Abstract & Commentary
Synopsis: If routine staining is negative for amyloid, Congo red and thioflavine S staining need be performed, with ultrastructural examination of Epon-embedded nerve. Anti-light-chain and transthyretin immunostaining of frozen nerve completes the investigation.
Source: Vital C, et al. Amyloid Neuropathy: A Retrospective Study of 35 Peripheral Nerve Biopsies. J Peripher Nerv Syst. 2004;9:232-241.
Amyloid neuropathy may be familial or acquired, the former caused by transthyretin (TTR) gene mutation, the latter by kappa or lamda chain transformation into amyloid consequent to monoclonal gammopathy. Forty three cases of amyloid neuropathy, diagnosed from 1974-2003 at Victor Segalan University in Bordeaux, France, were reviewed to determine the clinical and pathological characteristics of amyloid neuropathy. Eight were excluded from analysis due to lack of clinical information (n = 7), or due to the presence of a biclonal gammopathy (n = 1). Twenty two men and 13 women, ages 27-82 years, including 26 French Caucasians, 7 Portuguese, and 1 each Spaniard and Caribbean, comprised the study population (n = 35).
Chronic sensorimotor polyneuropathy of the distal legs was the presenting clinical picture in 32 patients, with chronic inflammatory demyelinating polyneuropathy, pure motor peripheral neuropathy, and impotence with minor sensory disturbances in the feet the presenting picture in 1 patient each. Amyloidosis was previously documented in 13, newly suspected in 6 based on family history or co-existence of multiple myeloma, and unexpectedly discovered on peripheral nerve biopsy in 16. Biopsies were taken from the superficial peroneal nerve and peroneus brevus muscle.
Acidophilic amyloid deposits were easily seen under light microscopy in 22 specimens, and also when stained both with Congo red and thioflavine S. Solitary, small deposits of endoneurial amyloid were seen in 4, but ultrastructural examination was required to reveal amyloid in 6, and Congo red and thioflavine S staining was needed in 3. Striking myelinated fiber loss was evident in 34, affecting predominantly large (n = 15), or both large and small fibers (n = 15), with 4 showing primarily small fiber loss. Unmyelinated fibers were affected in all cases, and segmental demyelination was seen in 10. Amyloid must be included in the differential diagnosis of axonal and demyelinating polyneuropathy and, given the occasional paucity of findings, whole-nerve biopsy with muscle taken from the same incision is recommended. If routine staining is negative for amyloid, Congo red and thioflavine S staining need be performed, with ultrastructural examination of Epon-embedded nerve. Anti-light-chain and transthyretin immunostaining of frozen nerve completes the investigation.
Amyloidosis, the result of insoluble fibril deposition in the extracellular space, due to an abnormality of protein folding, is classified according to the fibril precursor protein (Sem Cell Dev Biol. 2004;15;39-44). Deposits may occur in multiple organs or be restricted to certain tissues or vessels. Primary (AL) amyloidosis is the most common systemic amyloidosis, and is seen with monoclonal plasma cell dyscrasias, developing consequent to monoclonal immunoglobulin light chain fragments depositing as fibrils in any organ other than the brain. Prognosis is poor. Secondary (AA) amyloidosis, a reactive disease associated with chronic inflammatory diseases, results from the acute phase reactant serum amyloid A protein acting as the fibril precursor. Unlike AL amyloid, it is rare in the heart and peripheral nervous system, most often affecting the kidneys. Long-term hemodialysis is often complicated by 2-microglobulin amyloidosis (A 2M), due to impaired clearance of this HLA class I cell surface molecule. Senile systemic amyloidosis (ATTR), with normal plasma transthyretin serving as the fibril precursor protein, is often asymptomatic or may cause cardiac failure.
Hereditary amyloidoses are more recently recognized. Fibrinogen A-chain, transthyretin, apolipoprotein AI or AII, lysozyme, cytostatin C, and gelsolin are among an increasing number of proteins, mutations of which result in amyloidosis. Familial amyloid peripheral, autonomic neuropathy (genetically variant transthyretin), and cerebral amyloid angiopathy with recurrent lobar hemorrhage (genetically variant cytostatin C) are some of the neurologic diseases identified for which rational therapies may be devised as understanding of these conditions advances. — Michael Rubin
Dr. Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, is Assistant Editor of Neurology Alert.