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  • Updated 03.02.2024
  • Released 05.06.1996
  • Expires For CME 03.02.2027

Neuropathies associated with cryoglobulinemia



Cryoglobulins are plasma proteins that precipitate on cooling and dissolve after rewarming. Cryoglobulinemia may arise in association with an identifiable cause like an infection (mainly hepatitis C virus infection), a lymphoproliferative disorder, or an autoimmune disease (such as Sjögren syndrome). Alternatively, cryoglobulinemia may arise without a detectable underlying disease, in which case the term “essential cryoglobulinemia” is used. Cryoglobulinemia may lead to a variety of systemic complications, including purpura, arthritis, glomerulonephritis, and peripheral neuropathy, which could be potentially disabling. In this review, the authors review the pathogenesis, management, and treatment of neuropathies associated with cryoglobulinemia.

Key points

• Cryoglobulins are serum proteins (predominantly immunoglobulins) that precipitate at temperatures below 37° C and dissolve on rewarming.

• The majority of cryoglobulins are mixed antigen-antibody complexes that occur in autoimmune or infectious disorders, especially hepatitis C virus infection.

• Cryoglobulinemic neuropathy is one of the most common forms of vasculitic neuropathy.

• Sensory neuropathy is the commonest form of neuropathy in mixed cryoglobulinemia; however, sensory motor neuropathy and mononeuritis multiplex are not uncommon.

• Treatment of neuropathy associated with cryoglobulinemia depends on whether the patient has an identifiable cause such as hepatitis C virus infection.

Historical note and terminology

The term "cryoglobulin" was first employed in 1947, although the first description in the literature was that of Heidelberger in 1929 (46; 40). Wintrobe and Buell initially described the clinical manifestations accompanying the presence of a cryoglobulin in the serum, which included Raynaud phenomenon, purpura, and thrombosis of retinal veins (87).

The first description of cryoglobulinemic neuropathy was by Garcin and colleagues in 1957 (35). They described a 43-year-old patient who, over a period of months, developed mononeuritis multiplex, which was associated with purpura of the lower limbs and increased neuropathic symptoms in cold temperatures. In 1962, Lospalluto and colleagues showed that cryoglobulins contain more than one immunoglobulin and that there may be rheumatoid factor activity within the cryoprecipitate (50). Since the report of Brouet and colleagues, cryoglobulinemia has been classified into three types (16):

Type I. The cryoprecipitate only consists of a monoclonal component (commonly IgM or IgG, less often IgA or free immunoglobulin light chains), usually in the setting of a B cell lymphoproliferative disease.

Type II. The cryoprecipitate consists of a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG in the setting of hepatitis C infection (most common cause for type II cryoglobulinemia), a lymphoproliferative disorder, or an autoimmune disease.

Type III. The cryoprecipitate only contains a polyclonal IgG and polyclonal IgM with RF activity, in the setting of a collagen vascular, infectious (including hepatitis C), or chronic inflammatory disease.

Types II and III are called mixed cryoglobulinemia.

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