Polyneuropathy associated with monoclonal gammopathy, cause and consequence

Abstract

The relation between monoclonal antibodies and polyneuropathy is best supported for polyneuropathy associated with IgM monoclonal anti-myelin associated glycoprotein (anti-MAG) antibodies. These anti-MAG antibodies are reactive against peripheral nerve autoantigen, thereby causing an autoimmune mediated polyneuropathy.

To further discriminate clinical entities, we analyzed the presence of T cells in sural nerve biopsies in primary demyelinating and primary axonal polyneuropathies associated with monoclonal gammopathy. Increased T cell densities were found in: 1) patients with progressive demyelinating polyneuropathy associated with IgG monoclonal gammopathy, with T cell densities (T cells/mm2) comparable to densities in patients with chronic inflammatory demyelinating polyneuropathy (CIDP); 2) patients with progressive axonal polyneuropathy associated with monoclonal gammopathy. The pathologic features in the biopsies of these patients resembled those found in vasculitic neuropathy.

In polyneuropathy associated with IgM monoclonal gammopathy, antibodies to myelin-associated glycoprotein (MAG), sulfoglucuronyl paragloboside (SGPG) and sulfatide have been associated with specific clinical and electrophysiologic features. However, it is not known whether the results of antibody tests provide additional information for the individual patient (and the neurologist) on future neurologic deficit or outcome. Therefore, we studied the potential prognostic value of clinical, electrophysiologic, pathologic and antibody determination (Chapter 3). In multivariate analysis initial sensory symptoms of the feet is associated with a slowly progressive disease course and less disability at four years, demyelination on electrophysiologic examination is prognostic for development of weakness and symptoms of upper extremities at four years.

Half of the patients with polyneuropathy associated with IgM monoclonal gammopathy have anti-MAG antibodies. Since patients with IgM monoclonal gammopathy without anti-MAG antibodies have similar symptoms and comparable response to treatment, it is most likely that these patients have antibody reactivity against other components of the nerve. We found monoclonal anti-ganglioside antibodies in half of the patients with polyneuropathy associated with IgM monoclonal gammopathy without anti-MAG antibodies (Chapter 3). Monoclonal IgM anti-GQ1b antibodies were associated with ataxia.

Monoclonal gammopathy is of undetermined significance (MGUS) as long as no hematologic malignancy, like multiple myeloma or lymphoma is found. In patients with polyneuropathy associated with monoclonal gammopathy the frequency of hematologic malignancy is high (22%). A follow-up study of patients with polyneuropathy associated with MGUS showed that the incidence of malignant transformation is higher (2.7/100 patient years, 95% CI 1.52-4.22) than in patient with MGUS without polyneuropathy (1/100 patient years, 95% CI 0.85-1.24). Progression of the polyneuropathy, weight loss, unexplained fever or night sweats and M-protein level were independent predictors (Chapter 4).

To find an explanation for the increased frequency of hematologic malignancies in polyneuropathy associated with monoclonal gammopathy we studied the occurrence of genetic aberrations (Chapter 5) by using interphase fluorescence in situ hybridisation (FISH), multiplex ligation-dependent probe amplification (MLPA) assay and genome-wide array-based comparative genomic hybridisation (CGH). We identified different genetic aberrations in patients with polyneuropathy associated with IgM monoclonal gammopathy. Half of the patients had chromosome 14 translocations, which are also frequently identified in multiple myeloma and B cell malignancies.

The variable part of the immunoglobulin is responsible for the antigen binding and consists of V, D, J gene segments. We determined the immunoglobulin gene usage in patients with polyneuropathy associated with IgM monoclonal gammopathy (Chapter 6). We found a preferential use of immunoglobulin genes associated with immune responses to encapsulated bacteria (preferentially VH3-23).

In patients with polyneuropathy and monoclonal gammopathy, after excluding other causes, the disease course leads the diagnostic process and the additional investigations (Chapter 7, flow chart). We advise a yearly follow-up of all patients with polyneuropathy associated with monoclonal gammopathy, including M-protein level determination. A hematologic screening, including bone marrow examination should be performed if the patient has clinical risk factors of malignant transformation (weight loss, night sweats, bone pain, anemia, rise of M-protein level) or a progressive polyneuropathy.