Primary systemic amyloidosis: neurologic complications

John J Kelly MD (Dr. Kelly of George Washington University has no relevant financial relationships to disclose.)
Elham Bayat MD (Dr. Bayat of George Washington University has no relevant financial relationships to disclose.)
Raymond P Roos MD, editor. (Dr. Roos of the University of Chicago owns stock in Amgen, Best Doctors, Express Scripts, Ionis, and Merck.)
Originally released May 13, 1996; last updated October 30, 2015; expires October 30, 2018

Overview

Amyloid neuropathy remains a serious, usually rapidly fatal disease. However, in this updated article, the authors discuss evidence indicating that peripheral blood stem cell transplantation has proven to be effective treatment in carefully chosen patients. In one study from the Mayo Clinic, patients with limited organ involvement have shown a good response to peripheral blood stem cell transplantation (PBST) with prolongation of survival. Early PBST in well-selected patients is the current treatment of choice for amyloid neuropathy. Thus, early diagnosis and referral for treatment is essential before the disease spreads to multiple organs. Prognosis has improved with the use of early mortality risk scores to recognize those patients most at risk for early death. Diagnosis is still based on discovery of amyloid deposits in tissue biopsy identified by immunohistochemistry, but new techniques, such as mass spectrometry, show promise in determining amyloid types. Neurologists, who are most likely to see patients with neuropathy only, are in a favorable position to make an early diagnosis. The discussion of the clinical presentation and laboratory findings in this article can aid in early recognition of this disease.

Historical note and terminology

Primary systemic amyloidosis is caused by the secretion of a monoclonal serum protein (M-protein) by a plasma cell dyscrasia. The serum proteins are degraded locally in tissues and are deposited in sheets that are insoluble and damage organs. Other forms of amyloid are caused by genetic changes in circulating proteins or chronic inflammation. The term "amyloid" denotes a waxy, amorphous, eosinophilic material named by botanist Mathias Schlieden in 1838 for the waxy components of plants and later used by Virchow in 1853 to describe similar pathological findings in humans. Virchow believed that it was composed of polysaccharides. All varieties of amyloid have similar physical properties such as staining red with Congo-red dye and showing a distinctive apple-green birefringence under polarized light.

Initially, the classification of the amyloidoses (Table 1) was based on the clinical and pathological presentation and familial attributes (Glenner 1980a; Glenner 1980b). Most current classifications are based on the molecular composition of amyloid (Buxbaum and Tagoe 2000), as determined by immunohistochemical testing or direct gene studies. Clinically, however, classification of these disorders into localized and systemic forms is still useful. In localized forms, amyloid can be deposited in the brain (hereditary cerebral hemorrhage with amyloidosis of the Icelandic and the Dutch type, and Alzheimer disease), or in the endocrine system (medullary carcinoma of the thyroid). Systemic amyloidosis includes familial amyloid polyneuropathy, primary and myeloma-associated amyloidosis, secondary amyloidosis, senile amyloidosis, and hereditary renal amyloidosis. This review will focus on primary systemic amyloidosis and associated neurologic and medical manifestations, but will also discuss familial amyloid polyneuropathy because it often enters into the differential diagnosis of primary systemic amyloidosis.

Table 1. Classification of Amyloidoses

Type

Clinical name

Protein

Amyloidosis

Primary systemic amyloidosis

Multiple myeloma-associated

Monoclonal light chain, kappa or lambda

Secondary amyloidosis

Secondary amyloidosis due to infection and inflammation

Protein A

Familial amyloid polyneuropathy

Familial amyloid neuropathy

Due to amino acid substitutions in circulating serum proteins

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