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Peripheral Neuropathy in Systemic Amyloidosis
Abstract & Commentary
By Norman Latov, MD, PhD
Professor of Neurology and Neuroscience and Director of the Peripheral Neuropathy Center, Weill Medical College of Cornell University. Dr. Latov receives grant/research support and is a retained consultant for Taleris Biotherapeutics; is a retained consultant for Novartis Pharmaceuticals and Octapharm Pharmaceuticals; and is a stockholder at Therapath LLC..
Synopsis: Peripheral nerve involvement is common in systemic amyloidosis and may be the initial clinical manifestation.
Source: Matsuda M, et. al. Peripheral nerve involvement in primary systemic AL amyloidosis: A clinical and electrophysiological study. Eur J Neurol 2010 doi:10.1111/j.1468-1331.2010.03215.x
The authors investigated the presence, clinical manifestations, and electrodiagnostic findings of peripheral neuropathy in 43 consecutive patients with primary systemic AL amyloidosis. Fifteen of the patients (35%) had neuropathic symptoms, including 11 (25.6%) with polyneuropathy, 4 (9.3%) with bilateral carpal tunnel syndrome, and 8 (18.6%) with autonomic dysfunction. The polyneuropathy was characterized by distal and symmetric impairment of all sensory modalities and early onset of painful paresthesias primarily in the legs, with autonomic involvement or orthostatic hypotension in more advanced stages. Electrodiagnostic studies revealed both motor and sensory axonal changes, including in patients without symptoms of neuropathy. Treatment consisted of high-dose melphalan with stem cell transplantation, or other chemotherapy regimens, with improvement or stabilization of the neuropathy in most patients.
Primary systemic amyloidosis is caused by proliferation of B-cells or plasma cells that secrete monoclonal antibodies, with deposition of amyloid fibrils derived from the immunoglobulin light chains in visceral organs and peripheral nerves. Primary amyloidosis is a progressive and potentially fatal disease, so it is important to recognize the condition and institute treatment directed at eliminating the monoclonal B-cell population and light chain deposition.
Neuropathy can be the presenting symptom of primary amyloidosis, so that the diagnosis should be considered in patients presenting with distal and symmetric axonal neuropathy, particularly if it is painful or associated with autonomic manifestations such as orthostatic hypotension, decreased sweating, urinary incontinence, sexual dysfunction, or alternating constipation and diarrhea. If other organs are involved, patients might also manifest symptoms of myopathy, congestive heart failure, or renal failure. Suspected patients can be screened by serum or urine immunofixation electrophoresis, with a monoclonal gammopathy present in approximately 90% of cases.1 A tissue biopsy of nerve or another involved organ, demonstrating the amyloid deposits, is necessary to make the diagnosis, as a monoclonal gammopathy may not always be present, or the gammopathy can be associated with other causes for neuropathy, such as chronic inflammatory polyneuropathy, osteosclerotic myeloma, or anti-MAG or ganglioside antibodies in the absence of amyloidosis. In blind biopsies, abdominal fat pad biopsy is positive in approximately 70% of cases, but is less specific; bone marrow biopsy is positive in about 50% of cases; and rectal biopsy, including of the submucosa, is positive in approximately 80% of cases.2
Once amyloid deposits are identified, immunohistochemical staining is required to identify the specific light chain that is deposited, and to distinguish primary amyloidosis from secondary, or hereditary amyloidosis resulting from mutations in transthyretin, apolipoprotein A-1, or gelsolin. Familial transthyretin amyloidosis is currently treated with liver transplantation.
1. Kissel JT, Mendell JR. Neuropathies associated with monoclonal gammopathies. In: Diagnosis and Management of Peripheral Nerve Disorders. Eds. Mendell JR, Kissel JT, Cornblath DR. Oxford, UK: Oxford University Press Inc. 2001: 272-296.
2. Kyle RA, Dyck PJ. Amyloidosis and neuropathy. In: Peripheral Neuropathy. Eds. Dyck PJ, et al. Philadelphia: WB Sauders. 3rd Ed. 1993: 1294-1309.