Paraproteinemic (IgM) polyneuropathy with features of widely spaced myelin, segmental demyelination, onion bulbs and axonal changes.
Along with a clonal transformation of plasma cells in the bone marrow a monoclonal protein consisting of two heavy polypeptide chains of the same subclass and two light polypeptide chains of the same type emerges. Sixty per-cent of patients with paraproteinemia have a monoclonal gammopathy of unknown significance (MGUS), which denotes a serum protein value of less than 3 grams/dL, fewer than 5% of plasma cells in the bone marrow, no proteinuria, normal hematology and absence of systemic signs and symptoms. About 5 % of patients with peripheral neuropathy are found to have MGUS. Conversely, about one third of patients with MGUS display peripheral neuropathy. While IgG is the most common class of paraprotein in patients with benign paraproteinemia, IgM is more common in those with neuropathy (60 %) followed by IgG (30%) and IgA (10%). Approximately one half of patients with peripheral neuropathy and IgM monoclonal gammopathy have IgM antibodies that bind to myelin associated glycoprotein (MAG) and or sulfate-3-glucuronyl paragloboside (SGPG). These patients exhibit a fairly distinctive subset of the syndromes of paraproteinemic neuropathies: the condition is slowly progressive, affects older individuals, initially is predominantly sensory with features of large fiber dysfunction foremost (loss of joint and position sense with ataxia and tremor) and late development of distal limb weakness. The disease in some patients progress slowly but inexorably over decades, mimicking a genetically determined condition. Nerve conduction tracing discloses low velocities. Histologic studies demonstrate segmental demyelination and by immunolabelling deposition of the clonal immunoglobulin in the myelin sheath in the region of widely spaced change.
About 17% of patients with MGUS develop eventually a malignant lymphoproliferative disorder in 10 years and 33% by 20 years (2), including multiple myeloma, Waldenstrom's macroglobulinemia and lymphoma. At presentation our patient had Waldenstrom's without the classic manifestations of bleeding tendency, anemia and lymphadenopathy but rather the polyneuropathy dominated, presumably related to the IgM idiotype with anti-MAG specificity.
The differentiation of paraproteinemic (anti-MAG) neuropathy from chronic inflammatory demyelinating polyneuropathy (CIDP) is sometimes difficult because: a) about 20 % of patients with CIDP also have a paraproteinemia, b) both neuropathies respond to immunosuppresants (4) and c) in both conditions there is increase protein in CSF. Electrophysiologic studies are of some help in that CIDP shows focal block of conduction in motor nerves whereas in the anti-MAG paraprotein associated neuropathy, sensory fibers are severely affected, and conduction slowing (without block) is more diffuse and distally predominant.
Although MAG (and the related glycoconjugate SGPG) is a minor component of peripheral nerve it is essential to the understanding of the pathogenesis of paraproteinemic neuropathies. Its structure includes five immunoglobulin-like domains exposed extracellularly and accessible to antibodies. Confirmation that anti-MAG activity of the paraprotein is responsible for myelin damage has been derived from indirect immunofluorescence immunoblotting experiments using purified human white matter myelin reacted against patient's sera (1), followed by immunolabelling staining of endoneurial deposits of IgM at the site of myelin separation in the patient's nerve biopsy. For the latter best results are obtained by direct immunofluorescence on cryosections (3) (Fig 8) and by electronimmunohistrochemistry (immunogold) (Fig 11). The intrusion of anti-MAG antibodies into the intraperiod line accounts for the characteristic wide spacing between the myelin lamellae that leads to myelin breakdown and remodeling in this disorder. The intraperiod line consists of two thin leaflets 2-4 nm apart, in WSM this distance increases to 20-30 nm (Figs 9& 10). The antibodies "open up" the intraperiod line, which is a space contiguous with the extracellular compartment.
In addition to identifying the anti-MAG myelin alteration, biopsy of a peripheral nerve is an important diagnostic adjunct in patients with paraproteinemia and polyneuropathy because it detects specific changes such as amyloidogenic and non-amyloidogenic light chain deposition, the vasculitis and inflammatory infiltrate of cryoglobulinemia, and may unmask CIDP.
* Portions of this case were presented at the Saturday slide conference during the annual meeting of the AANP, Minneapolis, 1998.
Contributed by Juan M Bilbao, MD, Gyl Midroni, MD and Neville Bayer, MD