Mononeuritis multiplex is regarded as the classic manifestation of vasculitic neuropathy, as the multifocal process affects nerves throughout the body (more often peroneal, ulnar, tibial, and the sural) including the cranial nerves. Patients experience an abrupt onset of pain, paresthesia, and paralysis in the distribution of a single nerve trunk evolving over hours to days, with newly involved nerves appearing over days to months. Atypical forms of presentation include pure sensory ataxia and radiculoplexopathy (Vrancken and Said 2013). When the lesions are disseminated, and their territories overlap, the presentation is in the form of an asymmetric polyneuropathy. Notwithstanding that biopsy is more likely to be performed in patients with mononeuritis multiplex, an acutely, subacutely, or chronically progressive symmetric distal sensorimotor polyneuropathy, where vasculitis is often not suspected, has been described in 19–76 % of biopsy-proven vasculitic neuropathies (Harati and Niakan 1986; Dyck et al. 1987; Hawke et al. 1991; Wees et al. 1981; Kissel et al. 1985; Panegyres et al. 1990; Said et al. 1988). This indicates that progressive symmetric distal polyneuropathy is a common clinical presentation of vasculitic neuropathy. Experience with vasculitic neuropathy at St. Michael’s Hospital includes 39 cases, for which adequate clinical information was available in 32. Fourteen (44 %) presented with a distal symmetrical pattern, 12 (38 %) with obvious mononeuritis multiplex, 5 (16 %) with asymmetrical polyneuropathy, and 1 was asymptomatic. Evolution can occur rapidly enough to result in an initial clinical diagnosis of GBS (Suggs et al. 1992).

Nerve conductions give evidence of axonal abnormalities and are invaluable for demonstrating the asymmetry and multifocality that are most suggestive of a vasculitic neuropathy (Hawke et al. 1991; Kissel et al. 1985; Olney 1992). Although demyelination is generally not a significant element of the histologic picture, conduction block has occasionally been documented as part of an ischemic or vasculitic neuropathy (Hughes et al. 1982; Jamieson et al. 1991; Kaku et al. 1993). Significant demyelinating electrophysiological features were observed in 3 of 32 adequately documented cases of vasculitic neuropathy identified in our laboratory.

In patients known to have a systemic vasculitic illness, nerve biopsy is of questionable value. Of greater interest to the pathologist are those situations where a diagnosis of vasculitis is unsuspected, either because the disease seems confined to the peripheral nervous system, or because it is not yet fully evident

Vasculitis involving the peripheral nerves can be seen in isolation and results in a peripheral nerve syndrome indistinguishable from that of vasculitic neuropathy in multisystem disease. Approximately 25 % of cases with vasculitis neuropathy are diagnosed with primary vasculitis neuropathy. These patients usually present with a subacute or chronic neuropathy, often with a mononeuritis multiplex, and have few or no systemic abnormalities on history, physical, or laboratory investigation. Cases fulfilling these criteria are found in all large series of vasculitic neuropathy (Dyck et al. 1987; Hawke et al. 1991; Vincent et al. 1985; Harati and Niakan 1986; Kissel et al. 1985; Panegyres et al. 1990), and the pathogenesis is probably heterogeneous, as the pathology seems to be (vide infra). It has been argued that these cases do not represent a truly isolated PNS disease because a very high incidence of concurrent vasculitis was found in muscle biopsy (Said et al. 1988). The apparent selectivity of peripheral nerve involvement may reflect an increased vulnerability of this tissue to multifocal microvascular insults, and the presence of a milder disease sufficient to clinically affect nerve but no other tissues might explain the better outcome observed in these patients (Said et al. 1988; Said 1989; Dyck et al. 1987). Some authors have suggested that NSVN should be considered a low-grade systemic vasculitis that is symptomatic in nerves only (Said and Lacroix 2005).

A peripheral neuropathy is said to occur in as many as 14 % of patients with giant cell (temporal) arteritis and frequently precedes the diagnosis by several months (Caselli et al. 1988). Isolated reports exist documenting necrotizing vasculitis, with or without giant cells, involving neural vessels of all sizes in cases of clear-cut temporal cell arteritis (Bridges et al. 1989; Torvik and Berntzen 1968; Merianos et al. 1983; Pons et al. 1987; Nesher et al. 1987). Sites involved include brachial plexus, peroneal nerve, mononeuropathies, and polyneuropathies. Histopathologic features consist of transmural lymphohistiocytic inflammation in the absence of fibrinoid necrosis. Multinucleated giant cell formation occurs associated to degeneration of internal elastica.

A group of nonsystemic, localized vasculopathies termed diabetic lumbosacral radiculoplexus neuropathy and nondiabetic lumbosacral radiculoplexus neuropathy (LRPM) are characterized by intense pain and weakness in the thighs and progressing to affect lower extremities including feet and toes. The clinical course is monophasic but results in protracted morbidity (Gwathmey et al. 2014). Histopathological studies revealed reduction in the number of nerve fibers, perineurial thickening, neuroma formation, neovascularization, and half of the cases featured changes suggestive of microvasculitis.

A heterogeneous group of diseases termed hypersensitivity vasculitis or cutaneous small-vessel vasculitis may present as an idiopathic condition, or secondary to infections, adverse reaction to pharmaceuticals, in the setting of malignancy or autoimmune diseases. Peripheral neuropathy occurs only rarely, except in patients suffering from autoimmune disorders. The hypersensitivity vasculitis that results from the administration of heterologous sera has received the most interest in the past (Iqbal and Arnason 1984).

Paraneoplastic Vasculitic Neuropathy. The most common paraneoplastic vasculitis is leukocytoclastic vasculitis, 75 % of which are caused by hematological malignancies. Second in frequency is small-cell carcinoma of the lung followed by malignancies of the colon, breast, and kidney (Solans-Laqué et al. 2008). In a review of 14 cases, nine cases involved microvasculitis and five cases involved necrotizing vasculitis in medium-sized vessels (Oh 1997; Naka et al. 1991; Choi et al. 2013; Paul 1996).

The most frequently described neuropathy in chronic hepatitis C is a vasculitic neuropathy in the setting of essential cryoglobulinemia (Ferri 2008; Gwathmey et al. 2014; Ramos-Casals et al. 2006). Peripheral neuropathy is more common in essential mixed cryoglobulinemia, but reports of pathological studies are rare (Vrancken and Said 2013).

Vasculitic neuropathy is rare in sarcoidosis, but it is well documented (Said et al. 2002; Vital et al. 2008), including epineurial necrotizing vasculitis in the vicinity of granulomata. Our experience with this disease indicates the presence of naked granuloma in perivascular spaces of epineurial medium-sized vessels, with intrusion into the vessel wall. Some patients suffering from sarcoidosis exhibit the clinical syndrome of mononeuritis multiplex.

VPS may develop in association with leprosy (ENL), HIV, CMV, HCV, and Lyme disease (see Chaps. 11 and 12).

Nerve biopsy is critical for the diagnosis of vasculitis in two clinical situations: “atypical” presentation of systemic vasculitis masquerading as a cryptogenic polyneuropathy and isolated vasculitis of the peripheral nervous system.

The sensitivity of nerve biopsy in the detection of vasculitis is not known because of the variability of selection criteria in published series and the absence of a “gold standard” against which to measure the biopsy. In a study which identified 35 consecutive patients with mononeuritis multiplex from a hospital EMG laboratory, 11 had a previously known rheumatic disease, 9 had the simultaneous onset of systemic disease, and 15 showed only peripheral nerve manifestations (Hellmann et al. 1988). Biopsies showed definite vasculitis in 3 of 5 patients strongly suspected of having polyarteritis nodosa clinically, but in none of 7 biopsies in patients with isolated PNS disease. In the latter group, however, nerve “infarction” was seen in 5 of 7. Dyck et al. (1987) noted that of 45 patients with a biopsy-proven systemic vasculitic illness with neuropathy, nerve biopsy was positive in 58 % in patients, suggestive in 29 %, and nondiagnostic in 23 %. It is possible to find necrotizing vasculitis in an electrically normal nerve (Kissel and Mendel 1992), as has been our experience with 3 patients who underwent nerve and muscle biopsy for suspected systemic vasculitis despite normal nerve conductions studies and EMG. However, the yield is lower than in clinically or electrically involved nerves (Wees et al. 1981). Such data do not make possible estimation of the sensitivity of sural nerve biopsy for the diagnosis of vasculitic neuropathy.

Epineurial vascular involvement usually predominates over endoneurial involvement and is often exclusive; thus, fascicular biopsy is not appropriate when vasculitis is suspected (Dyck et al. 1972; Oh 1990); this is the strongest argument against the utility of fascicular nerve biopsy for diagnostic purposes.

If muscle biopsy can be added to the procedure, the yield may increase an additional 15–45 % (Hawke et al. 1991; Vincent et al. 1985; Dyck et al. 1987). In one series of 83 patients who underwent nerve and muscle biopsy, necrotizing arteritis in the muscle alone was found in 45 %, as compared with 20 % in the nerve alone, and 30 % in both, including patients with seemingly isolated PNS vasculitis (Said et al. 1988). We thus advocate combined nerve and muscle biopsy whenever vasculitis is being considered.

Perivascular inflammation is a common and nonspecific finding in peripheral nerve pathology and should be differentiated from “vasculitis.” Throughout this book, the term “vasculitis” indicates inflammation of the vessel and evidence of destruction such as fibrinoid necrosis, thrombosis, hemorrhage, or disruption of the endothelium (Fig. 13.1a, b). Transmural inflammation accompanied by karyorrhexis has substantially the same value as fibrinoid necrosis (Fig. 11.​2), whereas the presence of leukocytes within the vessel wall is suggestive but not diagnostic of vasculitis. At times, what seems to be prominent perivascular cuffing around small vessels (Fig. 13.2) has been called “microvasculitis” by some (Oh et al. 1991; Vincent et al. 1985), but in our experience this lesion does not have the same diagnostic specificity as necrotizing vasculitis. For example, some of the patients reported by Leger et al. (1988) as showing neural “vasculitis” likely suffered from CIDP. Vasculitis can involve small-sized endoneurial and epineurial vessels for which the designation of microvasculitis is preferred. The anatomy of peripheral nerve vasculature is reviewed in Chap.​ 6.