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  • Updated 02.12.2020
  • Released 05.13.1996
  • Expires For CME 02.12.2023

Primary systemic amyloidosis: neurologic complications



Amyloidosis is a generic term and refers to the extracellular deposition of fibrils composed of low weight chain of a variety of normal serum proteins.

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. Patients with limited organ involvement have shown a good response to autologous hematopoietic cell transplantation with prolongation of survival. Early hematopoietic cell transplantation 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. Review of neurologic manifestations of primary systemic amyloidosis, early recognition of the disease by new methods, and considering early treatment (especially autologous hematopoietic cell transplantation) with prolongation of survival are all covered.

Historical note and terminology

Primary systemic amyloidosis or light chain amyloidosis is caused by the secretion of a monoclonal serum protein (M-protein) by a plasma cell dyscrasia. The serum proteins, derived from immunoglobulin light chain fragments, are degraded locally in tissues and are deposited in sheets that are insoluble and damage organs. Primary systemic amyloidosis is a malignant plasma cell dyscrasia that is treated with autologous hematopoietic cell transplantation or chemotherapy to eradicate the underlying clone and should be differentiated from other forms of amyloidosis (eg, secondary amyloidosis and hereditary amyloidosis) as they are nonneoplastic and will not benefit from chemotherapy. 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 amyloidosis (Table 1) was based on the clinical and pathological presentation and familial attributes (47; 48). Most current classifications are based on the molecular composition of amyloid (14), 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.

Immunoglobulin light chain (AL) amyloidosis is a clonal, nonproliferative plasma cell disorder in which fragments of immunoglobulin light chain are deposited in tissues. Presentation includes restrictive cardiomyopathy, nephrotic syndrome, hepatic failure, peripheral/ autonomic neuropathy, and atypical multiple myeloma based on involved organ.

Acquired light chain amyloidosis should be considered in the differential diagnosis of any patient with chronic inflammatory demyelinating polyneuropathy and a monoclonal protein or a monoclonal gammopathy in a patient with unexplained fatigue and paresthesia.

Table 1. Classification of Amyloidosis


Clinical name


Primary amyloidosis

Primary systemic amyloidosis

Multiple myeloma-associated

Monoclonal light chain, kappa or lambda

Secondary amyloidosis

Secondary amyloidosis due to infection and inflammation

Protein A, fibrils are composed of fragments of the acute phase reactant serum amyloid A

Familial (hereditary) amyloid

Familial amyloid

Due to mutated forms of transthyretin (TTR), the alpha chain of fibrinogen A, apolipoprotein AI and AII, lysozyme, and gelsolin

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