Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports he is a consultant for Merck Sharp & Dohme Corp.
SYNOPSIS: Vasculitic neuropathy is characterized by stepwise progression of sensorimotor neuropathy, usually with axonal features on electrodiagnostic studies, and often the presence of antimyeloperoxidase and rheumatoid factor antibodies and cryoglobulins. However, peripheral nerve biopsy is necessary for a definitive diagnosis.
SOURCE: Nathani D, Barnett MH, Spies J, et al. Vasculitic neuropathy: Comparison of clinical predictors with histopathological outcome. Muscle Nerve 2019; Jan 31. doi: 10.1002/mus.26431. [Epub ahead of print].
Vasculitis may affect any organ or tissue. However, when it affects the vasa nervorum, vasculitic neuropathy is the result, often as one component of a systemic vasculitis typically affecting skin, lungs, and kidneys. Most commonly, systemic vasculitis involving either small- or medium-sized arteries is implicated in vasculitic neuropathy. In 10% to 30%, the peripheral nervous system is the sole organ involved, which is termed nonsystemic vasculitic neuropathy or isolated peripheral nervous system vasculitis. The mode of presentation in either scenario is variable, making diagnosis challenging. What features might improve diagnostic accuracy, perhaps precluding the need for nerve biopsy and its attendant complications?
Nathani et al performed a retrospective analysis of clinical, serologic, electrophysiologic, and biopsy data for all patients referred for nerve biopsy over a 21-month period at the Brain and Mind Centre, University of Sydney, and Royal Prince Alfred Hospital, Sydney, Australia. Stepwise progression was defined by a history of acute, multifocal attacks separated by time. Symptoms were categorized as acute (less than one month), subacute (one to three months), or chronic (more than three months). C-reactive protein (CRP) and antinuclear antibody (ANA) titer were defined as clinically relevant when values were > 10 mg/L and 1:160 or above, respectively. When a premorbid erythrocyte sedimentation rate (ESR) was available for comparison, an increase of at least 25% was considered clinically relevant. Otherwise, an ESR greater than age/2 for males or (age plus 10)/2 for females was considered significant. Based on electrodiagnostic studies, neuropathy was determined to be primarily axonal, primarily demyelinating, or mixed. Nerve biopsy, including teased fiber analysis, was reported as normal, axonal, demyelinating, or mixed. A statistical analysis encompassed the t-test and either the χ2 or Fisher’s exact test, using SPSS Statistics for Windows Version 24.0.
Among 202 patients referred for nerve biopsy, 78 (38.6%) were suspected to have vasculitis and served as the study group. Biopsy of the sural nerve was performed in 75 (96.2%), with the superficial radial or superficial peroneal nerve in the remainder, and muscle biopsy was concomitantly done in 17 (21.8%), usually the vastus lateralis (55.6%). Based on histopathology, vasculitis was diagnosed as definite in eight (10.3%), probable in 15 (19.2%), possible in nine (11.5%), and absent in 46 (59%).
Patients with confirmed vasculitis reported stepwise progression of sensorimotor symptoms and signs more frequently, with 18.2% of those with purely sensory symptoms and signs and 14.2% of those with purely motor symptoms and signs showing vasculitis. Among those with purely sensory symptoms and signs, 50% had motor involvement on nerve conduction studies, and among those with purely motor symptoms and signs, all had sensory abnormalities on nerve conduction studies. Pure axonal neuropathy was seen in 76.2% of confirmed vasculitis cases, asymmetric was seen in 66.7%, and demyelination seen in 10.8% of the study group, 87.5% of whom had pathologically unlikely vasculitis. Arm-dominant symptoms were seen in only three patients, and neither pain nor length-dependent symptoms distinguished the presence of vasculitis. Among patients presenting with a chronic, symmetric neuropathy, only 14.8% had biopsy-confirmed vasculitis. Vasculitis was confirmed in 85.7% of myeloperoxidase (MPO)-positive patients, 72.7% of rheumatoid factor (RF)-positive patients, and 80% of cryoglobulin-positive patients. Neither positive ANA titer, raised inflammatory markers, the presence of a paraprotein, cerebrospinal fluid findings, nor pattern of electrodiagnostic abnormalities correlated with biopsy-proven vasculitis. Stepwise progression, anti-MPO antibody and RF seropositivity, and the presence of cryoglobulins best differentiated pathologically confirmed vasculitis. Vasculitis is unlikely in patients with arm-predominant symptoms, clinically and electrodiagnostically pure motor presentations, and electrodiagnostic studies with normal findings or demyelinating features.
Immunosuppression of any identifiable systemic vasculitis or connective tissue disease associated with vasculitic neuropathy remains the mainstay of therapy. Medications include glucocorticoids for mild vasculitic neuropathy, without, or combined with, cyclophosphamide. Rituximab may be substituted for cyclophosphamide, and, in antineutrophil cytoplasmic antibody-associated vasculitis, mycophenolate mofetil appears noninferior to cyclophosphamide to induce remission, although with a higher relapse rate. No satisfactory controlled trials for the treatment of nonsystemic vasculitic neuropathy are available and, hence, treatment must be based on experience.1
- Jones RB, Hiemstra TF, Ballarin J, et al. Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: A randomised, non-inferiority trial. Ann Rheum Dis 2019;78:399-405.