Anti-MAG neuropathy is a well-defined autoimmune disorder caused by an immune attack directed against peripheral nerve myelin. The condition was first recognized in the early 1980s when Latov et al. showed binding to a component of myelin in a patient with a peripheral neuropathy and an IgM paraprotein.¹ A subsequent report demonstrated that the binding was against a specific glycoprotein component of myelin, referred to as myelin-associated glycoprotein (MAG).² Over the subsequent years, the condition took on the name of "anti-MAG neuropathy" and others have elaborated upon its clinical features. Anti-MAG neuropathy is marked by three distinguishing abnormalities: a length dependent phenotype presenting with sensory loss in the distal lower extremities; demyelinating nerve conduction abnormalities with uniform slowing that is maximal in the terminal segments of the nerve; and the presence of an IgM paraprotein on serum protein electrophoresis.^1-3 The more descriptive term "distal acquired demyelinating symmetric neuropathy with an IgM paraprotein" or "DADS-M neuropathy" has recently been proposed as a single term that better reflects the main features of this condition.³

In academic centers, the incidence of anti-MAG/DADS-M neuropathy is roughly equal to that of chronic inflammatory demyelinating polyneuropathy. More than 80% of anti-MAG/DADS-M patients are males, and the disease onset is almost always in the sixth decade or later. The chief complaint is the loss of sensation in the feet or distal lower limbs. Gait unsteadiness is also a common early complaint. While sensory symptoms dominate, ankle weakness will occur, predictably, if the distribution of the sensory symptoms is severe enough to reach the mid to upper calves, a characteristic of a "length dependent" neuropathy. In less severe cases, the sensory loss will remain confined to the feet over time, without any weakness. In most cases, the natural history of this disorder is for there to be little or no progression over many years.

Motor nerve conduction studies demonstrate widespread uniform slowing despite the lack of significant motor symptoms.³ In nearly all cases, there is a characteristic pattern where distal latencies are prolonged to a greater degree than proximal latencies. A small "terminal latency index" (TLI) describes this relationship (Figure 1). A small TLI is considered a highly sensitive diagnostic feature of this neuropathy; therefore, its absence should always place the diagnosis in question. However, it is not perfectly specific and can be seen in other demyelinating neuropathies, such as CIDP. Conduction slowing in sensory nerves is prominent in mild cases. When the disease becomes more severe the sural response and the sensory responses in the upper limbs become unobtainable.

Figure 1: Calculating the terminal latency index: (Distance at terminal stimulation site) / (Terminal latency) x (Conduction velocity across forearm)   This is equivalent to: (Terminal Conduction Velocity) / (Proximal Conduction Velocity)

In this example you have (8.0 cm) / (8msec x 31 meters per second) or a TLI of 0.32. The normal limit for the median nerve is greater than 0.34.

Anti-MAG/DADS-M neuropathy has a wide differential diagnosis because it has so many atypical findings. The differential diagnosis of chronic neuropathies that present with numb feet is extensive. Diabetic and idiopathic neuropathies are most common in this category. However, the vast majority of these will be axonal neuropathies, and other findings should readily differentiate anti-MAG/DADS-M neuropathy from demyelinating diabetic or idiopathic neuropathies. The remaining differential diagnosis for length dependent neuropathies includes toxic, metabolic, hereditary and vasculitic disorders. Treatable CIDP with length dependent features is very rare.

If one focuses on the profoundly demyelinating nerve conduction findings, CIDP becomes the most important alternative consideration. However, CIDP patients characteristically complain of generalized weakness, typically affecting both the upper and lower limbs, rather than distal sensory loss. Anti-MAG/DADS-M neuropathy has the pattern of generalized slowing, which is worst in the distal segments of motor nerves, while CIDP causes multifocal slowing, focal temporal dispersion of waveforms, and conduction blocks. Unfortunately, some of the literature refers to anti-MAG neuropathy as "CIDP with a paraprotein." This label is confusing and is being abandoned because the conditions have many clinical differences and different responses to therapy. Therefore, the terms anti-MAG and DADS-M neuropathy help emphasize that these are distinct entities.

Anti-MAG/DADS-M neuropathy also needs to be distinguished from other neuropathies that are associated with paraproteins. The main considerations are the lymphoproliferative disorders that can cause neuropathy including osteosclerotic myeloma with POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes), multiple myeloma, and amyloidosis. However, these conditions are often more subacute in onset or have completely different clinical presentations. CIDP may be associated with a paraprotein, but in cases with the typical motor presentation of CIDP, it is usually IgG. Finally, Waldenstrom macroglobulinemia is the one blood disorder associated with very high concentrations of IgM antibodies. Because of this, the condition is sometimes confused with anti-MAG/DADS-M neuropathy. Waldenstrom macroglobulinemia is a blood disease characterized by hyperviscocity and increased plasma cells in the bone marrow. It is, in rare cases, associated with an axonal neuropathy that should be easily distinguished from anti-MAG/DADS-M neuropathy. The term ‘monoclonal gammopathy of uncertain significance" or "MGUS" applies to cases where the significance of the paraprotein is not known. It should be recalled that up to 5% of a normal elderly population harbor a paraprotein. However, in all other conditions associated with a paraprotein, anti-MAG antibodies are normal, and binding to nerve has not been shown to be the cause of the neuropathy in these other conditions.

If the features of DADS-M are present, anti-MAG antibodies will be positive in high titers in upwards of 70% of cases. Of the remaining 30% of cases, some will have antibodies against sulfate-3-glucuronyl paragloboside (SGPG) and some will not have any detectable antibodies. It is important to test for both antibodies in order to detect the maximum number of affected patients. Although most of the IgM antibodies react with both MAG and SGPG, some may react with MAG or SGPG alone. As a result, testing for both increases the yield. Western blot confirmation is also important since the false positive rate associated with MAG and SGPG ELISA results is quite high. Also note that a small number of DADS-M patients lacking antibodies to MAG and SGPG will have antibodies against Sulfatide or GD1b.

Despite the immune nature of this neuropathy, several studies show that anti-MAG/DADS-M neuropathy responds poorly to immune therapies.⁴ Patients will often describe subjective improvements to IVIg, plasmapheresis, Prednisone or other immune agents, and several early studies suggested immune therapy could be effective and reduce antibody concentrations. However, recent work shows that in the long run, these patients probably do not benefit from therapies, and that there are significant risks to using any sort of immune therapy in elderly populations over years. Still, it is comforting to note that patients with anti-MAG/DADS-M neuropathy do not show significant progression with time.

One important reason for documenting the presence of anti-MAG antibodies is to clearly differentiate this disorder from CIDP or CIDP with a paraprotein. These latter conditions are treatable and patients clearly benefit from immunosuppressive therapy. In contrast, the "risk to benefit" ratio is too high in anti-MAG/DADS-M neuropathy to warrant long-term aggressive therapy. In addition, the identification of the specific anti-MAG antibody helps patients understand their diagnosis and prognosis. Ultimately, unneeded side effects can be avoided, since patients understand treatment is not likely to significantly improve the neuropathic state, and they take comfort that the condition has little progression over long periods.

A 58 year-old man noticed numbness in his feet that gradually ascended to the lower calves over a period of two years. There was no pain and the patient did not complain of weakness. Electrodiagnostic testing revealed profound slowing and he was diagnosed with chronic inflammatory demyelinating polyneuropathy. Normal laboratory testing included thyroid studies, vitamin B12, antinuclear antibodies and sedimentation rate. He was diagnosed with CIDP.

Initial treatment was with Prednisone 60mg daily for two months. This was associated with subjective improvement of sensory function, although no change was documented by examination. The Prednisone dose was tapered slowly to 30mg daily without change. Plasmapheresis was with little benefit. He subsequently received IVIg 2 gms per kg on four separate occasions, again with only subjective sensory improvement. Finally, he was started on Imuran 3mg/kg/day. He was unable to taper these medications without a sensation that his legs were clumsier, but he never had satisfactory improvement that allowed him to remain stable on a single therapy.

He was referred to our neuromuscular center for consideration of a more aggressive immune therapy. Laboratory testing showed an IgM paraprotein on serum electrophoresis. Electrodiagnostic studies revealed generalized symmetric motor slowing with absent sensory potentials and prolonged F-waves (see tables):

Due to the triad of a chronic demyelinating neuropathy, generalized slowing with a small terminal latency index, and the distal sensory phenotype the patient was diagnosed with anti-MAG/DADS-M neuropathy. This raised a high suspicion for anti-MAG antibodies and testing was ordered. Tests results showed a MAG IgM autoantibody titer level of 1:102,400 using the ELISA method. Results were confirmed positive by the Western blot method. Anti-Sulfatide antibodies were also positive with a titer of 1: 466, 875.

With the confirmation of anti-MAG/DADS-M neuropathy, the patient was better able to understand that his condition was not CIDP and he comprehended his history of responding poorly to therapy. Both his Prednisone and Imuran were tapered during which time he experienced mild transient increases in his sensory symptoms. However, there was no change in his examination and ultimately there had been no change in his clinical status from the time of onset until the time that tapering was completed.

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