Historical note

In 1848 Bence-Jones first suggested that there was abnormal protein synthesis in myelomatosis after observing a precipitate combined with nitric acid and the urine of a patient with severe bone pain (10). Ellinger reported the presence of an abnormal protein in the blood of a patient suffering from multiple myeloma (59). McFarlane was the first to report observations on myeloma serums using the ultracentrifuge method, noting a peak in the globulin range (131). Bing and Plum clearly associated hyperglobulinemia with an increase in plasma cells (15).

IgM monoclonal gammopathy and neuropathy. In 1936, Bing and Neel reported the first case of peripheral neuropathy associated with macroglobulinemia (14). Peripheral nerve involvement by the infiltration of tumor cells was thought to be the mechanism of neuropathy (123). However, because tumor cells infiltrating nerves were rarely found, an autoimmune mechanism was suspected. The demonstration of monoclonal IgM deposits in sural nerves further supported an autoimmune hypothesis (80). A monoclonal IgM antibody that bound to peripheral nerve myelin was first reported in 1980 (115). This antigen was later identified as myelin associated glycoprotein (19).

IgG monoclonal gammopathy and neuropathy. Although the documentation is incomplete, the report of Senator may have been the first case described of multiple myeloma with neuropathy (177). Peripheral nerve involvement by amyloidosis was described pathologically in 1938 (40). Clarke proposed that systemic amyloidosis might be the cause of peripheral neuropathy in myelomatosis (30). Walsh and Sydney reported a 13% incidence of peripheral neuropathy in multiple myeloma with axonal degeneration as the primary mechanism (201). Chazot reported the first case of nonmalignant IgG monoclonal gammopathy and neuropathy (28).

Nomenclature

Monoclonal immunoglobulin antibodies are produced by expanded single B-cell clones and are variably known as monoclonal proteins, M protein, M component, monoclonal gammopathy, or paraprotein. They are classified as IgM, IgG, or IgA according to the heavy chain type; light chain types include kappa and lambda. Monoclonal gammopathy can be associated with nonmalignant or malignant lymphoproliferative B-cell disorders. The nonmalignant monoclonal gammopathies without any end organ damage, have been referred to as “monoclonal gammopathies of undetermined significance,” or MGUS (96; 196; 83), or by the alternative term “nonmalignant monoclonal gammopathy.” Depending on associated symptoms and signs the same monoclonal gammopathy may be clinically significant (MGCS) (140; 92). Monoclonal gammopathy associated with a polyneuropathy has been called monoclonal gammopathy of neurologic significance (MGNS) (83).

Monoclonal antibodies are found in 10% of patients with peripheral neuropathy of otherwise unknown etiology (89), a higher proportion than in the general population. In patients with peripheral neuropathy and monoclonal antibodies, long-term follow-up reveals that two thirds will have monoclonal gammopathy of undetermined significance (MGUS) and one third will have a plasma cell dyscrasia or lymphoproliferative disorder (98). Due to biological behavior, it is useful to classify MGNS as IgM and non-IgM (IgG and IgA). IgM monoclonal gammopathies originate form CD20+ lymphoplasmocytic devoid of class switch recombination cells whereas non-IgM ones originate from mature plasma cells (107). Most IgM MGNS exhibit autoantibody reactivity to neural antigens, but such autoantibody activity has not been associated with IgG or IgA monoclonal gammopathies.

Clinical manifestations

Table 1 lists the malignant lymphoproliferative diseases associated with monoclonal gammopathy and neuropathy. Table 2 lists the neuropathy syndromes associated with the monoclonal gammopathies.

Table 1. Malignant Lymphoproliferative Diseases Associated with Monoclonal Gammopathies

IgM:
	• Waldenstrom macroglobulinemia • Chronic lymphocytic leukemia • B-cell lymphoma
IgG, IgA:
	• Myeloma • Smoldering multiple myeloma • Osteosclerotic myeloma/POEMS syndrome • B-cell lymphoma

Table 2. Neuropathy Syndromes Associated with Monoclonal Gammopathies

IgM: Neuropathy with antibody reactivity to the following glycoconjugate antigens:
	• Myelin associated glycoprotein/sulfoglucuronyl paragloboside/sulfated glucuronic acid lactosaminylparagloboside • Sulfatide • GM1 • GM2 • GD1a • GD1b • GT1b • CNS myelin antigen • beta-tubulin
IgM>IgG, IgA: Cryoglobulinemia:
	• Type 1: monoclonal gammopathy, most frequently IgM • Type 2: monoclonal gammopathy, most frequently IgM, and polyclonal, usually IgG
IgG, IgA>IgM: Primary amyloidosis

In routine practice a monoclonal gammopathy is identified either in the context of a workup of an idiopathic polyneuropathy (most common reason to find one) (169) or as part of the workup for unexplained hypercalcemia, renal failure, anemia, bone lesions (CRAB features), acute osteoporosis, or unexplained skin changes (16; 42; 140; 194).

Nonmalignant monoclonal gammopathy/monoclonal gammopathy of undetermined significance (MGUS). Nonmalignant monoclonal gammopathy is defined by the presence of a monoclonal protein in a patient without a plasma cell or lymphoproliferative disorder. It is a preneoplastic disorder (20). Patients should have a serum M-protein of less than 3.0 g/dL, bone marrow clonal plasma cells less than 10%, less than 500 mg protein in a 24-hour collection specimen, and the absence of organ or tissue involvement. There should be no lytic bone lesions, anemia, hypercalcemia, renal insufficiency, symptomatic hyperviscosity, amyloidosis, or recurrent bacterial infections (191). Patients should be free of B type symptoms: weight loss, night sweats, fatigue.

Approximately 79% of all cases of nonmalignant monoclonal gammopathy are IgG, followed by IgM (17%) and IgA (11%) (16). On the other hand, 50% to 60% of cases of nonmalignant monoclonal gammopathy associated with neuropathy are IgM, 25% to 30% are IgG, and 10% to 15% are IgA (145; 143; 166; 27).

Nonmalignant IgM monoclonal gammopathy–associated polyneuropathy (MGNS). IgM monoclonal gammopathies frequently have autoantibody activities that are implicated in the pathogenesis of the neuropathy (171; 65). The pathogenesis of IgM-associated polyneuropathies is dominated by B cells or plasma cells (188). Several studies have shown that 50% of patients with peripheral neuropathy and IgM monoclonal gammopathy have antibodies reactive with myelin-associated glycoprotein (115; 148; 87; 143; 140). Several data support the pathogenic role of anti-MAG IgM in polyneuropathy (143; 65). Autoantibody reactivity to neural antigens can be identified in 65% of patients with IgM monoclonal gammopathy and neuropathy, compared to only 7% of patients without neuropathy (149).

Several distinct neuropathic syndromes can be recognized among patients with autoreactive IgM monoclonal antibodies. These syndromes include (but are not limited to) the following:

(1) A slowly progressive, chronic, distal and symmetrical, demyelinating sensory predominant or sensorimotor neuropathy with late and mild distal motor involvement has been associated with IgM anti-MAG antibodies (DADS-M) (143; 128; 36; 140). The typical age of onset is later than 50-years-old, and clinical features include large and small fiber sensory symptoms (100%), tremor (30%), and sensory gait ataxia (70%). The phenotype can present in the absence of an IgM monoclonal spike (distal acquired demyelinating symmetric - DADS). Twenty-five percent of patients are disabled after 10 years and 50% after 15 to 20 years of symptoms. Spinal fluid protein count is usually elevated. The hallmark electrophysiological abnormality is disproportionately prolonged distal motor latencies (87) out of proportion to proximal conduction velocity slowing and absent proximal dispersion or conduction blocks (166). This constitutes an electroclinical dissociation, as the electrophysiological findings are unexpected in the face of a clinical phenotype suggestive of a length-dependent axonal polyneuropathy. On close observation, the electrophysiological findings support an acquired length-dependent demyelinating polyneuropathy. This is important to mention as the demyelinating electrophysiological findings should not be construed as supportive of a diagnosis of chronic inflammatory demyelinating polyneuropathy (multifocal demyelination), which, in addition, has a different clinical phenotype. DADS-M phenotype can also be seen in Waldenstrom macroglobulinemia or B-cell lymphoma. If the presentation is a small fiber neuropathy without large fiber involvement, the IgM spike is likely coincidental, but amyloidosis should still be considered (140).

(2) A predominantly motor demyelinating polyneuropathy (multifocal motor neuropathy) has been associated with anti-GM1 IgM antibodies, present in 50% of patients (163), and rarely with anti-GM2 IgM or anti- GD1ab IgM antibodies (143). These patients present with slowly progressive asymmetric weakness, preferentially affecting the upper extremities, and conduction block on electrophysiological testing (159). Of note is that monoclonal gammopathy is found in less than 10% of patients with multifocal motor neuropathy and anti-GM1 antibody (143). A polyradiculoneuropathy akin to CIDP has also been described (140).

(3) A large fiber chronic sensory ataxic neuropathy has been associated with IgM antibodies, NeuAc(α2-8)Neu-Ac(α2-3) disialosyl epitopes common to many gangliosides: anti-GD1b, GD3, GT1b, and GQ1b antibodies, often with cross-reactivity to anti-GQ1b and anti-GD1b antibodies (61). The syndrome has been designated as CANOMAD: chronic ataxic neuropathy with ophthalmoplegia, M protein, cold agglutination (50%), and disialosyl antibodies (204). Bulbar weakness and facial numbness have also been described (140).

Men are more often affected than women, mean age of onset is 40 to 72 years, and mean duration of symptoms is 13 years. There is variable presence of perioral and limb paresthesias with preserved small fiber function, areflexia, upper limb sensory ataxia/pseudoathetosis, areflexia, ophthalmoplegia (more common is third nerve involvement), and facial or bulbar weakness. Limb weakness is commonly absent or very mild. There is a pattern of relapsing symptoms affecting multiple regions in descending frequency: ocular, sensory, bulbar, and motor function. This may mimic a brainstem vascular or demyelinating process. Up to half of patients have elevated spinal fluid protein and electrophysiologically there is sensory axonal loss with mild motor amplitude reductions and demyelinating features in only one third.

(4) A demyelinating or axonal sensory neuropathy has been associated with IgM antisulfatide antibodies. However, the phenotype can vary, anywhere from isolated small fiber to sensory or sensory motor polyneuropathy, axonal, or demyelinating. This heterogeneity brings into question a true pathogenic association of these antibodies (Joint Task Force of the EFNS and PNS 2010).

(5) Most patients with IgM monoclonal gammopathy and neuropathy who have no detectable antigenic reactivity may have a predominately sensory distal polyneuropathy (149); some have cryoglobulinemia, which can present as a mononeuropathy, mononeuritis multiplex, or a polyneuropathy. Other subgroups may have lymphocytic infiltration of nerves, a microangiopathy of the vasa vasorum, or endoneurial accumulation of M protein. Some patients might have M proteins that react with unidentified neural antigens.

Some authors have reported that as a group, patients with IgM monoclonal gammopathy have worse nerve conduction abnormalities, and a higher frequency of sensory loss and ataxia, compared with patients with IgG and IgA monoclonal gammopathies (75; 189; 152); however, other studies have not found these differences (21; 181; 182).

For a patient with an IgM related neuropathy, it is important to pay attention to red flags: acute onset, rapid progression, pain, autonomic symptoms, weight loss, and cutaneous or central nervous system signs. If red flag symptoms are present, consider amyloidosis, cryoglobulinemia, Bing-Neel syndrome, or neurolymphomatosis (92).

Nonmalignant IgG and IgA monoclonal gammopathy and neuropathy (MGNS). Non-IgM monoclonal gammopathies have not been associated with high-affinity binding antibodies to neural antigens. The pathophysiology of neuropathy is not well understood. Two syndromes have been reported with approximately equal frequency in patients with nonmalignant IgG monoclonal gammopathy.

(1) One form seen in 50% of patients is a moderately severe, predominantly motor demyelinating neuropathy that is indistinguishable from chronic inflammatory demyelinating polyneuropathy (CIDP).

(2) The other form is a mild, slowly progressive, predominantly sensory neuropathy that has an axonal or mixed axonal and demyelinating electrophysiologic pattern (52). Nonmalignant IgA monoclonal gammopathy is only rarely associated with neuropathy, and limited reports describe patients with sensory or motor axonal peripheral neuropathy. In some reports, there is no evidence of deposition of IgA on nerve or myelin sheath (141); however, other authors have described nerve biopsies showing widening of myelin lamellae, like the nerve biopsy findings in IgM anti-MAG neuropathy (195).

Waldenstrom macroglobulinemia. Waldenstrom macroglobulinemia may be associated with IgM monoclonal gammopathy and peripheral neuropathy. There are various neuropathies described with Waldenstrom macroglobulinemia, including an axonal peripheral neuropathy, a demyelinating peripheral neuropathy with anti-MAG antibodies, a demyelinating peripheral neuropathy with other antiganglioside antibodies, mononeuropathy multiplex or symmetric polyneuropathy associated with type I cryoglobulinemia, or amyloid polyneuropathy (46).

Multiple myeloma. Multiple myeloma may rarely be associated with IgG or IgA monoclonal gammopathy and neuropathy. The neuropathy of multiple myeloma may be sensory, motor, or sensorimotor. Usually, an axonal pattern is found on electrophysiological studies. The neuropathy associated with multiple myeloma, excluding osteosclerotic myeloma, may be secondary to amyloid deposition in up to 40% of cases (97).

POEMS syndrome. POEMS syndrome has been strongly associated with osteosclerotic myeloma, a rare subtype of myeloma, but may also occur with other lymphoproliferative disorders, including lymphatic hyperplasia or Castleman syndrome. The acronym POEMS stands for polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; these clinical features may be variably present in patients with the disease. Common skin changes include hyperpigmentation, pitting edema, hypertrichosis, skin thickening, flushing, white nails, and clubbing (48). The current diagnostic criteria require patients to have polyneuropathy, M protein, one other major diagnostic criterion (sclerotic bony lesions, Castleman disease, or VEGF elevation), and one minor criteria (48). Whereas polyneuropathy is only rarely associated with multiple myeloma, 50% of patients with osteosclerotic myeloma have an associated peripheral neuropathy (54). The polyneuropathy of POEMS syndrome is often rapidly progressive, disabling, and may start with sensory symptoms, but is predominantly motor in nature (may resemble a motor predominant CIDP picture). The polyneuropathy is demyelinating in nature, with proximal and distal weakness and variable sensory loss resembling chronic inflammatory demyelinating polyneuropathy (CIDP), but there is early drop in distal motor amplitudes on nerve conductions and marked distal atrophy of legs more than arms. Pain is more common (76%) than CIDP (7%) and there is rare cranial nerve involvement (129).

In POEMS syndrome with osteosclerotic myeloma, the sclerotic bony lesion consists of a plasmacytoma producing an M protein, most often of the IgG or IgA lambda class. Overproduction of VEGF has been reported to be important in the pathogenesis of the syndrome (203) and may lead to leg edema or organomegaly through promotion of vascular leakage. Common skin changes include hyperpigmentation, pitting edema, hypertrichosis, skin thickening, flushing, white nails, and clubbing (48). Incorporating the acronym PEST in the clinical evaluation is helpful: papilledema, extravascular volume overload, sclerotic bone lesions, thrombocytosis (85).

Primary systemic amyloidosis. Primary systemic amyloidosis is a multisystem disorder caused by the deposition of amyloid fibrils (the monoclonal protein is the disease-causing agent) in various tissues. Nerve infiltration with amyloid fibrils composed of the variable portion of immunoglobulin light chains or, less commonly, the entire light chain is thought to be the cause of polyneuropathy in primary systemic amyloidosis. Most patients with primary systemic amyloidosis have an associated monoclonal gammopathy, whereas those with familial amyloidosis do not. Amyloidosis is more frequently associated with IgG and IgA rather than IgM monoclonal gammopathy. Forty percent of patients with nonmalignant primary systemic amyloidosis present with a polyneuropathy whereas malignancy associated primary systemic amyloidosis has an associated polyneuropathy in 13% of cases (40% by electrophysiological testing).

There are five patterns of primary systemic amyloidosis polyneuropathy (202): (1) generalized autonomic failure and painful polyneuropathy (62%); (2) generalized autonomic failure and painless polyneuropathy (17%); (3) isolated autonomic failure (11%); (4) isolated polyneuropathy (5%); and (5) sensory (small fiber) autonomic polyneuropathy (5%).

The neuropathy of amyloidosis is characterized by painful paresthesias distally in the hands and feet, followed by the development of motor manifestations. One half to two thirds of patients develop autonomic symptoms, including orthostatic hypotension, bowel and bladder dysfunction, and impotence. Autonomic manifestations may become severe and debilitating and resemble autonomic failure. Pain and temperature are more affected than proprioception and vibration. The neuropathy is similar in cases of amyloidosis, regardless of coexisting multiple myeloma. Carpal tunnel syndrome is seen in 25% of patients. The electrodiagnostic findings are usually consistent with an axonal polyneuropathy, with predominant involvement of small myelinated and unmyelinated fibers (201; 103). Fatigue, weakness, and weight loss are common complaints. Renal failure (30%) or congestive heart failure (20%) is also common at presentation (100). The mean duration of symptoms in patients presenting with a dominant neuropathy before diagnosis is 29 months (167).

Cryoglobulinemia. Cryoglobulinemia may cause a triad of arthralgia-purpura-weakness (93) and is caused by serum proteins that precipitate in the cold and redissolve when warmed. Cryoglobulinemia is classified according to the type of immunoglobulin excess. Type 1 cryoglobulinemia is a monoclonal immunoglobulin, most frequently IgM. Type 2 cryoglobulinemia is both monoclonal and polyclonal immunoglobulins, most often monoclonal IgM, but the autoantibody activity is against the polyclonal component, most often IgG. Type 3 cryoglobulinemia possesses polyclonal immunoglobulins and is often associated with HIV and hepatitis B or C infections (93). Types 2 and 3 are referred to as mixed cryoglobulinemias. IgM monoclonal gammopathy can be associated with type 1 or type 2 cryoglobulinemia, wherein the neuropathy may be caused by immunoglobulin mediated demyelination or by vasculitic occlusion involving the vasa nervorum (192). If the cryoglobulinemia is not associated with an underlying process such as autoimmune disease, malignancy, or systemic illness, the condition is referred to as essential cryoglobulinemia.

Patients with type 1 cryoglobulinemia present with primarily vascular manifestations that include purpura, Raynaud phenomena, and infarcts of the digits on exposure to cold. A symmetric sensorimotor polyneuropathy, usually painful, is more prevalent in type 2; a mononeuritis multiplex is more prevalent in type 3 (63; 69). Types 1 or 2 are often associated with Waldenstrom macroglobulinemia, multiple myeloma, chronic leukemias, and lymphomas. Type 3 is often associated with collagen vascular disease and infections. An estimated 43% to 84% of patients with essential mixed cryoglobulinemia have hepatitis C virus infections, suggesting an etiologic role of this virus (03).

Epidemiology

Older studies have estimated the prevalence of monoclonal gammopathy in the adult population at approximately 1%. When stratified by decade, monoclonal gammopathy has been identified in 0.1% to 0.2% of people under 50 years of age, 2% to 2.8% in the eighth decade, 4.2% to 11% in the ninth decade, and 20% in the general population over 95 years of age (165; 174; 35). However, a study in Olmstead County, Minnesota, found the presence of a monoclonal protein in 3.2% of people over the age of 50 years; the higher detection rate is thought to relate to the newer use of immunofixation (a more sensitive test) in place of immunoelectrophoresis (111). This study cites a prevalence of 5.3% over the age of 70 and 7.5% over the age of 85 (111). The prevalence of MGUS is twice as high in African Americans as in Caucasians (32). In addition, first-degree relatives of patients with MGUS carry a higher risk of developing MGUS, multiple myeloma, Waldenstrom macroglobulinemia, or chronic lymphocytic leukemia (112).

The distribution of heavy chain classes in patients with monoclonal gammopathy is 60% to 80% IgG; 8% to 24% IgM; 0% to 17% IgA; and 0% to 0.5% IgD (05; 64; 102; 174; 119; 97). A biclonal gammopathy is detected in 2% to 5% of patients with monoclonal gammopathy (05; 108; 174).

The proportion of patients with monoclonal gammopathy found to be harboring malignancy has been reported in a range of 0.5% to 35% (164; 99). The higher value represents patients from a tertiary referral center, and the lower value from a general population survey. In another series, two of 64 cases (3%) of monoclonal gammopathy were found to be malignant (05). In a community population survey in Minnesota, none of 15 people with a monoclonal gammopathy of 1200 surveyed had evidence of multiple myeloma or macroglobulinemia (102). In a survey of 13,400 sera from blood donors, four of 20 (20%) identified patients with monoclonal gammopathy were determined to have multiple myeloma or Waldenstrom macroglobulinemia (64).

The largest so far populational study of MGUS and clinically diagnosed polyneuropathy found a prevalence of polyneuropathy in MGUS to be 6.5% compared to 2.8% in the normal age matched population (172). Prevalence of polyneuropathy in MGUS is thought to be more in the range of 15% to 20%, suggesting that clinical diagnosis of polyneuropathy underestimates true prevalence. MGUS conferred a 2.7 times higher risk to develop polyneuropathy compared to controls. The presence of polyneuropathy in a patient with MGUS is associated with a 2.9 times higher risk for progression to primary amyloidosis and 82% of this progression occurs in the first year after the diagnosis of polyneuropathy. Polyneuropathy was associated with 1.3 times higher risk of death in a patient with MGUS.

Historically, the reported prevalence of peripheral neuropathy in patients with any type of nonmalignant monoclonal gammopathy varies greatly due to definitions of polyneuropathy and hematology versus neurology center data: 3% to 32% (81; 156; 94; 200) and 17% to 71% (166). A population-based study examined sera from over 17,000 residents of Olmstead County, Minnesota, for the presence of an M protein. This large study confirmed an association between MGUS and both chronic inflammatory demyelinating polyneuropathy (CIDP relative risk 5.9; 95% CI, 1.2-28.4) and autonomic neuropathy (relative risk 3.2; 95% CI, 1.3-8.3), but it did not find a correlation between MGUS and other forms of peripheral neuropathy (13). There remains some uncertainty as to the pathogenic relationship between nonmalignant monoclonal gammopathy and various forms of peripheral neuropathy.

The incidence of neuropathy in patients with nonmalignant IgM monoclonal gammopathy has been reported at 16% overall, with the highest incidence (31%) associated with IgM gammopathies, followed by IgA (14%) and IgG (6%) (145; 113). Kahn and colleagues found a 28% incidence of neuropathy in a cohort of patients with benign monoclonal gammopathy; of these patients, over 50% had IgM M proteins (81).

Waldenstrom macroglobulinemia. Waldenstrom macroglobulinemia has an annual incidence of 6.1 cases per 1 million in white men, and 2.5 cases per 1 million in Caucasian women (76). A populational study yielded an age adjusted incidence rate for males at 0.92/100.000 person-years and 0.30/100.000 for females (106). The median age at diagnosis is 60 years (07). Several studies have indicated that 20% to 35% of patients with IgM monoclonal gammopathy and neuropathy have Waldenstrom macroglobulinemia at the time of initial evaluation (114; 198; 149; 197). Waldenstrom macroglobulinemia has been associated with neuropathy in 5% to 50% of patients and is the presenting symptom in approximately 20% (123; 176; 04; 150). The heterogeneity of IgM monoclonal gammopathies and risk of progression to Waldenstrom macroglobulinemia is apparent from gene expression and mutational studies. MYD88 (90% of Waldenstrom) and CXCR4 (25% to 30%) mutations are responsible for the initiating the process. Other genomic alterations may explain progression to malignancy and further differentiation between smoldering and symptomatic Waldenstrom macroglobulinemia (78; 20).

Myeloma. Multiple myeloma has an annual incidence of 3 per 100,000 (121) and a median age of onset of 68 to 70 years. Clinical evidence of neuropathy in multiple myeloma is estimated to occur in 3% to 13% of patients (180; 201). Osteosclerotic bony lesions are found in less than 3% of all myeloma cases, but a striking 50% of patients with osteosclerotic myeloma have neuropathy (54). Osteosclerotic myeloma generally affects younger patients, with a median age of 51 years at onset (135). Smoldering myeloma describes patients with clinical stability in the context of having bone marrow plasmacytosis (42).

Primary systemic amyloidosis. Primary systemic amyloidosis is an uncommon plasma cell disorder with an incidence of 8 per 1 million persons per year. Two thirds of patients are male, with a median age at diagnosis of 65 years (105; 103). The frequency of neuropathy in amyloidosis is 15% to 20% (12; 101). It is estimated that 25% of patients with monoclonal gammopathy and neuropathy have amyloidosis (193; 105). In a study of 210 patients with amyloidosis, 67% of patients with a monoclonal gammopathy had IgG; 20% had IgA; 7% had IgM; and 4% had IgD (105). The prevalence ratio of light chains is 2:1 lambda to kappa.

Cryoglobulinemia. Types 1 and 2 cryoglobulinemia each comprise 25% of cases, and type 3 comprises 50% of cases (22). Among the monoclonal components present in types 1 and 2, IgM represents about 70% of cases, and IgG and IgA about 30%. Neuropathy has been reported in 7% to 86% of patients with cryoglobulinemia, and most frequently occurs in type 3 (22; 91; 29). The studies that found higher percentages generally represent patients with neuropathy detected by electrophysiological examination that may not have been clinically apparent. Small-fiber sensory neuropathy is by far the most common cryoglobulinemic neuropathy (68).

POEMS. POEMS is a rare disorder; thus, true incidence and prevalence are unknown. The condition is 2.5 times more frequent in men than in women (86).

Differential diagnosis

The demyelinating neuropathy that is associated with monoclonal gammopathy may be clinically indistinguishable from chronic inflammatory demyelinating neuropathy (CIDP). Chronic inflammatory demyelinating neuropathy with MGUS is viewed the same as chronic inflammatory demyelinating polyneuropathy without associated MGUS. IgM monoclonal gammopathy is typically associated with a distal predominantly sensory neuropathy, whereas CIDP may be associated with greater motor involvement, or proximal involvement, or both. Also, in CIDP without monoclonal gammopathy, the course tends to be subacute with a greater tendency for fluctuations, and onset is often at a younger age than in demyelinating neuropathy with monoclonal gammopathy (56; 09). The distal acquired demyelinating symmetric phenotype needs to also be differentiated from inherited demyelinating polyneuropathies. Multifocal neuropathies associated with gammopathies require differentiation from inherited demyelinating and acquired vasculitic polyneuropathies. The predominantly ataxic polyneuropathies associated with paraproteinemia require differentiation from acquired large fiber sensory polyneuropathies including nutritional and paraneoplastic polyneuropathy. Predominant autonomic neuropathic presentations, as in primary systemic amyloidosis, requires differentiation from autoimmune autonomic ganglionopathy, diabetic autonomic neuropathy, and early-onset autonomic synucleinopathies. Once progressive systemic amyloidosis has been diagnosed, familial amyloidosis disorders need to be ruled out, particularly if there is an incidental age-related monoclonal gammopathy.

Diagnostic workup

Monoclonal proteins are detected by serum protein electrophoresis and immunoelectrophoresis. Immunofixation electrophoresis is used to identify the immunoglobulin type and is a more sensitive assay for monoclonal protein. If warranted by clinical suspicion, immunofixation electrophoresis should be performed, even if serum protein electrophoresis is negative. In fact, immunofixation should be the screening test (162) for all clinical situations including workup for an idiopathic polyneuropathy. Quantitative measurement of immunoglobulin levels can be used to identify an excess of an immunoglobulin type, or a decrease in the background production of immunoglobulins. A decrease in the background production of immunoglobulins is a frequent finding in patients with malignancy but is also present in 12% to 60% of patients with nonmalignant monoclonal gammopathy, making it an unreliable indicator (127; 99). Serum-free light chain analysis is the main method of diagnosis and monitoring/prognostication in primary systemic amyloidosis (137). Serial quantitative measurements are useful for monitoring immunoglobulin levels initially after 3 months, then annually if levels are stable.

The amount of serum M-protein present can help differentiate nonmalignant monoclonal gammopathy from a malignant condition. A serum M-protein above 3.0 g/dl for IgG or IgM and above 2.0 g/dl for IgA, is usually an indicator of overt multiple myeloma or macroglobulinemia. One study found that 78% of patients with IgG greater than 2 g/dl, 67% with IgM greater than 2 g/dl, and 82% with IgA greater than 1 mg/dl had evidence of malignancy (06). No correlation has been proven between the level of M protein and the severity of neuropathy (139; 75). Elevated protein in the cerebrospinal fluid is a frequent feature of neuropathy with nonmalignant monoclonal gammopathy. One series reported an elevated cerebrospinal fluid protein in 57 of 65 patients (87%), with a mean of 100 mg/dl (75).

Urine protein immunoelectrophoresis may detect the presence of immunoglobulin light chain or Bence-Jones protein, sometimes in the absence of a serum monoclonal protein. It should be performed in all patients with serum monoclonal protein and in the absence of serum monoclonal protein, if multiple myeloma, macroglobulinemia, or amyloidosis are suspected. The presence of urine monoclonal light chains and a serum M-protein is suggestive of malignancy. The presence of urine light chains at a concentration of greater than 1 g/l clearly indicates multiple myeloma (120). However, up to 40% of patients with nonmalignant monoclonal gammopathy also have low levels of urine monoclonal protein (120). However, the availability of serum free light chain analysis has made urine studies almost obsolete: serum SPE+IFE+FLC has a sensitivity of 97.4 for monoclonal detection. The addition of urine studies increases sensitivity to 98.6% (82). Free light chain analysis is difficult to interpret in patients with renal failure (157).

If an IgG or IgA gammopathy is present in patients with neuropathy, a skeletal survey or better a low dose body CT with bone windows should be performed to evaluate for multiple myeloma. One or more bony lesions may be detected by skeletal survey, and the diagnosis may be confirmed by greater than 10% plasmacytosis on bone marrow biopsy of an affected region. In osteosclerotic myeloma the M protein is IgG or IgA and is almost always associated with lambda light chains. The monoclonal protein peak is often small and may not be detectable by serum protein electrophoresis. The plasma cell proliferation occurs as a focal mass known as a plasmacytoma, which is radiographically either sclerotic or mixed sclerotic and lytic. The bone marrow biopsy of an osteosclerotic myeloma lesion usually contains less than 5% plasma cells. In POEMS cases with isolated osteosclerotic bone lesions, one third may have normal bone marrow biopsies. This creates false reassurance for the absence of a plasma cell disorder and constitutes a clinical diagnostic trap to be avoided (85).

In cases of IgM monoclonal gammopathy with neuropathy, the presence of antibodies reacting with either glycoproteins or glycolipids can be detected and quantified by the enzyme-linked immunosorbent assay system. The ELISA technique for anti-MAG antibodies is more sensitive than the Western blot technique but suffers from low specificity at low antibody titers below 7000 BTU (Bühlman titer units) (41; 118). The antigenic region of MAG is a specific carbohydrate epitope called human natural killer 1 (HNK1). Antibodies for HNK1 using ELISA assay have a sensitivity of 98% and specificity of 99%. Furthermore, in anti-MAG neuropathies anti-HNK1 antibody titers are correlated with sensory deficits and disability and decrease after rituximab therapy (41).

The antiglycolipid and antiglycoprotein antibodies can also occur in the absence of monoclonal protein and, thus, should be tested for in the absence of an M protein if clinical suspicion is high (148). If an IgM monoclonal protein is present and Waldenstrom macroglobulinemia, lymphoma, or chronic lymphocytic leukemia is suspected, a blood lymphocyte count followed by a bone marrow or lymph node biopsy and cell-typing studies can establish the diagnosis.

Because POEMS is a multisystem auto inflammatory condition, the clinical examination of a subacute motor predominant polyradiculoneuropathy needs to include assessments for organomegaly (including lymph node enlargement), a good skin examination, and evaluation for an endocrine disorder (85). High prevalence of diabetes mellitus and thyroid disease precludes these from being included in the POEMS diagnostic criteria. Most common endocrinopathy though is hypogonadism/hypopituitarism manifesting in men as erectile dysfunction/gynecomastia and as early menopause in women. Serum levels of cortisol, ACTH, TSH, free T4, FSH, LH, IGF-1, prolactin, testosterone, estradiol, PTH, and hemoglobin A1c should be considered in the right clinical scenario. Vascular endothelial growth factor (a cytokine that induces neovascularization of the dermis and the perineurium) level determination should be considered early on in patients with a CIDP-like presentation, non-IgM MGUS, and normal bone marrow biopsies. VEGF is a mediator of some features of the disease but is not an initiating factor in pathogenesis. Elevations two to three times normal values in the absence of connective tissue disorders, vasculitis, hypoxemia, anemia, and low iron levels can greatly help in the diagnosis of POEMS (85). Finally, mass spectrometry is an exquisitely sensitive and specific technique for detecting small amounts of paraprotein, thus, offering the gateway to early diagnosis (90).

Nerve conduction studies and electromyography can distinguish between a demyelinating and axonal neuropathy. The neuropathy in patients with nonmalignant monoclonal gammopathy is axonal in nature in 13% to 44% of cases and demyelinating or mixed in 56% to 87% of cases (206; 152; 73). Axonal neuropathy is more common among patients with IgG and IgA monoclonal gammopathy (47%) than patients with IgM monoclonal gammopathy (27%) (152). In addition, a feature of nerve conduction studies distinguishing anti-MAG demyelinating neuropathy from chronic inflammatory demyelinating neuropathy without monoclonal gammopathy is a disproportionate distal conduction slowing in anti-MAG associated neuropathy (31). In POEMS there is evidence for a primary demyelinating polyneuropathy with uniform slowing and rare conduction block (6.7%) or temporal dispersion (13.3%). The uniform slowing is explained by greater slowing in intermediate nerve segments, less increase in distal latencies, and higher terminal latency indices (129). For approximately the same clinical course duration, there is more significant axonal loss compared to a polyradiculoneuropathy seen in CIDP.

Nerve biopsy can also help distinguish between a demyelinating and axonal neuropathy but is generally not necessary for diagnosis. In addition, it can show deposition of IgM and complement, as well as widening of the myelin lamellae at minor dense lines; this finding is characteristic of the neuropathy associated with monoclonal IgM anti-MAG antibodies (133; 184; 185; 186; 132). On nerve biopsy the polyneuropathy of POEMS has primary demyelination, higher axonal degeneration, fewer normal myelinated fibers on teased fiber preparations, and prominent epineurial inflammatory infiltration and neovascularization compared to chronic inflammatory demyelinating polyneuropathy (161). This is accompanied on electron microscopy by uncompacted myelin lamellae in every case (199).

A monoclonal protein is present in the blood or urine of 89% of patients with primary systemic amyloidosis (100) and is more often IgG or IgA than IgM. A monoclonal protein is found in the serum in 72% of cases and in the urine in 73% of cases (100). To establish the diagnosis of amyloidosis, a fat pad or rectal biopsy, or specific organ system biopsy may be performed. Fat pad biopsy avoids the risk of organ biopsy and is positive for amyloid fibrils in 80% of patients with primary systemic amyloidosis. Cryoglobulins are associated with Waldenstrom macroglobulinemia, multiple myeloma, chronic lymphocytic leukemia, B-cell lymphoma, collagen vascular diseases, and systemic infections. Specimens should remain near body temperature prior to testing to minimize the risk of false negative cryoglobulin test results.

Patients with nonmalignant monoclonal gammopathy should receive close follow-up to detect the possible development of malignant transformation. The clinician should be alert to the development of symptoms that arouse suspicion of malignant transformation, such as skeletal pain, increased fatigue, infections, symptoms of organ failure, or a bleeding diathesis.

Prognosis and complications

Nonmalignant monoclonal gammopathy (MGUS). The risk of malignant transformation of nonmalignant monoclonal gammopathy has been investigated in a number of series and varies between patient populations. In a prospective long-term follow-up of 241 patients with nonmalignant monoclonal gammopathy for 24 to 38 years, 27% eventually developed malignant transformation, most commonly to multiple myeloma (69%) (99). The median duration from diagnosis of nonmalignant monoclonal gammopathy to diagnosis of multiple myeloma was 10 years (99). Overall, the rate of malignant transformation was 1.5% per year, demonstrating that patients with monoclonal gammopathy require regular medical follow-up.

Some studies have found that no factors can reliably predict the risk of malignant transformation (99; 110); however, other studies have found predictors. In a study, progression of polyneuropathy, unexplained weight loss, and M-protein levels greater than 1 gm/dL were independent risk factors for the development of an underlying malignancy (62). Another large study looking at 1384 patients with MGUS demonstrated that initial serum M-protein concentration was the most important risk factor for progression to plasma cell cancer (109). At 10 years following M-protein discovery, the risk of transformation to plasma cell cancer was 6% for an M-protein concentration of less than or equal to 0.5 mg/dL, 7% for 0.5 to 1.0 mg/dL, 11% for 1.0 to 1.5 mg/dL, 20% for 1.5 to 2.0 mg/dL, 24% for 2.0 to 2.5 mg/dL, and 34% for less than or equal to 3.0 mg/dL. In addition, patients with IgM and IgA gammopathy had a significantly higher risk of transformation, as compared to IgG gammopathy (109). Finally, an abnormal serum free light chain assay (168) or bone marrow plasma cell levels of 6% to 9% (26) also appear to predict a higher risk of malignancy. The risk of malignant transformation in patients with MGUS does not differ based on the presence or absence of neuropathy (156). In patients with anti-MAG reactivity and neuropathy, the malignant transformation rate was 16% over a follow-up period of 7.4 years (183).

Populational long-term follow-up (median of 34 years) of patients with MGUS, allowed for important observations: MGUS progressed to malignancy in 11% of patients (a rate that was 6.5 times higher than general population without MGUS). Risk of progression was 1.1 events/100 person-years among IgM and 0.8 events/100 person-years for non-IgM cases.1%/year. Risk of progression for IgM cases increased with longer follow-up duration whereas for non-IgM, risk of progression stayed fixed at 1% per year. Original concentration of M component and free light chain ratio were the most important univariate risk factors for progression. Other risk factors included age at onset and low concentration of two uninvolved immunoglobulins. Patients with MGUS had a shorter survival than the control population. Death rates in patients with MGUS were related to malignant plasma cell disorders in 11% and other unrelated causes in 87% (107). Thus, long-term risk of death due to other causes is much higher than risk of MGUS malignant transformation.

In cases that do not undergo malignant transformation, the prognosis is largely dependent on the course of the neuropathy. Despite the slowly progressive course, 45% of patients with IgM monoclonal gammopathy and neuropathy have been described as having severe disability (58). In 17 patients with nonmalignant IgM monoclonal gammopathy followed for up to 14 years, there was worsening of neuropathy over the first 2 to 5 years, followed by slow (but subclinical) progression thereafter (183). Some patients appear to stabilize in later years, after early progression, even without treatment (58). Another study found the course of neuropathy associated with MGUS (IgG, IgM, or IgA) to be slowly progressive in approximately 70% of patients and relapsing in 20% (75; 73). In another study, after 5 years of follow-up of 32 untreated patients with MGUS and neuropathy, severe progression was noted in 16% (152). In a series of patients with anti-MAG IgM, a disability rate of 42% was reported after a mean duration of neuropathy of 11.8 years (151).

Waldenstrom macroglobulinemia. The most important prognostic factors are hemoglobin, age, weight loss, and the presence of cryoglobulin (70). The prognosis of the neuropathy is similar to that in the nonmalignant condition. Anemia, constitutional symptoms, symptoms related to the IgM paraprotein, and organomegaly are the most common reasons for initiation of treatment. With current approaches of frontline Rituxan-based chemoimmunotherapy, the 10-year survival is 69% (23). Higher response rates and improved median progression-free survival were reported after adding ibrutinib to rituximab (47; 20).

Myeloma. The prognosis for multiple myeloma is poor, with a median survival after diagnosis of 3 years in older patients (01) and 5 to 6 years in younger patients (17). Progressive worsening of polyneuropathy is the usual outcome in patients with myeloma, osteosclerotic myeloma, or POEMS syndrome. The 5-year survival in patients with osteosclerotic myeloma or POEMS syndrome has been reported as 60% (135). Another study reported the median survival of patients with POEMS syndrome as 165 months (50).

Amyloidosis. The neuropathy in primary systemic amyloidosis is relentlessly progressive. The prognosis of primary systemic amyloidosis is poor, with a median survival of 13 months (103). Cardiac involvement is the primary predictor for prognosis (71). Death usually results from the complications of organ failure. With the use of melphalan and prednisone, the median survival among all patients increases to 17 or 18 months (99). The prognosis of primary systemic amyloidosis is better in patients presenting with neuropathy than in patients presenting with other organ failure (167). A median survival of 25 to 35 months in patients with primary systemic amyloidosis has been reported for patients presenting with neuropathy as the predominant clinical manifestation (55; 167).

POEMS. POEMS is a treatable disorder, particularly if recognized early. Untreated mean survival is 33 months. Some studies have shown 5- and 10-year survival rates of 79% to 84% and 62% to 67%, respectively (86).

Management

The therapy of neuropathy associated with monoclonal gammopathy is directed at removing the autoantibody, reducing the number of monoclonal B-cells, and interfering with effector mechanisms, such as complement activation and macrophage recruitment. Specific treatments are based on the particular monoclonal gammopathy syndrome and whether or not evidence of malignancy is present. Although no correlation between enzyme-linked immunoabsorbent (ELISA) antibody titer and neuropathy severity has been found (149), when followed serially, the titers may follow clinical changes in individual cases (87; 144; 60). Some authors suggest that a treatment-induced reduction in monoclonal protein by 50% or more for a period of 3 months is an adequate treatment trial (87). IgM monoclonal gammopathy associated neuropathy is frequently more refractory to therapy than the IgG form.

IgM demyelinating neuropathy. The treatment of IgM demyelinating neuropathy with anti-MAG antibodies was assessed in a Cochrane Review (125), and only a limited number of randomized controlled trials existed at the time. Overall, there was felt to be inadequate evidence to recommend a particular therapy (125). A lack of convincing evidence was also noted in the treatment of IgM monoclonal gammopathy and neuropathy without anti-MAG antibodies (Joint Task Force of the EFNS and PNS 2010). Since then, several advances have been made (146).

A trial of plasmapheresis in 39 patients with MGNS (21 of whom had IgM) showed no significant improvement in strength or functional outcome in the IgM cohort (57). Anti-MAG reactivity was not measured in this study. Another randomized open trial (Class III) in 33 patients with anti-MAG neuropathy demonstrated no benefit of chlorambucil plus plasmapheresis over chlorambucil alone (155). Earlier case series or smaller nonrandomized trials estimated a benefit in 50% of patients treated with plasmapheresis (Joint Task Force of the EFNS and PNS 2010).

Intravenous immunoglobulin (IVIg) therapy has shown conflicting data in neuropathy associated with nonmalignant IgM monoclonal gammopathy (125). In a double-blinded randomized controlled trial, two of 11 patients with nonmalignant IgM gammopathy treated with IVIg showed improvement (37), not significantly higher than placebo. However, a study found that almost half of patients with demyelinating neuropathy and IgM monoclonal gammopathy improved with IVIg treatment (34). Generally, the response to intravenous immunoglobulin is short-lived, making repeated treatments necessary. CANOMAD cases do respond to IVIg and Rituximab (92). CANOMAD has a relative contraindication to plasmapheresis due to agglutination in the extracorporeal line.

Steroids have been reported to be effective only when used in combination with other therapies (151), except in rare cases (153), but there are no randomized control data available.

Chemotherapeutic agents that have shown questionable efficacy include fludarabine (205), chlorambucil, and cyclophosphamide (144). Myelosuppression and immunosuppression are the primary side effects. A trial of intermittent pulse-dose cyclophosphamide with prednisolone versus placebo failed to meet its primary outcome measure (the Rivermead Mobility Index); however, multiple secondary measures showed statistical significance, including Medical Research Council power grading, sensation, ataxia, and quality of life (142).

Rituximab, a chimeric anti-CD20 monoclonal antibody, may stabilize or improve the neuropathy associated with anti-MAG IgM monoclonal gammopathy (116; 170; 11). Rituximab has also shown efficacy in reducing IgM titers and improving strength (160). The efficacy of rituximab has been evaluated in 80 patients enrolled in two randomized controlled trials groups (38; 117). Neither trial met the primary outcomes but 30% of rituximab-treated patients had improved disability compared to 10% in placebo-treated patients. The subjective impression of change was also better in Rituxan-treated patients. Subacute progression, proximal weakness, minimal axonal loss, and FcϒRIIIA-R/H131 genotype are associated with Rituxan response (187; 84; 146). In the only randomized, controlled trial of rituximab (in 26 patients with anti-MAG neuropathy), the intention-to-treat analysis did not identify a statistically significant benefit; however, in post hoc analysis with removal of one patient from the treatment group, there was a statistically significant difference between treatment and placebo groups for gait ataxia (38; 36). A meta-analysis of rituximab demonstrated improvement in disability at 8 to 12 months. A transient flare up of symptoms was seen in 12% after Rituxan initiation (190) and long-term efficacy was seen in 30% of cases (126).

Interferon-alpha produced improvement in the sensory symptoms in eight of 10 patients with anti-MAG IgM neuropathy; however, a larger study did not confirm these findings (Joint Task Force of the EFNS and PNS 2010). In a small series of patients with anti-MAG antibody polyneuropathy and Waldenstrom macroglobulinemia, ibrutinib provided class IV evidence for benefit in both subjective and objective responses (24).

Cytokine profile data suggest that the anti-IL-6R antibody agent tocilizumab may be a candidate for the treatment of IgM polyneuropathies (188). The investigational glycopolymer PPSGG, which selectively binds to anti-MAG IgM antibodies, prevented the binding of human anti-MAG antibodies to primate sciatic nerve myelin in a rapid fashion (02). Human PPSGG trials for fast (hours) pathogenic anti-MAG autoantibody depletion are being planned.

IgM axonal neuropathy. Nonmalignant IgM monoclonal gammopathy with an axonal neuropathy does not respond as well to therapy as the demyelinating form (153; 73). The axonal neuropathy may respond to plasmapheresis (73) but will often require the addition of chemotherapy. Chemotherapy with cyclophosphamide is reserved for refractory cases (158), and again no randomized controlled data are available.

Nonmalignant IgG and IgA monoclonal gammopathy. Patients with IgA or IgG MGUS and demyelinating forms of peripheral neuropathy will often respond to the same treatments as CIDP, including steroids, intravenous immunoglobulin, or plasmapheresis (147). IgG and IgA monoclonal gammopathy may respond better to plasmapheresis than IgM monoclonal gammopathy (178; 57), as suggested in the only randomized controlled trial in this patient population. In a retrospective study, IVIg was found to be beneficial in 40% (eight of 20) of patients with peripheral neuropathy and IgG MGUS (74); however, no randomized prospective trials have been performed. Demyelinating features on electrodiagnostic studies were associated with a response to IVIg therapy (74). Axonal forms of IgA and IgG neuropathy are more resistant to therapy and often require the addition of chemotherapy (73; 52).

Waldenstrom macroglobulinemia. The neuropathy of Waldenstrom macroglobulinemia may respond transiently to plasmapheresis; however, this treatment is not effective long-term. Benefits from IVIG are minimal (36). Fludarabine, cladribine, and chlorambucil achieve response rates of at least 50% in Waldenstrom macroglobulinemia (45; 154; 66; 01); the response rate in many studies is defined as a greater than 50% reduction in IgM paraprotein levels. Improvement in the neuropathy has been observed as a delayed effect after high dose melphalan therapy, followed by autologous stem cell transplant (173). Treatment strategies have included rituximab, which may be effective in patients with peripheral neuropathy and IgM autoantibodies (44); however, this benefit has not been evaluated prospectively.

Myeloma. The recommendation for patients with disseminated multiple myeloma is induction treatment followed by double autologous stem cell transplant (17), in patients who can tolerate this regimen. This is followed by consolidation regimens. Immunomodulatory drugs (thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (bortezomib, carfizomib) also inhibit proliferation of myeloma cells, angiogenesis, induce apoptosis, and influence interactions between myeloma cells and stroll cells (124). The neuropathy often improves with therapy of the underlying myeloma (88). Thalidomide and bortezomib have been effective in the treatment of multiple myeloma, but their neurotoxicity limits their use (08). Thalidomide may induce a predominant sensory neuropathy in 70% of patients after 12 months of therapy (124). Bortezomib is most commonly associated with painful sensory neuropathy (40%), but cases of demyelinating neuropathy with notable weakness and autonomic neuropathy are described. Both of these peripheral nerve toxic entities are reviewed in other sections.

Patients with solitary plasmacytomas can be treated with radiation with or without surgical excision. Radiotherapy of solitary lesions can sometimes be curative, with substantial improvement in the neuropathy in greater than 50% (99). However, 50% of cases will eventually develop overt multiple myeloma (99).

The neuropathy of POEMS syndrome and osteosclerotic myeloma can respond to radiotherapy (1-3 bone lesions), melphalan, and prednisone (53). Plasmapheresis has been reported to be of benefit in some cases (179). Importantly though, plasmapheresis may lower VEGF levels, thus, delaying the diagnosis (77). A trial demonstrated benefit of high-dose melphalan chemotherapy, followed by autologous stem cell transplantation, in nine patients with POEMS syndrome. There was reduction in VEGF levels within 1 month, substantial neurologic improvement beginning within 3 months, and improvement in electrophysiological markers (95). High dose chemotherapy with autologous bone marrow transplantation is the treatment of choice for fit patients with disseminated disease (77). Lenalidomide, thalidomide, and bortezomib are promising treatments but may be limited by neuropathic complications. Importantly, the polyneuropathy in POEMS does not respond to usual initial treatments for chronic inflammatory demyelinating polyneuropathy, which should be a clue for searching for a malignant disorder.

Amyloidosis. Primary systemic amyloidosis can be treated with melphalan and dexamethasone (99), but the neuropathy rarely stabilizes or improves (167). High-dose chemotherapy and autologous stem cell transplantation is common therapy (51) except for patients with cardiac involvement (67). There appears to be a significant survival benefit of this combination treatment that is partially mitigated by transplant complication rates; a randomized study failed to demonstrate an overall significant benefit (72). Newer agents include bortezomib and immunomodulatory drugs such as rituximab (67). Early diagnosis is paramount in order to avoid irreversible end organ damage, and this includes peripheral nerve function.

Cryoglobulinemia. Cryoglobulinemia with mild manifestations can be treated with low-dose steroids and avoidance of cold exposure. More severe cases can be treated with high-dose steroids, plasmapheresis, or immunosuppressive drugs (122; 49). Mixed cryoglobulinemia can be treated with interferon-alpha, with a response rate of 60% to 89% (39; 136; 130; 134; 33). The vasculitic neuropathy associated with cryoglobulinemia in the setting of hepatitis C virus infection may respond to interferon-alpha (91). However, there have been reports of worsening of neuropathy with interferon-alpha therapy (18). Rituximab may represent an alternative in patients with type 2 cryoglobulinemia (207; 175). In an open prospective study of rituximab in 13 patients with type 2 cryoglobulinemic neuropathy, there was improvement in sensory symptoms, clinical neuropathy disability score, and electrophysiologic findings (25). It may be beneficial to eliminate hepatitis C virus infection by using direct acting interferon free antiviral treatment and to stop the immune response by using rituximab (138).