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KOS 2007: Paraproteinemia Related Neuropathies
By Eduardo Nobile-Orazio, MD
Eduardo Nobile-Orazio, MD
Department of Neurological Sciences
Milan University
Milan, Italy
06.28.07

Department of Neurological Sciences
Milan University
Milan, Italy

NOTE: THE AUDIO FOR THIS PRESENTATION IS NOT AVAILABLE DUE TO TECHNICAL PROBLEMS WITH THE RECORDING.

Introduction
Even if the association of neuropathy with monoclonal gammopathy has been known for several years, the clinical and pathogenetic relevance of this association as well as its therapeutical implication are not completely established. This is not a marginal problem as: a) monoclonal gammopathy, which in 75% of cases are or of undetermined significance and therefore asymptomatic not requiring per se any treatment, can be found in 1% of the population above 50 years and in 3% of those above 70 years, and b) a symptomatic neuropathy can be found in at least 8% of patients with monoclonal gammopathy, so that the prevalence of this neuropathy in the population above 50 years may be of 80 per 100.000, representing, after diabetes, one of the leading causes of neuropathy in aged people. Monoclonal gammopathy may result from malignant lymphoproliferative diseases including multiple myeloma or solitary plasmocytoma, Waldenstrom's macroglobulinemia (WM), other IgM secreting lymphoma or chronic lymphocytic leukaemia, as well as from primary amyloidosis (AL) and cryoglobulinemia. In most instances monoclonal gammopathy is not associated with any of the above mentioned disorders and is per se totally asymptomatic, being named benign monoclonal gammopathy or, more appropriately, monoclonal gammopathy of undetermined significance (MGUS) for the possible, though infrequent (approximately 1% per year), evolution into malignant forms (Kyle & Rajkumar 2003). In these patients neuropathy is often the only clinical manifestation of the underlying haematological disorders. The prevalence of a symptomatic neuropathy in patients with monoclonal gammopathy varies according to the haematological diseases and, for the same disease, from series to series, depending on the criteria used to define the presence of neuropathy. In two large series of patients with MGUS for instance, the prevalence of a symptomatic neuropathy ranged from 8% to 36% of patients being significantly higher in patients with IgM than with IgG or IgA MGUS, reinforcing the hypothesis, at least for IgM monoclonal gammopathy, of a possible pathogenetic role of IgM M-proteins in the neuropathy. This issue has bee recently reviewed by a panel of experts (Hadden et al 2006).

Neuropathy and IgM monoclonal gammopathy
A symptomatic neuropathy has been reported in up to 50% of patients with IgM monoclonal gammopathy. Some of these patients have WM or other forms IgM secreting lymphoprolipherative disease. The majority of them have however an IgM MGUS whose only clinical manifestation is the neuropathy leading a panel of haematologist to include them in a clinically distinct group that they proposed to name IgM- related disorders (Owen et al 2003). Different forms of neuropathies have been associated with IgM monoclonal gammopathy, possibly reflecting the different mechanisms involved in their pathogenesis (Nobile-Orazio 1998): cranial nerve palsies, mononeuropathies or mononeuritis multiplex have been reported in WM and lymphoma and were related to lymphoplasmacytic infiltration of nerves, amyloid deposition, cryoglobulinemic vasculitis or microangiopathy of endoneurial vessels. The vast majority of these patients, as well as of those with IgM MGUS, have however a chronic progressive, symmetric and predominantly distal neuropathy which was occasionally related to endoneurial accumulation of the M-protein, or diffuse microangiopathy but most frequently to a reactivity of the M-protein with a number of neural antigens including MAG, cytoskeletal proteins, chondroitin sulfate C, sulfatide and several gangliosides. Overall these reactivities are found in at least two thirds of patients with neuropathy and IgM monoclonal gammopathy being more frequent in MGUS (84%) than WM (38%) (Nobile- Orazio et al. 1998). Some of these IgM reactivities have been associated with homogeneous neuropathy features, which will be here briefly reviewed.

Neuropathy associated with anti-MAG IgM. In almost 50% of patients with neuropathy associated with IgM monoclonal gammopathy the M-protein react with MAG and other nerve glycoconjugates sharing with MAG the HNK-1 carbohydrate epitope (Nobile-Orazio et al. 1998). Almost 80% of patients with anti-MAG IgM have IgM MGUS while most remaining patients have an otherwise asymptomatic WM.
The neuropathy in patients with high anti-MAG IgM antibodies is quite homogeneous, mostly affecting men in the sixties or seventies. The neuropathy is characterized by a distal and symmetric, predominantly deep sensory involvement, with gait ataxia and postural tremor in the upper limbs. Motor impairment is usually less prominent and often appears later. The neuropathy usually runs a slowly progressive course with most of the patients having a long-term favourable functional prognosis with only a minority of them becoming disabled after several years (Nobile-Orazio et al. 2000). Electrophysiological and morphological studies are consistent with a demyelinating neuropathy.

Several data support the pathogenetic role of anti-MAG IgM in the neuropathy: 1) high titres of anti-MAG IgM antibodies are almost invariably associated with an homogeneous clinical pattern and predict the development of neuropathy in asymptomatic patients with IgM monoclonal gammopathy; 2) pathological studies on nerve biopsies show segmental demyelination with abnormally spaced myelin lamellae and deposits of IgM M-protein and complement on nerve myelin, i.e. the target of the anti-neural reactivity; 3) therapeutical reduction of anti-MAG IgM most often correlates with clinical improvement; 4) complement mediated demyelination of nerve has been experimentally induced in animals by intraneural or systemic injection of anti-MAG IgM M-proteins.

Several therapies directed at reducing the presumably pathogenic IgM paraprotein or B-cell clone have been used in these patients, including steroids, plasma exchange, cytotoxic agents, high-dose intravenous immunoglobulin (IVIg) and interferon-α Even if almost 50% of patients have been reported to improve, at least temporarily, after one of more of these therapies’ their effect on the long-term prognosis of the neuropathy remains unclear as in only few studies the follow-up exceeded two years. This data would be particularly important in consideration of the usually slow progression and relatively favourable prognosis of the neuropathy associated with anti-MAG IgM, and the frequent adverse effects of most of these therapies. In addition very few controlled trials have been performed in these patients with only one showing a modest short-term efficacy of IVIg so that there is insufficient evidence to recommend any particular immunotherapy in this neuropathy (Lunn et al 2003). The preliminary positive effect on the neuropathy reported with the humanised monoclonal antibody (Rituximab) directed against the CD20 antigen on B-lymphocytes has been now confirmed by a randomized trial (Dalakas et al 2006).

Neuropathy with other anti-nerve reactivities. Several other anti-neural reactivities of IgM M-proteins have been reported in patients with IgM related neuropathies. Anti-sulfatide IgM have been reported in several patients with neuropathy, half of whom had IgM monoclonal gammopathy, and were initially associated with chronic progressive, predominantly sensory axonal neuropathy or with painful small fiber neuropathy with normal electrophysiological studies, while in subsequent reports this reactivity has been associated with sensorimotor demyelinating neuropathy. Morphological studies on sural nerve biopsy showed in some patients deposits of the M-protein and complement. Few data are available on the clinical response to treatment in these patients so that their strict association with a dysimmune neuropathy mainly supports the possible pathogenetic relevance of these antibodies. IgM reactivity with the ganglioside GM1 has been originally reported in patients with IgM monoclonal gammopathy and a peculiar neuropathy named multifocal motor neuropathy, even if the vast majority of subsequently reported patients with these antibodies did not to have an IgM monoclonal gammopathy. More recently a number of patients have been reported with neuropathy associated with an IgM monoclonal gammopathy reacting with gangliosides containing disialosyl groups including GQ1b, GD1b, GT1b, GD3 and GD2 (Willison et al (2001). Most of these patients had a chronic sensory neuropathy with prominent ataxia, usually mild or no weakness, recurrent ophthalmoplegia and cold agglutinin activity of the M-protein that often bind to the Pr2 antigen on red cell membranes. Willison proposed for this syndrome the acronym CANOMAD (Chronic Ataxic Neuropathy with Ophthalmoplegia, M-protein, cold Agglutinins and anti-Disyalosil antibodies). In most of these patients electrophysiological and morphological studies were consistent with a demyelinating process. In none of them myelin deposits of the M-protein were found in sural nerve, but in one inflammatory cells infiltrates were found reminiscent of CIDP. This may explain the reported improvement of some of these patients after IVIg therapy. Monoclonal IgM reactivities with other gangliosides have been occasionally reported in these patients including GD1a, GM2 and GD1b. The possible pathogenetic and clinical relevance of these and other even less frequent IgM reactivities remains unclear as in none of these patients IgM deposits were found in sural nerves and little is known on their response to immune therapies. At the same time the very small number or reported observations does not permit to clarify the clinical phenotype of these reactivities.

Neuropathy with IgM not reacting with neural antigens. In approximately one third of the patients with neuropathy associated with IgM monoclonal gammopathy no reactivity of the M- protein with any of the above mentioned nerve antigens could be detected. This is particularly true for patients with WM or lymphoma, two thirds of whom have no detectable reactivity. Several other mechanisms have been implicated in the pathogenesis of the neuropathy in this group of patients including vasculitis of vasa nervorum or intravasal precipitation of immunoglobulins when the IgM M-protein is a cryoglobulin, direct lymphoplasmacytic infiltration of nerves, hyper viscosity, microangiopathy of vasa nervorum, endoneurial accumulation of the M-protein or amyloidosis. As already mentioned, these mechanisms are often associated with a mononeuropathy or mononeuritis multiplex, but can also underlie a symmetric polyneuropathy. Whatever is the mechanism for the neuropathy in this heterogeneous group, this is also often strictly related to the M-protein or to its producing cells explaining why treatment directed at reducing IgM M-protein production may result in clinical improvement. Since a malignant lymphoproliferative disease with concomitant life-threatening extra-neurological impairment affects most of these patients, an aggressive chemotherapy under the supervision of competent haematologists is usually required.

Neuropathy and IgG monoclonal gammopathy
While neuropathy associated with IgM monoclonal gammopathy is well characterised, less clear is the relationship between the neuropathy and IgG M-protein. Some patients have multiple myeloma in which neuropathy is occasionally the presenting symptom but more frequently occurs in patients with an established disease, with a prevalence of 3% to 13%. The neuropathy associated with multiple myeloma is clinically heterogeneous (Kelly 1998) probably reflecting the presence of different pathogenetic mechanism. In approximately half of the patients the neuropathy is caused by light chain amyloidosis with a predominantly sensory distal impairment, postural hypotension and other signs of autonomic impairment, and is often associated with signs of systemic amyloidosis including malabsorbtion, cardiac and renal dysfunction. Nerve or nerve root direct infiltration by myeloma or compression by bone lesions cause an asymmetric mono or multineuropathy or radiculopathy often characterized by excruciating pain. Neuropathy also occurs as a complication of therapy used in myeloma including vincristine, thalidomide and, more recently, bortezomib.

More typical are the features of the neuropathy associated with osteosclerotic myeloma where neuropathy is found in up to 50% of the patients and where it is often the presenting symptom of the disease. These patients often have a severely disabling predominantly motor demyelinating neuropathy frequently starting with sensory symptoms. This neuropathy is sometime associated with other non-neurological manifestations including, organomegaly, endocrinopathy, lymphoadenopathy, ascites, peripheral oedema and a very typical brown reddish “tanned” colour of the skin. This constellation of symptoms has been collected under the eponym of POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, M-protein and Skin changes) and has been occasionally reported also in patients with non-malignant gammopathies (Dispenzieri et al 2003). The clinical and pathogenetic relevance of this association is supported by the improvement of the neuropathy observed in more than half of the patients who respond to the treatment of the osteosclerotic lesion(s) which include local radiotherapy or resection of the tumor and a variable combination of steroids and melphalan, and more recently autologous peripheral blood stem cell transplantation (Dispenzieri et al. 2004).

The majority of patients with neuropathy and IgG M-protein have an IgG MGUS, which is found during the work-up or the follow-up of the neuropathy. The prevalence of a symptomatic neuropathy is however lower (3%) than IgM MGUS (15%) (Nobile-Orazio et al 2002), possibly explaining the lower representation of IgG in large series of patients with neuropathy and MGUS. Several forms of neuropathy have been associated with IgG MGUS even if in more recent studies, almost half of the patients had a chronic demyelinating neuropathy clinically and therapeutically indistinguishable from chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) (Hadden et al 2006) while the remaining had a predominantly sensory axonal or mixed neuropathy. The possible pathogenetic role of IgG M-proteins in the neuropathy remains however unclear as in very few patients reactivity of IgG M-proteins with neural antigens or endoneurial deposits of IgG have been reported, while in over 50% of them the M-protein become manifest several months to years after onset of the neuropathy. Still the improvement observed with immunotherapy not only in patients with a CIDP-like neuropathy but also in some of those with an axonal neuropathy suggest that even if the presence of IgG MGUS might not be primarily pathogenetic, its finding may represent a marker of a possibly dysimmune origin of the neuropathy.

Neuropathy and IgA monoclonal gammopathy
Only few patients with neuropathy and IgA monoclonal gammopathy have been reported representing in most large of patients with neuropathy and monoclonal gammopathy a very small proportion of the patients. Some of these patients have myeloma or a POEMS syndrome (see above) while a few of them had IgA MGUS. The clinical and electrophysiological features of the neuropathy in these patients are quite heterogeneous (Nobile-Orazio et al 2002) making it impossible to identify a prevailing type of presentation except that the neuropathy was chronic progressive in all but one patient who had an acute onset. As in the case of neuropathy associated with IgG MGUS there is little evidence that IgA M-proteins have a primary pathogenic role in the neuropathy since anti-neural reactivity or endoneurial deposits of IgA M-proteins have been occasionally reported. Few patients have been reported to improve with immune therapies but their limited number and the consequent elevated risk of a publication bias are not sufficient to justify the assumption that the identification of an IgA M-protein reveal a dysimmune origin of the neuropathy which might benefit of immune therapies.

References
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