Waldenström macroglobulinemia Macroglobulinemia was the term applied by Waldenström to a systemic condition occurring mainly in older persons and characterized by fatigue, weakness, and a bleeding diathesis. Immunoelectrophoretic examination of the blood disclosed a marked and mostly monoclonal increase in the IgM plasma fraction. About half of patients with Waldenström disease and polyneuropathy will have specific anti-MAG antibodies, similar to the approximately one-third of patients with nonmalignant IgM paraproteins. (An uncertain proportion of patients with a “benign” IgM paraprotein will, over the years, develop Waldenström disease.) A few patients with Waldenström hyperproteinemia have a hyperviscosity state manifest by diffuse slowing of the retinal and cerebral circulations, giving rise to episodic confusion, coma, impairment of vision, and sometimes strokes (Bing-Neel syndrome). Most reports attribute this syndrome to infiltration of neural by malignant plasma cells rather than to hyperviscosity.
The polyneuropathy, when present, evolves over months or longer and may be asymmetrical, particularly at the onset, but becomes bilateral, mainly sensory, and distal. The pattern in our patients has been very slowly progressive, and initially limited to the feet and legs with sensory ataxia and loss of knee and ankle jerks. The CSF protein is usually elevated and the globulin fraction increased. In a case recorded by Rowland and colleagues, the polyneuropathy was purely motor and simulated motor neuron disease. Treatment is discussed further on.
Cryoglobulinemia As mentioned in the section on vasculitic neuropathies, cryoglobulin, a serum protein that precipitates on cooling, is usually of the IgG or IgM type and most often polyclonal. While cryoglobulinemia may occur without any apparent associated condition (essential cryoglobulinemia), it also accompanies a wide variety of disorders such as multiple myeloma, lymphoma, connective tissue disease, chronic infection, and particularly, hepatitis C. Peripheral neuropathy occurs in a small proportion both of the essential and symptomatic cases. Occasionally the neuropathy evolves over a period of a few days and remits rapidly. More often it takes the form of a distal symmetrical sensorimotor loss, which develops insidiously (76 percent of the cases in the series reported by Gemignani et al) in association with the Raynaud phenomenon and purpuric eruptions of the skin. Initially, the neuropathic symptoms may consist only of pain and paresthesias that may be precipitated by exposure to cold (as often, there is no cold sensitivity). Later, weakness and wasting develop, more in the legs than in the arms, and more or less in the same distribution as the vascular changes. In some cases there may be a mononeuropathy multiplex with severe denervation in the territory of the involved nerves (9 percent of the series reported by
Gemignani et al; see also Garcia-Bragado et al). In a few cases, the two neuropathic syndromes have been combined. As remarked earlier, detection of cryoglobulin requires special handling of the blood sample. The specimen should be carried to the laboratory in a bath of warm water to prevent precipitation of the protein.
Any of the paraproteinemic states may be associated with an amyloid polyneuropathy, a subject accorded a separate section later in the chapter.