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1790 Part XI: Malignant Lymphoid Diseases Chapter 109: Macroglobulinemia 1791

A

B

Figure 109–4. Cryoglobulinemia manifesting with severe acrocyanosis in a patient with Waldenström macroglobulinemia before (A) and follow-
ing warming and plasmapheresis (B).

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(2) endoneurial granulofibrillar deposits of IgM without antibody activ- patients with IgM monoclonal gammopathy and neuropathy. Motor
ity, associated with axonal polyneuropathy; (3) occasionally by tubular neuron disease has been reported in patients with WM and monoclo-
deposits in the endoneurium associated with IgM cryoglobulin; and, nal IgM with anti-GM and sulfoglucuronyl paragloboside activity.
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rarely, (4) by amyloid deposits or by neoplastic cell infiltration of nerve Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin
structures. 73,76 Half of the patients with IgM neuropathy have a distinctive changes (the POEMS syndrome) are rare in patients with WM. 89
clinical syndrome that is associated with antibodies against a minor 100-
kDa glycoprotein component of nerve known as the myelin-associated Cold Agglutinin Hemolytic Anemia
glycoprotein (MAG). Anti-MAG antibodies are generally monoclonal Monoclonal IgM may have cold agglutinin activity, that is, it can rec-
IgMκ, and usually also exhibit reactivity with other glycoproteins or ognize specific red cell antigens at temperatures below 37°C, producing
glycolipids that share antigenic determinants with MAG. 77–79 The anti– chronic hemolytic anemia. This disorder occurs in less than 10 percent
MAG-related neuropathy is typically distal and symmetrical, affecting of WM patients and is associated with cold agglutinin titers greater
both motor and sensory functions; it is slowly progressive with a long than 1:1000 in most cases. The monoclonal component is usually an
90
period of stability. 72,80 Most patients present with sensory complaints IgMκ and reacts most commonly with red cell I/i antigens, resulting
(paresthesias, aching discomfort, dysesthesias, or lancinating pains), in complement fixation and activation. 91,92 Mild to moderate chronic
imbalance and gait ataxia, owing to lack proprioception; leg muscles hemolytic anemia can be exacerbated after cold exposure. Hemoglobin
atrophy in advanced stage. Patients with predominantly demyelinating usually remains above 70 g/L. The hemolysis is usually extravascular,
sensory neuropathy in association with monoclonal IgM to gangliosides mediated by removal of C3b opsonized red cells by the mononuclear
with disialosyl moieties, such as GD1b, GD3, GD2, GT1b, and GQ1b, phagocyte system, primarily in the liver. Intravascular hemolysis from
have also been reported. 81,82 Anti-GD1b and anti-GQ1b antibodies complement destruction of red blood cell membrane is infrequent. The
were associated with sensory ataxic neuropathy. These antiganglioside agglutination of red cells in the skin circulation also causes Raynaud
monoclonal IgMs present core clinical features of chronic ataxic neur- syndrome, acrocyanosis, and livedo reticularis. Macroglobulins with
opathy sometimes with present ophthalmoplegia and/or red blood cell the properties of both cryoglobulins and cold agglutinins with anti-Pr
cold agglutinating activity. The disialosyl epitope is also present on red specificity can occur. These properties may have as a common basis
blood cell glycophorins, thereby accounting for the red cell cold agglu- the binding of the sialic acid-containing carbohydrate present on red
tinin activity of anti-Pr2 specificity. 83,84 Monoclonal IgM proteins that blood cell glycophorins and on Ig molecules. Several other macroglob-
bind to gangliosides with a terminal trisaccharide moiety, including ulins with antibody activity toward autologous antigens (e.g., phospho-
ganglioside M (GM ) and GalNac-GD1A, are associated with chronic lipids, tissue and plasma proteins) and foreign ligands have also been
2
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demyelinating neuropathy and severe sensory ataxia, unresponsive described.
to glucocorticoids. Antiganglioside IgM proteins may also cross-
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react with lipopolysaccharides of Campylobacter jejuni, whose infection Immunoglobulin M Tissue Deposition
is known to precipitate the Miller-Fisher syndrome, a variant of the The monoclonal protein can deposit in several tissues as amorphous
86
Guillain-Barré syndrome. Thus, molecular mimicry may play a role in aggregates. Linear deposition of monoclonal IgM along the skin base-
93
this condition. Antisulfatide monoclonal IgM proteins, associated with ment membrane is associated with bullous skin disease. Amorphous
sensory-sensorimotor neuropathy, have been detected in 5 percent of IgM deposits in the dermis result in IgM storage papules on the extensor

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