The pathology of the cryoglobulinemic and macroglobulinemic neuropathies has been incompletely studied and the mechanisms by which these disorders cause neuropathy are uncertain. One presumes that some component of the paraprotein acts as an antineural antibody or that deposition of the protein is in some way toxic to the nerves or to the endoneurial vessels. In our most thoroughly autopsied case, there was widespread distal axonal degeneration of nonspecific type without amyloid deposition or inflammatory cells; yet in other reported cases, amyloid has been found in the nerve and the neuropathy has been attributed directly to it. Immune deposits of IgM had impregnated the inner layers of the perineurium in the case reported by Ongerboer de Visser and colleagues. Dalakas and Engel (1981b) have made similar observations. In yet other instances, the neuropathy of cryoglobulinemia is a result of the intravascular deposition of cryoglobulins, causing a more acute vasculitic mononeuropathy multiplex, as discussed earlier (Chad et al).
Treatment In the Waldenstrom-related neuropathies, the use of prednisone, the alkylating agent chlorambucil, cyclophosphamide, and repeated plasma exchange has at times led to improvement both in the systemic and neuropathic symptoms, although recovery has been incomplete. The monoclonal antibody rituximab has been effective in small studies. The optimal treatment of cryoglobulinemic neuropathy has not been settled. We have used plasma exchange and added immunosuppression in the vasculitic variety of this disease.
Acquired Primary (Nonfamilial, AL) Amyloid Neuropathy
A heredofamilial type of amyloidosis (familial amyloidosis [FA]) is well known and is described further on. In addition, there are numerous sporadic instances of a peripheral neuropathy caused by amyloid deposition. As in the familial variety, the heart, kidneys, and gastrointestinal tract may be involved. This acquired type of amyloid disease has also been called primary systemic amyloidosis to distinguish it from the variety associated with chronic diseases. The term is misleading in that in most cases the amyloid is derived from a circulating paraprotein, but the proportion of “benign” and malignant plasma cell sources of the protein varies from one report to another. For example, in the large series collected by Kyle and Bayrd, only 26 percent of patients with primary amyloidosis had a malignant plasma cell dyscrasia. This agrees with our own experience, but other series have found rates of myeloma as high as 75 percent. In any case, 90 percent of primary amyloidosis is the result of a monoclonal protein in the blood (rarely polyclonal). Macrophage enzymes cleave the larger immunoglobulin molecules and the light chains aggregate to form amyloid deposits in tissue, or the plasma cells may produce light chains directly (“light chain disease”). Lambda light chain predominates in the idiopathic variety of amyloidosis and kappa light chain is more common in myeloma. In a few cases, the light chain is found only in the urine (as Bence Jones protein).
In primary amyloidosis there is no evidence of preceding or coexisting disease (except the association with paraproteinemia or multiple myeloma). Secondary amyloidosis (AA), an infrequent occurrence nowadays, is the result of chronic infection or other chronic disease outside the nervous system and, as a rule, is not associated with neuropathy (e.g., it is not cited in the large recent series by Lachmann and colleagues [2007]). In contrast, familial amyloidosis, a third variety, is almost invariably associated with neuropathy but is associated with a paraprotein in only a small proportion of cases and the amount of immunoglobulin is small (see “Inherited [Familial Amyloidosis] Amyloid Neuropathies” later).