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1724 Part XI: Malignant Lymphoid Diseases Chapter 106: Essential Monoclonal Gammopathy 1725

in renal insufficiency. 94,95,97,100 The term “dangerous small B-cell clone” a minority have sensory axonal or mixed neuropathy. 108,118,120–122 The
has been applied to a monoclonal gammopathy that can produce dis- neuropathy may be (1) mild with minor motor and/or sensory signs
ease, often quite serious, without lymphoproliferation and progression with or without mild functional impairment, (2) moderately disabling
of the neoplastic cell population. The principal approach to therapy is to but with full range of activities, or (3) severely disabling, interfering
attempt to suppress the small B-cell clone and, thereby, its monoclonal with walking, dressing, and eating. The course may be relapsing and
118
protein secretion with chemotherapy. Cyclophosphamide, thalidomide, remitting or progressive. IgA gammopathy is associated with dysauto-
123
bortezomib, or bendamustine are favored because they have much less nomia. The presence or absence of antibody to myelin-associated gly-
renal toxicity than congeners such as melphalan or lenalidomide. A coprotein may have an effect on the specific nature of the neuropathic
glucocorticoid and rituximab can, also, be useful. 100,101 One should also manifestations. 108,109,114–117
consider the possibility that the monoclonal protein may be secreted by
a solitary plasmacytoma, which would be amenable to local radiation Diagnostic Findings
therapy. Thus, in the face of significant renal impairment a careful eval- Demyelinization is reflected in decreased nerve conduction velocity.
uation, including positron emission tomography, should be considered Axonal loss is reflected in decreased sensory potentials. 109,113,114,120–124
to exclude a solitary lesion. In exceptional cases, ablative therapy with Electromyography may show denervation of muscles. 109,113 Immuno-
an autologous hematopoietic stem cell transplant may be considered. 101 fluorescence studies of sural nerve or of skin biopsies may uncover Ig
binding to nerve. 109,114 Morphologic studies of nerve biopsies may show
Ophthalmic Injury decreased or absent myelinated fibers or axonal degeneration. A rare
Corneal deposits of crystalline Ig 102,103 and a monoclonal copper bind- case of crystal formation in the epineurium has been described. 125
ing Ig resulting in copper deposits in the eye, 104,105 each associated with
classical monoclonal gammopathy, have led to loss of visual acuity. Management
Remarkably, despite very high serum copper levels in the latter cases, no At least seven treatment approaches have been used to ameliorate the
other organ damage ensued. Iritis, vitritus, and maculopathy with loss neuropathies: (1) intravenous Ig administration; (2) glucocorticoids
of visual acuity have also been described in association with a monoclo- alone; (3) immunoadsorption of perfused blood with staphylococcal
nal gammopathy. 106 protein A; (4) plasma exchange or plasmapheresis; (5) immunosuppres-
sive cytotoxic chemotherapy, such as cyclophosphamide, chlorambucil,
NEUROPATHIES or fludarabine with or without added glucocorticoids; (6) rituximab
(anti–cluster of differentiation [CD]20 antibody) to deplete B cells; and
Frequency of Occurrence (7) high-dose cytotoxic therapy with autologous hematopoietic stem cell
A significant association exists between the incidence of neuropathies rescue. 107–109, 117,118,124,126–135 In some cases, use of plasmapheresis has been
and essential monoclonal gammopathy. 107–114 Approximately 10 per- followed by cytotoxic therapy in an effort to produce a sustained effect.
cent of patients with idiopathic neuropathy have a monoclonal Ig, a Plasma exchange has shown benefit in a small clinical trial. The other
frequency about eight times that of age-adjusted healthy comparison modalities of treatment await such studies. Response rates to each
107
groups. 107–111 The frequency of neuropathy among patients with mono- form of therapy are low and duration of response is variable, 109,118,126–131
clonal gammopathy varies depending on the distribution of Ig classes, but some patients obtain coincidental significant improvement for pro-
but is in the range of 3 to 5 percent. IgM monoclonal gammopathy has longed periods. A recommendation has been made to start therapy with
a significantly higher frequency of neuropathy than does IgG or IgA intravenous Ig, especially in essential monoclonal IgM-associated neur-
monoclonal gammopathy. 107,108 opathy, because of the relative safety of this approach. Mild symptoms
107
and signs may not be an indication for treatment because of the low
Mechanisms of Nerve Damage response rate and the potential noxious effects of therapy. 107
Monoclonal antibodies, especially IgM, can react with peripheral nerve
myelin, specifically with myelin-associated glycoprotein, glycolipids,
or sulfatides. 112–117 Although various antinerve antibodies are pres- COINCIDING DISORDERS
ent in approximately 40 percent of patients with neuropathy and IgG Monoclonal gammopathy unrelated to a clinically evident prolifera-
monoclonal gammopathy, a similar frequency has been found in such tion of B lymphocytes or plasma cells has been observed in association
patients without neuropathy. Neuropathy in the absence of reactivity with a wide variety of conditions (Table 106–3). 136–201 Although they are
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of the monoclonal protein with nerve antigens implies other mecha- grouped under the designation monoclonal gammopathy with a coin-
nisms also operate to cause nerve damage. 107,109,116 Deposition of mono- cidental disease, few such reports have examined whether the coinci-
clonal protein in the epineurium has been proposed as an alternative dence is greater than expected in a control group matched for age and
mechanism of nerve injury. Also, in one report, four of 16 patients ethnicity, the two variables having the greatest impact on the incidence
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with IgG monoclonal gammopathy and neuropathy had polyclonal, not of monoclonal gammopathy. Non–B-cell malignancies, including solid
monoclonal, antibodies against neurofilament protein. In addition, a tumors, 3,5,6,18,178–181 myeloproliferative disorders, 182–189 and Hodgkin and
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proportion of patients develop a detectable monoclonal protein after the T-cell lymphomas, 190–193 are associated with monoclonal Ig. These rela-
onset of the neuropathy, sometimes years later. 118 tionships could result from various factors: (1) patients with a monoclo-
nal Ig have an increased risk of developing cancer; (2) the monoclonal
Signs and Symptoms Ig is an antibody against some antigen associated with the cancer;
Patients with essential IgM monoclonal gammopathy and neuropathy (3) the monoclonal Ig is the product of cancer cells; or (4) coincidence.
can have dysesthesia of the hands and feet, loss of vibration and position The last possibility is favored by two epidemiologic studies that found
sense, atrophy of distal muscles, ataxia, and intention tremor. 114,115,117 The the same frequency of monoclonal gammopathy in a matched control
monoclonal antibodies reactive with nerve antigens usually are of the group as in cancer patients. Furthermore, when the monoclonal Ig is
9,18
IgM type. Serum often contains antibodies to myelin-associated glyco- associated with a cancer, it usually persists after successful resection of
protein. 107,108 In contrast, patients with IgG or IgA monoclonal gammop- the tumor. A convincing case for an association of acute myelogenous
athy usually have chronic inflammatory demyelinating polyneuropathy; leukemia and myelodysplasia with monoclonal gammopathy was made

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