Peripheral neuropathy and central nervous system involvement in cryoglobulinemia

Cryoglobulins (CG) are immunoglobulins that persist in the serum and have the physical property of precipitating on exposure to cold and resolubilizing when returned to body temperature. Three categories of cryoglobulins are recognized, either essential or secondary to chronic hepatitis C virus (HCV) infection, autoimmune diseases, and lymphoproliferative disorders. Peripheral neuropathy (PN) can occur with all types of CG, although it is usually found in patients with HCV-associated type II CG. PN has different clinical manifestations, ranging from subclinical involvement to symmetrical or asymmetrical sensory, sensorimotor, or motor forms. The mechanisms of nerve involvement are related to small vessel vasculitis, complement-mediated microangiopathy, and HCV-triggered dysimmune responses. The central nervous system (CNS) can be also involved in CG and clinical manifestations are highly variegated. In recent years, the study of HCV-infected individuals has revealed an increased prevalence of cognitive changes and behavioral/neuropsychological symptoms, suggesting a major pathogenic role of HCV, following neuroinvasion and replication. Here, we review the range of neurological complications associated with essential and secondary CG and discuss the available therapeutic options.