The diabetic and nondiabetic radiculoplexus neuropathies are now commonly included in the spectrum of nonsystemic/localized variants of vasculitis associated with neuropathy. The typical presentation of radiculoplexus neuropathy includes that of acute to subacute buttock, hip, or thigh pain followed by weakness and atrophy that typically affect the thigh muscles but can also affect other regions, including the distribution of the brachial plexus and thoracic nerve roots. Neuropathic pain is a prominent feature of all types of vasculitis and appears to be more common and severe in vasculitic neuropathy than in any other type of neuropathy, occurring in over 90% patients.

Diagnosis

The extent of testing in a patient with suspected vasculitic neuropathy depends largely on the presenting signs and symptoms. The workup for possible vasculitis includes a thorough history and physical examination, neurophysiological testing with electromyography (EMG) and nerve conduction studies (NCSs), specific laboratory testing to identify or exclude coexistent or associated disorders, and usually nerve biopsy. EMG and NCSs are indicated for essentially all patients presenting with suspected vasculitic neuropathy, because they define the distribution of involvement (focal, multifocal, or length dependent), fiber type involved (sensory and/or motor), neuropathophysiology (axonal loss versus demyelination), and the most appropriate nerve for biopsy. NCSs in vasculitic neuropathy usually demonstrate reduced sensory and motor amplitudes, signifying axonal loss, with normal or mildly reduced conduction velocities. The needle electrode examination demonstrates findings of active and/or chronic denervation depending on the chronicity of the patient’s symptoms. Findings of axonal loss in the distribution of an asymmetric length-dependent pattern or in the distribution of multiple named nerves (i.e. multiple mononeuropathy) on electrodiagnostic studies are strongly suggestive of an underlying vasculitic neuropathy. Conversely, a symmetric distribution of findings by EMG/NCSs makes vasculitis much less likely. Significantly reduced conduction velocities or other findings of demyelination including temporal dispersion or persistent conduction block should also prompt the clinician to look for alternative diagnoses, although rarely a pseudoconduction block may be seen in the acute phase of nerve injury with ongoing nerve ischemia.

EMG and NCSs are helpful in excluding other peripheral nerve disorders which may present with asymmetric or multifocal features. Here­ditary neuropathy with predisposition to pressure palsies (HNPP) is a relatively rare, autosomal dominantly inherited neuropathy related to PMP-22 deletion on chromosome 17 which can mimic the presentation of vasculitic neuropathy. Patients with HNPP present with asymmetric complaints of multiple nerve entrapments but do not typically present with the pain characteristic of vasculitis. The presence of demyelinating changes on neurophysiological testing typically makes HNPP easily distinguished from vasculitis. Similarly, diabetic neuropathy is associated with increased susceptibility to compression or entrapment neuropathies, which may lead to a neuropathy with asymmetric clinical and examination features. Findings of mononeuropathies with features of demyelination only at common sites of nerve entrapment usually help to distinguish this from a vasculitic process.

The laboratory evaluation of vasculitic neuropathy should include testing for any systemic conditions suggested by the history and examination. The typical evaluation of vasculitic neuropathy includes complete blood count with differential, renal and hepatic panels, urinalysis, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA), rheumatoid factor, serum electrophoresis with immunofixation, glucose tolerance testing, cryoglobulins, and serum complement. Hepatitis B surface antigens and hepatitis C antibodies are also usually obtained because vasculitis can occur in the setting of hepatitis. Testing for other infectious agents associated with secondary systemic vasculitis, including human immunodeficiency virus (HIV), rickettsiae, Mycobacterium tuberculosis, Lyme disease, and syphilis, should be considered in select cases.

Nerve biopsy remains a critical part of the evaluation of suspected vasculitic neuropathy because the toxicity associated with chronic immunomodulatory therapy used in vasculitic neuropathy demands diagnostic certainty. Commonly biopsied nerves include the sural, superficial peroneal, and superficial radial nerves, but the clinical examination and electrodiagnostic evaluation should guide the biopsy site. A normal examination and nerve conduction response in the nerve to be biopsied significantly lessens the chance of abnormal findings and thus the diagnostic yield of a nerve biopsy. A nerve that is clinically involved should be selected, keeping in mind the morbidity that is associated with a nerve biopsy which can include pain, dysesthesia, and persistent numbness. When feasible, a combined nerve and muscle biopsy may increase diagnostic sensitivity. In systemic vasculitis multiple organs may be involved in addition to the peripheral nervous system. If the patient’s symptoms, examination, and diagnostic testing suggest involvement of other organs, consideration should be given to obtaining tissue in the least invasive manner.

A definite histological diagnosis requires endoneurial or epineurial vessel wall infarction in association with perivascular or transmural infiltration by inflammatory cells (Plate 26.1). In the absence of true vessel wall infarction and necrosis, a presumptive diagnosis of probable vasculitis is reasonable if transmural or perivascular inflammation is associated with at least one of the following: chronic thrombosis, hemosiderin deposition, asymmetric nerve fiber loss, or prominent wallerian degeneration.

Treatment

The initiating factors for most cases of vasculitic neuropathy remain incompletely understood, although the disorder is presumed to be an immune-mediated process, most likely related to both immune complex deposition and cellular-mediated mechanisms. In the case of the hypersensitivity vasculitides associated with cancer, medications, or infection, antigen removal through treatment of the primary underlying process is an important therapeutic strategy. Otherwise, nonspecific immunomodulation is the cornerstone of therapy for vasculitic neuropathies of any cause.

Most patients with vasculitic neuropathy require treatment. The major determinations to be considered in the management of vasculitic neuropathy include the need for monotherapy with corticosteroids alone versus combination therapy with a cytotoxic agent, the length of induction treatment using corticosteroids with or without combination therapy before transitioning to maintenance therapy with less toxic agents, and the length of treatment with maintenance therapy after a clinical remission is apparent. Corticosteroids remain the primary modality of treatment during induction therapy, most often as monotherapy in patients with mild primary systemic vasculitic neuropathy and NSVN. Typically steroids are initiated orally with prednisone at 1.5 mg/kg per day as a single, morning dose for mild cases or intravenously with methylprednisolone in particularly severe or fulminant cases. In some cases continued progression will be observed despite high-dose corticosteroid management, and combination therapy is necessary.

The presence of rapidly progressive weakness or multiorgan involvement, particularly renal or central nervous system, should also prompt consideration for combination therapy. The use of combination therapy carries additional risk and should be used only by clinicians familiar with prescribing precautions. Cyclophosphamide is the best studied agent for combination therapy. Traditionally, cyclophosphamide has been administered orally at 1.5–2.5 mg/kg per day, but pulsed intravenous dosing has demonstrated benefits of less toxicity, improved tolerability, and decreased cumulative dose with nearly equal efficacy. A typical protocol for intravenous pulse cyclophosphamide administration is 0.6 g/m² every 2 weeks for three doses, followed by 0.7 g/m² every 3 weeks for three to six additional doses. In elderly patients or patients with renal impairment the dose should be decreased (0.5 g/m²). Patients should also be administered mesna or aggressive hydration to help reduce the risk of bladder toxicity.

After a period of induction therapy, typically 6 months, using corticosteroids with or without combination therapy, patients should be transitioned to less toxic maintenance immunomodulatory treatment. Azathioprine and methotrexate are both considered first-line agents for maintenance immunomodulatory therapy. The standard dose of azathioprine is 2.0–2.5 mg/kg per day. Methotrexate is typically initiated at a starting dose of 15 mg/week and titrated to 25 mg/week over a period of 1–2 months. The ideal length of maintenance immunomodulatory treatment after clinical remission is not entirely clear, but treatment should continue until improvement maximizes. If there is no evidence of recurrence after 6 months of clinical stability, discontinuation of immunomodulation can be considered. Continued treatment with low dose prednisone (5–7.5 mg daily) and/or a steroid-sparing agent such as methotrexate or azathioprine for 18–24 months may be considered in the hope of reducing the risk of future disease recurrence.