media (can be highlighted by elastin and antismooth muscle actin staining), vascular or perivascular hemorrhage, acute thrombosis, and leukocytoclasia. Immunocytochemistry may reveal immunoglobulin (IgM and/or IgG), complement, and membrane attack complex deposition on blood vessels.³² Signs of repair may be seen in chronic vasculitis and include intimal hyperplasia, fibrosis of media, adventitial/periadventitial fibrosis, and recanalization of the lumen. Common findings are asymmetrical nerve fiber loss between and within individual nerve fascicles and active axonal degeneration. Nerve biopsies can also demonstrate immunostaining for the receptor for advanced glycosylation end products, nuclear factor-kappaB, and interleukin-6 that are expressed by CD4(+), CD8(+), and CD68(+) cells invading nerves. Immunostaining can be identified in mononuclear cells, epineurial and endoneurial vessels, and in the perineurium.³³ This data suggest that the receptor for advanced glycosylation end products pathway plays a critical proinflammatory role in vasculitic neuropathy. Matrix metalloproteinases (e.g., MMP-9) are upregulated as well and may play an important role as means for inflammatory cell invasion.³⁴ In addition to vasculitis, muscle biopsies may show evidence of muscle infarction (Fig. 15-4). Skin biopsies have also demonstrated reduced epidermal nerve fiber density in some cases of vasculitic neuropathy.^26,35,36

GIANT CELL VASCULITIS

Temporal arteritis and Takayasu arteritis are the two forms of giant cell arteritis, but peripheral neuropathy only occurs in the setting of temporal arteritis.^10,37 Giant cell arteritis affects medium- and large-sized vessels, particularly the aortic arch and the internal and external carotid arteries, and the vertebral arteries. Patients may present with headaches, jaw and tongue claudication, generalized myalgias, vision loss secondary to ischemic optic neuropathy, or stroke. Approximately 14% of patients develop multifocal neuropathy/multiple mononeuropathies, radiculopathies, plexopathies, or a generalized sensorimotor peripheral neuropathy.¹⁰ The temporal artery is often tender and a palpable cord can be felt. Ultrasound of the arteries may reveal thickening. Temporal artery biopsies reveal inflammatory infiltrate with giant cells in only two-thirds of suspected cases. Patients generally respond quite well to treatment with corticosteroids.

POLYARTERITIS NODOSA

PAN, the most common of the necrotizing vasculitides, is a systemic disorder involving small- and medium-caliber arteries in multiple organs.^1,2,4,11,28 PAN has an incidence ranging from 2 to 9 per million and usually presents between 40 and 60 years of age. The most common pattern of nerve involvement is multifocal neuropathy/multiple mononeuropathies. The sciatic nerve or its peroneal or tibial branches are the most frequently involved nerves. Cranial neuropathies and central nervous system (CNS) involvement are rare, occurring in <2% of patients.² Other organ systems affected include the heart, liver, kidneys, gastrointestinal that may lead to liver or renal failure, abdominal pain, and gastrointestinal bleeding. Notably, the lungs are generally spared. Myalgias and arthralgias occur in 30–70% of patients. Vasculitis involving the skin results in petechiae, livedo reticularis, subcutaneous nodules, and distal gangrene.³⁸ Orchitis is also a common complication. Constitutional symptoms include weight loss, fever, and loss of appetite.

Although not as commonly found as in MPA and CSS, approximately 10–20% of PAN patients have MPO/pANCA. An elevated ESR is seen in the majority of patients.² One-third of cases are associated with hepatitis B antigenemia,^2,38 but PAN can also complicate hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections.^2,39 Abdominal angiograms can reveal a vasculitic aneurysm, a useful finding in patients with nondiagnostic biopsies.

Medium-sized arteries are usually affected; however, smaller-sized vessels can be involved in PAN.^2,4 Nerve biopsies may demonstrate transmural infiltration of CD8+ T cells, macrophages, and polymorphonuclear cells along with fibrinoid necrosis of the vessel wall. IgM, IgG, complement, and membrane attack complex deposition may be appreciated on blood vessels. Unlike CSS, granulomas and eosinophilic infiltration are not seen on nerve biopsies in PAN. The pathogenic mechanism of PAN is unknown, although a T cell–dependent process with secondary complement-mediated vascular damage has been postulated.⁴

CHURG-STRAUSS SYNDROME (ALLERGIC ANGIITIS/GRANULOMATOSIS)

CSS manifests with signs and symptoms similar to PAN except that respiratory involvement is common in CSS.^1,2,40–44 The incidence of CSS is about one-third that of PAN, but the frequency of neurological complications is about the same. In this regard, multifocal neuropathy/multiple mononeuropathies develop in as many as 75% of individuals who are affected.² People with CSS typically present with allergic rhinitis, nasal polyposis, sinusitis, and late-onset asthma (after the age of 35 years). Symptoms and signs of systemic vasculitis occur an average of 3 years after the onset of asthma and even longer after the onset of nasal symptoms. Anywhere from 16% to 49% of patients with CSS develop a necrotizing glomerulonephritis as opposed to an ischemic nephropathy that can complicate PAN. Several cases of CSS have been reported in patients treated with leukotriene antagonists after weaning corticosteroids.⁴⁵

Routine laboratory workup reveals eosinophilia, leukocytosis, elevated ESR, CRP, rheumatoid factor, and serum IgG and IgE levels. One should consider CSS in any patient with a neuropathy and peripheral eosinophilia. Approximately two-thirds of individuals who are affected have MPO/pANCA.^2,11 Chest x-rays reveal that pulmonary infiltrates are present in nearly half of patients.

Nerve biopsies may demonstrate necrotizing vasculitis with CD8+ cytotoxic T lymphocytes, CD4+ cells and, to a lesser extent, eosinophilic infiltrates (Fig. 15-5).^2,42,46 In addition, intravascular and extravascular granulomas are occasionally found in and around affected blood vessels.

GRANULOMATOSIS WITH POLYANGIITIS

Granulomatosis with polyangiitis (GAN) was formerly referred to as Wegener granulomatosis. The latter term is no longer recommended as Dr. Wegener was a high-ranking Nazi physician, and the facility he was assigned to in Poland was associated with unethical humane experimentation. GAN is characterized by necrotizing vasculitis and granulomas involving the upper and lower respiratory tract and kidneys (glomerulonephritis).^1,4,47–54 Early respiratory symptoms (e.g., nasal discharge, cough, hemoptysis, and dyspnea) can help distinguish this from other vasculitides. In a large prospective study of 128 patients with granulomatosis with polyangiitis, 64 patients (50%) developed CNS or PNS involvement.⁴⁷ Peripheral neuropathy occurred in 56 patients and in 9 cases the CNS was involved. Thirty-one patients had a distal symmetric polyneuropathy, while 25 had multifocal neuropathy/multiple mononeuropathies. Neuropathy is more common in patients with severe renal involvement.⁵¹ Cranial neuropathies, particularly the second, sixth, and seventh nerves, develop in approximately 5–10% of cases as a result of extension of the nasal or paranasal granulomas rather than vasculitis.^47,53

The majority of affected individuals have PR3/cANCAs, and this test has a specificity of 98% and sensitivity of 95%.⁵¹ The histological appearance of the vasculitis is similar to PAN, with involvement of medium- and small-sized blood vessels. In addition, granulomatous infiltration of the respiratory tract and necrotizing glomerulonephritis are also seen. The absence of peripheral eosinophilia, eosinophilic infiltrates on biopsy, and asthma help distinguish granulomatosis with polyangiitis from CSS.

MICROSCOPIC POLYANGIITIS

MPA clinically resembles PAN and CSS, except that diffuse alveolar damage and interstitial fibrosis develop due to involvement of pulmonary capillaries.^{1,2,4,42,43,55} The incidence of MPA is about one-third that of PAN. The average age of onset is 50 years and polyneuropathy complicates MPA in 14–36% of cases.^2,4,55