Neuropathy with Hepatitis C Virus-Related Cryoglobulinemia
Abstract & Commentary
By Michael Rubin, MD
Professor of Clinical Neurology, Weill Cornell Medical College
Dr. Rubin reports no financial relationships relevant to this field of study.
Synopsis: Most patients who develop cryoglobulinemia associated with hepatitis C infection will develop symptoms and signs of a symmetric, distal sensory neuropathy.
Source: Biasiotta A, et al. Clinical, neurophysiological, and skin biopsy findings in
peripheral neuropathy associated with hepatitis C virus-related cryoglobulinemia.
J Neurol 2014;261:725-731.
Cryoglobulinemia, one of several extrahepatic manifestations of chronic hepatitis C virus (HCV) infection, is a lymphoproliferative disorder that causes the deposition of circulating immune complexes in small- to medium-sized blood vessels, resulting in purpura, glomerulonephritis, and neuropathy, the latter usually a painful, distal, predominantly sensory polyneuropathy. Risk factors and mechanisms underlying neuropathic pain in these patients have been little studied but are now addressed.
Over a 2-year period, 74 consecutive unselected patients with HCV-related cryoglobulinemia were screened for this study. All had type II (essential mixed) cryoglobulinemia and none had oncologic or hematologic disease. Exclusionary criteria — which included cognitive impairment, non-neuropathic neurologic disease, or any condition that might cause neuropathy — resulted in the exclusion of five patients (four with diabetes, one with renal failure), leaving 69 for enrollment. Evaluation of all enrollees included neurologic examination, diagnosis and rating of various neuropathic pains using the Neuropathic Pain Diagnostic questionnaire and the Neuropathic Pain Symptom Inventory, respectively, and nerve conduction studies of sensory (sural, ulnar, superficial radial) and motor (peroneal, tibial, ulnar) nerves. To assess small myelinated fibers, laser-evoked-potential recordings were obtained, using a neodymium:yttriumaluminiumperovskite (Nd:YAP) laser to stimulate the dorsum of the right foot and left hand, with recording of the N1 and N2-P2 complexes from the temporal areas. To assess C-fiber terinals, skin biopsies were obtained from the proximal thigh and distal leg. Statistical analysis included the unpaired t test and MannWhitney test, using Spearman’s rank correlation coefficient for correlation analysis, with P < 0.05 considered significant.
Among the 69 patients, peripheral neuropathy was seen in 68% (n = 47), of which 96% (n = 45) had distal symmetric sensory polyneuropathy with the two remaining patients demonstrating mononeuropathy multiplex. Among the 45 patients with distal symmetric sensory polyneuropathy, 76% (n = 34) had both large and small fiber involvement, 15% (n = 7) had predominantly large fiber neuropathy with no pain or temperature sensation alteration, and 9% (n = 4) had a purely small fiber sensory neuropathy with pure pain and temperature involvement, abnormal laser-evoked potentials and intraepidermal nerve fiber density, and normal nerve conduction studies. Compared to patients without peripheral neuropathy, those with neuropathy tended to be older, with longer duration of HCV infection. No difference was seen for gender or duration of cryoglobulinemia. Sural sensory nerve action potential amplitude, foot laser-evoked potential amplitude, and intraepidermal nerve fiber density on skin biopsy correlated inversely with duration of HCV infection, with pain related to low laser-evoked potential amplitude, rather than sural amplitude or intraepidermal nerve fiber density. Peripheral neuropathy in HCV is related to age and duration of infection rather than to cryoglobulinemia, and pain is associated with nociceptive pathway injury.
Although induction therapy for mild-to-moderate chronic hepatitis C virus cryoglobulinemic vasculitis comprises pegylated interferon-α and ribavirin with boceprevir or telaprevir, severe disease, including progressive renal failure, mononeuritis multiplex, and extensive skin disease, requires additional immunosuppression. Rituximab, targeting B cells responsible for cryoglobulin production, is generally effective and well tolerated, and, combined with an optimal antiviral agent, is the recommended therapy. Adverse effects, including peripheralneuropathy or skin ulcers, may worsen with interferon therapy, and relapse of cryoglobulinemic vasculitis may presage B cell non-Hodgkin’s lymphoma. Low-dose corticosteroids are usually ineffective with major organ involvement.