Serum immunoelectrophoresis and immunofixation are necessary to confirm the presence of a monoclonal protein. In patients with a neuropathy and an IgM monoclonal protein, anti-MAG antibodies should be measured. The Western blot system, using myelin or MAG as antigen, is the most reliable method for detecting anti-MAG antibodies. Antibody titers are usually measured by the ELISA system, using MAG or sulfoglucuronyl paragloboside as antigen. Most normal individuals have absent or low antibody titers, but higher titers (usually greater than 1:6400) are closely associated with the presence of neuropathy. In the MAG ELISA system, however, impurities in the antigen preparation were thought to produce false positive results, and the ELISA assay can miss patients who are positive by Western blot (Van den berg et al 1996). More recently, a new ELISA technique was reported to be more sensitive than Western blot, with good specificity (Kuijf et al 2009).
The detection of a monoclonal protein requires further evaluation for a malignant plasma cell disorder. An M-protein greater than 3.0 g/dL suggests a plasma cell dyscrasia, whereas an amount less than 1.5 g/dL is characteristic of patients who have monoclonal gammopathy of undetermined significance. The serum also should be assessed for cryoglobulins, and serum viscosity should be measured when more than 3.0 g/dL of IgM protein is detected. A bone scan and bone marrow biopsy are usually indicated for patients who have a large amount (3.0 g or more) of monoclonal protein and systemic features suggesting multiple myeloma. A skeletal bone survey also is required in most cases to exclude osteosclerotic myeloma and POEMS syndrome, although this condition is more commonly associated with IgG, IgA, or lambda monoclonal proteins. In patients suspected of having lymphoma or chronic lymphocytic leukemia, chest and abdominal CT scanning and bone marrow biopsy should be performed.
Nerve conduction studies show polyneuropathy with some demyelinating features in over 90% of patients (especially those with anti-MAG titers greater than 5000), although most have evidence of axonal degeneration as well. It has a distinctive pattern with disproportionate prolongation of distal motor latencies in up to 75% of patients, indicating a length-dependent, distal demyelinating process, as previously noted (Kaku and Sumner 1992; Trojaborg et al 1995; Notermans et al 2000; Cocito et al 2001; Gorson et al 2001; Capasso et al 2002). This feature is perhaps best demonstrated by an abnormally short terminal latency index (distal conduction distance [mm]/ (conduction velocity [m/s] x distal motor latency [ms])) (Kaku and Sumner 1992; Cocito et al 2001). The terminal latency index is also useful to distinguish anti-MAG neuropathy from other acquired demyelinating neuropathies (Kaku and Sumner 1992; Cocito et al 2001), although others have suggested that a prolonged distal motor latency (greater than 7.0 msec) or residual latency (greater than 4.0 msec) may be more sensitive (Radziwill et al 2003). In a comparative study, all patients with a terminal latency index of less than 0.26 had MAG neuropathy and all patients with terminal latency index ≥ 0.32 had HMSN1 (Lupu 2007). In the remaining patients with intermediate terminal latency index values, an ulnar distal motor latency value of < 7.4 (at 6 cm distance) had an overall sensitivity of 100% and specificity of 98%.
Other demyelinating abnormalities are also common in anti-MAG neuropathy, including slowed conduction velocities and prolonged or absent F-responses. The finding of conduction block is more variable; most studies have indicated that conduction block is absent or distinctly uncommon (Kaku and Sumner 1992; Ellie et al 1996; Ponsford et al 2000; Capasso et al 2002), but others have demonstrated that it may be observed with some frequency (Notermans et al 2000; Gorson et al 2001). Disproportionate distal slowing with normal distal CMAP duration in the arms may be useful to differentiate chronic inflammatory demyelinating polyneuropathy from MAG neuropathy (Gondim 2007). The lack of temporal dispersion at the distal site suggests a uniform involvement of nerve fibers. One study has suggested a correlation between the anti-MAG titer and the degree of conduction slowing and prolongation of the distal motor latency (Trojaborg et al 1995). Others have demonstrated that the relative accentuation of distal motor latencies was no longer evident on serial nerve conduction studies after prolonged follow-up, indicating a centripetal progression of the demyelination or secondary axonal degeneration, leading to normalization of the terminal latency index (Ponsford et al 2000).
The classic sensory-ataxic form was observed in 20 of 34 patients with IgM gammopathy, whereas multiple mononeuropathy (5), polyneuropathy with predominant motor impairment (8) and painful small fiber neuropathy (1) was identified in the remaining 14 cases (Luigetti et al 2013). Nerve conduction studies revealed a pattern of definite demyelination in 30 of 34 patients and possible demyelination in 2 cases, and one case each had an axonal neuropathy and small fiber neuropathy pattern. Reduced terminal latency index, prolonged distal motor latency and reduced motor conduction velocity were significantly associated with the classic sensory-ataxic phenotype, whereas reduced compound muscle action potential amplitude of the peroneal nerve from the tibialis anterior was mostly associated with atypical forms.
The indications for nerve biopsy in clinical practice have not been defined. In the majority of patients with anti-MAG neuropathy, the diagnosis can be established by the clinical features, presence of an elevated anti-MAG antibody titer and IgM monoclonal protein, and appropriate electrodiagnostic studies; nerve biopsy is usually not necessary. However, nerve biopsy may provide important information in atypical cases, such as patients with a motor predominant pattern, high anti-MAG titer in the absence of a detectable monoclonal protein, or those with an axonal pattern on EMG studies. Pathologic findings include a decrease in the number of myelinated fibers, thin myelin sheaths, and segmental demyelination. Deposits of monoclonal IgM and complement on myelin sheath as well as widening of myelin lamella are characteristic features (Takatsu et al 1985; Hays et al 1988; Monaco et al 1990; Lach et al 1993). In some patients, however, findings of axonal degeneration may predominate in both electrophysiological and pathologic studies (Ellie et al 1996; Van den Berg et al 1996).
Investigators have demonstrated that distal limb skin biopsy can be helpful in the diagnosis of MAG neuropathy (Lombardi et al 2005). The authors detected diffuse deposits of IgM antibodies in subpapillary nerve plexus of dermis in hairy and in glabrous skin containing several MAG- or myelin basic protein-positive small nerve fibers. This was not present in chronic inflammatory demyelinating polyradiculoneuropathy or IgM paraproteinemic neuropathy controls.