Monoclonal Gammopathy and the CNS
Monoclonal Gammopathy and the CNS
Abstract & Commentary
By Russell L. Chin, MD, Assistant Professor of Neurology, Weill Cornell Medical College. Dr. Chin reports no financial interest in this field of study.
Synopsis: Nine of nineteen patients with monoclonal gammopathy, referred for evaluation of peripheral neuropathy, were found to have one or more clinical signs of CNS involvement.
Source: Lehmann HC, et al. Central nervous system involvement in patients with monoclonal gammopathy and polyneuropathy. Eur J Neurol 2010; doi:10.1111/j.1468-1331.2010.02977.x
In this case series, nineteen patients (9 men, 10 women) with M-protein, referred for suspected peripheral neuropathy, were evaluated consecutively over a four-year period. Sixteen patients had monoclonal gammopathy of unknown significance (MGUS), one patient had "chronic lymphatic leukaemia" and two patients were diagnosed with plasmacytoma. The M-protein was IgG in 10 patients, IgM in eight patients, and IgA and IgM in one of each. Four patients with IgM M-protein had ganglioside antibodies (including to GD1a, GD1b, GM1, GA1, and MAG). Peripheral neuropathy was diagnosed by clinical and electrodiagnostic examination in 17 patients (nine sensorimotor, five sensory, three motor).
Nine of the 19 patients had potential CNS involvement with one or more of the following clinical signs: tremor (5 patients), dysarthria (4), ataxia (4), extensor plantar responses (3), and nystagmus (1). Three of the 10 patients who had cranial MRI studies had extensive multifocal leukoencephalopathy that could not be attributed to age or small vessel disease. Diluted sera from two patients with IgM M-protein stained neurons of the cortex and cerebellum of paraffin-embedded human brain tissue. In the cortex, there was intense staining of axons and cell bodies in the grey and white matter. In the cerebellum, there was intense staining of granular cells with sparing of Purkinje cells. No staining was observed with sera containing IgG M-protein or normal serum. Disease duration was significantly longer in patients with clinical signs of CNS involvement. Serum M-protein was significantly increased in patients with IgM M-protein and signs of CNS involvement.
Commentary
Monoclonal gammopathy has been linked to the development of peripheral neuropathy and is associated with conditions such as monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (including osteosclerotic myeloma), Waldenström macroglobulinemia (also known as lymphoplasmacytic lymphoma), primary systemic amyloidosis and cryoglobulinemia. Careful assessment for these underlying conditions is important given potential therapies, ranging from observation to rituximab, IVIG, steroids, alkylating agents, or radiation therapy.
The IgM monoclonal gammopathies are often associated with anti-nerve antibodies such as myelin-associated glycoprotein (MAG) and glycolipids such as sulfoglucuronyl paragloboside and various gangliosides. Anti-MAG neuropathy is most frequently associated with a slowly progressive, demyelinating sensory neuropathy that may respond to rituximab therapy. Neuropathies associated with IgG or IgA monoclonal gammopathies have a more heterogenous clinical presentation, including a chronic inflammatory demyelinating polyneuropathy-like syndrome. Screening for osteosclerotic myeloma is warranted in these patients. Anti-nerve antibody activity, if found, is of unclear significance. The target antigens of circulating M-protein, however, are not confined to the peripheral nervous system. In this article, sera from two patients with IgM monoclonal gammopathy stained neurons of the cortex and cerebellum, corroborating another report of antibodies reactive against glycolipids in the CNS white matter.1
CNS involvement has long been suspected, given the observation of tremor and ataxia in 40% to 90% of patients with IgM paraproteinemic neuropathy. The other features of dysarthria and nystagmus highlighted in this article also implicate CNS (specifically cerebellar) involvement. Tremor is mostly seen in the upper extremities and has characteristics of an enhanced physiologic tremor that is increased with posture and action and typically without a resting component. A central etiology is suspected particularly in the absence of a deafferented state where there would be significant loss of large fiber sensory input. Deep brain stimulation of the VIM thalamic nucleus has also been reported to result in improvement of the tremor associated with an IgM monoclonal gammopathy and demyelinating peripheral neuropathy. As stated in this paper, ataxia is attributed to cerebellar dysfunction (rather than to peripheral sensory loss) when there are features of a lurching gait, with no or only minimal worsening with elimination of visual feedback.
Radiologic findings supporting CNS involvement include the presence of extensive white matter changes not attributable to age and microvascular disease.1 Enhancing perivascular and subcortical white matter changes have also been reported in a patient with Bing-Neel syndrome,2 a rare condition of lymphoplasmacytic infiltration of the CNS in patients with Waldenström macroglobulinemia.
References
1. Leger JM, et al. Frequency of central lesions in polyneuropathy associated with IgM monoclonal gammopathy: An MRI, neurophysiological and immunochemical study. J Neurol Neurosurg Psychiatry 1992;55:112-115.
2. Malkani RG, et al. Bing-Neel syndrome: An illustrative case and a comprehensive review of the published literature. J Neurooncol 2010;96:301-312.
Nine of nineteen patients with monoclonal gammopathy, referred for evaluation of peripheral neuropathy, were found to have one or more clinical signs of CNS involvement.Subscribe Now for Access
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