Pathogenesis and Pathophysiology. Osteosclerotic myeloma may be considered a rare variant of multiple myeloma, comprising only 3 percent of all patients with myeloma. Many of the typical features of multiple myeloma, including anemia, hypercalcemia, chronic renal failure,
fatigue, weakness, and bone pain, are rare or at least uncommon in osteosclerotic myeloma. Furthermore, the level of M-protein is lower, and there are fewer plasma cells in the bone marrow. In contrast to multiple myeloma, however, an associated polyneuropathy is relatively common in osteosclerotic myeloma, occurring in over 50 percent of patients. y Furthermore, the polyneuropathy associated with osteosclerotic myeloma may frequently be a component of the so-called POEMS syndrome.y
The precise pathophysiology of the polyneuropathy associated with osteosclerotic myeloma and the multi-organ features of POEMS syndrome is unknown. It is likely that the plasma cells secrete an immunoglobulin or some other substance that may cause both the polyneuropathy and the other systemic features of POEMS syndrome.y
Epidemiology and Risk Factors. Patients with polyneuropathies secondary to osteosclerotic myeloma typically range in age from the late fourth decade through the seventh decade with a mean age in the late fifth decade. There is a rather prominent predilection for the disorder to occur in males. For the above-mentioned reasons, it would be exceedingly rare for this disorder to occur in women of the childbearing age.
Clinical Features and Associated Disorders. The clinical features of polyneuropathy associated with osteosclerotic myeloma typically conform to those of a rather chronic, progressive sensorimotor polyneuropathy. In the majority of patients, the polyneuropathy progresses to the point of rather remarkable weakness involving proximal as well as distal muscles, and may result in significant disability. Typically, weakness is a more prominent symptom than sensory impairment. Autonomic symptoms are rare, and cranial nerve involvement is absent except for instances of papilledema. General systemic symptoms of bone pain, fatigue, and weakness typical of multiple myeloma usually are not seen. '39
The neurological examination typically discloses prominent weakness that is worse distally but with occasional proximal involvement. Sensory loss is less prominent and tends to affect the large fiber modalities of touch pressure, joint position sense, and vibratory sensation more so than smaller fiber modalities of pain and temperature. Papilledema may be seen in up to 50 patients of patients. y
One or more additional features of the POEMS syndrome often are observed, but in many cases, these are not prominent and must be carefully sought. Hepatomegaly may be found in up to 50 percent of patients, whereas lymphadenopathy and splenomegaly are less common. Manifestations of endocrinopathy include diabetes mellitus, hypothyroidism, impotence, gynecomastia, testicular atrophy, amenorrhea, hyperprolactinemia, and hyperestrogenemia. Skin changes include hyperpigmentation, thickening of the skin, hypertrichosis, skin angiomas, clubbing, and white nails. Some skin changes are suggestive of scleroderma. Peripheral edema, ascites and pleural effusions may also be seen. POeMs syndrome, sometimes referred to as Crow-Fukase syndrome, is not unique to osteosclerotic myeloma. It has been observed in multiple myeloma, Waldenstrom's macroglobulinemia, and angiofollicular lymph node hyperplasia, also referred to as Castleman's disease.y
Differential Diagnosis. In nearly all patients with polyneuropathy associated with osteosclerotic myeloma, the diagnosis is made during a comprehensive evaluation for a cryptogenic polyneuropathy. The findings on EDX examination of features consistent with an acquired SD polyneuropathy provide the differential diagnosis of CIDP and the related disorders, as noted earlier. Furthermore, the presence of an M-protein necessitates a hematological evaluation, which encompasses skeletal bone study and bone marrow aspirate. Careful attention to the possibility of the systemic features of the POEMS syndrome can yield important clues to the diagnosis of polyneuropathy associated with osteosclerotic myeloma.
Evaluation. Typically, the fact that there are EDX changes suggestive of an acquired SD polyradiculoneuropathy will already have been determined. The M-protein associated with osteosclerotic myeloma is usually IgG or IgA and is almost always of the lambda light chain type. '341 The concentration is typically low and rarely more than 3 g/dl, the usual range seen in multiple myeloma. An important point is that approximately 25 percent of patients with osteosclerotic myeloma may not have an M-protein detected in the serum or urine. y Thus, to evaluate a patient properly for this disorder, a skeletal survey is essential to uncover osteosclerotic lesions, the hallmark of the syndrome. These lesions typically involve the spine, pelvis, ribs, and proximal long bones of the limbs; occasionally they are not prominent and may be misinterpreted as benign bone sclerosis. Usually, the bony lesions show both osteosclerotic and lytic changes--sometimes they have the appearance of an osteosclerotic rim around a lytic lesion. The CSF usually is normal, except for an elevation of protein comparable to that noted in CIDP. EDX studies show features of an acquired SD polyneuropathy, although in some patients, axonal degeneration may be prominent. Sural nerve biopsies typically show combinations of both axon loss and segmental demyelination with occasional small foci of inflammatory cell infiltrates in the perivascular epineurium. Bone marrow aspirate usually discloses less than 5 percent of plasma cells. Routine laboratory studies most often are unrevealing, although thrombocytosis may be observed in nearly half of patients, with other features, including leukocytosis and polycythemia, present in a smaller number of patients.
Management. Patients with solitary osteosclerotic lesions appear to have the very best response to therapy. Local radiation of single or multiple lesions may result in substantial improvement in the polyneuropathy in the majority of patients. In patients with multiple osteosclerotic lesions, chemotherapy may result in improvement and stabilization of the polyneuropathy, although the responses appear to be less satisfactory than in those with isolated osteosclerotic lesions.
Prognosis and Future Perspectives. The polyneuropathy associated with osteosclerotic myeloma tends to be slowly progressive and may produce rather prominent generalized weakness and considerable disability, including wheelchair or bed confinement. The majority of patients with isolated osteosclerotic lesions respond to treatment, demonstrating stabilization, if not improvement, of their polyneuropathies. Patients with multiple osteosclerotic lesions do not respond as well.
Future research into this entity must provide a unifying pathophysiology that can explain the multisystem involvement
of the POEMS syndrome. The pathogenetic role of the M-protein lambda light chain is a likely candidate for further study. From a clinical viewpoint, a more systematic study of the optimal mode of therapy is needed. However, the relatively rare occurrence of this entity will make it difficult to perform controlled therapeutic trials.
Waldenstrom's macroglobulinemia is a chronic lymphoproliferative disorder characterized by a clonal proliferation of B lymphocytes or lymphoplasmacytic cells in bone marrow or in lymph nodes, or both and a high concentration of monoclonal IgM M-protein, typically exceeding 3 g/dl. In addition to the clinical features caused by the circulating macroglobulin, including hyperviscosity syndrome and cryoglobulinemic features, a polyneuropathy occurs in approximately one third of patients. 'd Half of all those with polyneuropathy are positive for anti-MAG antibodies. y In this latter group of patients, the pathophysiology of the polyneuropathy may be similar to that seen with MGUS IgM anti-MAG positive polyneuropathy. However, a more heterogenous group of polyneuropathies, predominantly axon loss in type but occasionally demyelinating, may be encountered in those patients who are anti-MAG negative, similar to what is observed in the other IgM MGUS polyneuropathies. The pathophysiology of these polyneuropathies also is similar to that noted for the MGUS polyneuropathies without anti-MAG activity. Waldenstrom's macroglobulinemia tends to occur in the middle to older age groups, with a mean age of onset in the early seventh decade, and there is a slight male predominance. The late age of onset essentially precludes it occurring in pregnant women.
The clinical features of the demyelinating polyneuropathy associated with macroglobulinemia and anti-MAG activity is essentially identical to that noted in MGUS IgM anti-MAG-positive patients.y The disorder typically is a chronic sensorimotor polyneuropathy with prominent sensory involvement, including sensory ataxia. Other peripheral nerve syndromes may occur in macroglobulinemia, however, including asymmetrical mononeuropathy associated with cryoglobulinemia and a rather typical amyloid polyneuropathy. A hyperviscosity syndrome may occur in 15 percent of patients with macroglobulinemia, usually in the setting of an underlying lymphoma. 'd This syndrome produces a wide spectrum of symptoms including general fatigue, blurred vision, and dizziness. Blurred vision may be secondary to distended retinal veins, retinal hemorrhages, and papilledema. Easy bleeding of mucous membranes is also observed and usually is due to abnormal platelet function induced by the IgM M-protein. In addition, the IgM M-protein may function as a cryoglobulin and contribute to other systemic symptoms, including renal disease, altered liver function studies, arthralgia, Raynaud's syndrome, and cryoglobulinemic neuropathy. 'd Moreover, a chronic hemolytic anemia occurs in approximately 10 percent of patients. Nearly one third of patients have lymphadenopathy or splenomegaly.
The presence of a high concentration of IgM M-protein in the context of an acquired SD polyneuropathy requires a careful evaluation for lymphoproliferative disorders. This usually necessitates skeletal bone survey to assess for multiple myeloma and osteosclerotic myeloma as well as bone marrow aspiration. The presence of lymphadenopathy and organomegaly coupled with the other systemic features of macroglobulinemia provide the key clinical clues to the diagnosis.
Evidence of an acquired SD polyradiculoneuropathy should be found on EDX studies. The evaluation of patients with IgM M-protein and acquired SD polyneuropathy is identical to that described for MGUS polyneuropathy. Testing for anti-MAG activity is essential to identify the subset of patients with macroglobulinemia who may have a more specific immune-mediated disorder. Results of nerve biopsies and CSF analysis are similar to those seen in MGUS IgM anti-MAG polyneuropathy. Routine laboratory studies in patients with macroglobulinemia often disclose anemia, monoclonal blood lymphocytosis, and Bence Jones proteinuria as well as elevated serum beta-microglobulin in nearly half of patients. Also, the presence of cryoglobulins is not an uncommon finding. Diagnosis is confirmed by the presence of a high concentration of IgM M-protein in the setting of underlying lymphoma characterized by infiltration of bone marrow, lymph nodes, and spleen.
Waldenstrom's macroglobulinemia typically is treated with combinations of chemotherapy and plasmapheresis. Chemotherapy for underlying lymphoma often incorporates a combination of an alkylating agent and a glucocorticoid. Plasma exchange often is recommended for patients who develop polyneuropathy and in those with clinical features of hyperviscosity syndrome and cryoglobulinemia. y Waldenstrom's macroglobulinemia is a serious disease with a median survival time of approximately 4 years. Therapeutic intervention with chemotherapy and plasmapheresis may be helpful in stabilizing or improving the associated polyneuropathy.
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