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Amyloidosis and Neuropathy
Abstract & Commentary
By Michael Rubin, MD, FRCP(C), Professor of Clinical Neurology, Weill Cornell Medical College, New York, NY. Dr. Rubin reports that he receives grant/research support from Pfizer and is on the speaker's bureau of Athena Diagnostics.
Synopsis: Generalized autonomic failure (GAF) in the presence of a sensory neuropathy strongly suggests amyloidosis.
Source: Wang AK, Fealey RD, Gehrking TL, et al. Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc 2008;83;1226-1230.
What forms of neuropathy and what patterns of autonomic failure may result from amyloidosis? To answer these questions, a retrospective chart review was undertaken at Mayo Clinic, Rochester, of all patients seen between January 1, 1985 and December 31, 1997, who had biopsy-proven amyloidosis and also had undergone autonomic testing. Sixty-five patients were captured, including 45 men and 20 women, with a mean age of 63 years (range 32–79 years). Amyloidosis was biopsy-proven by tissue from nerve, fat, skin, liver, stomach, colon, or flexor retinaculum. Neuropathy was diagnosed and characterized as either polyneuropathy, defined as distal weakness with vibratory and deep tendon reflex loss, or small-fiber, characterized by distal burning pain, loss of temperature or pain sensation with spared deep tendon reflexes, and relatively intact vibratory and position sensation. Autonomic symptoms included pupillary, secretomotor, vasomotor, orthostatic, gastrointestinal, genitourinary, or sexual dysfunction. Autonomic testing comprised the autonomic reflex screen (ARS), encompassing adrenergic, cardiovagal, and sudomotor function, the results of which produced a composite autonomic severity score (CASS) ranging from 0 (normal) to 10 (severe autonomic failure). Tests included the quantitative sudomotor axon reflex test (QSART), heart response to deep breathing, the Valsalva maneuver, and tilt-table testing of blood pressure and heart rate response. Statistical analysis included the two-sided Wilcoxon rank sum tests and the Wilcoxon signed rank test, with P<0.05 considered significant.
Systemic light-chain amyloidosis was diagnosed in 43 (66%) and familial amyloid polyneuropathy (FAP) in 22 patients (34%). Other than one instance of concomitant B12 deficiency that did not improve with replacement therapy, no other cause of neuropathy or autonomic failure was identified in any patient. Autonomic symptoms most commonly comprised orthostatic (74%) and gastrointestinal symptoms (71%), and less often secretomotor (54%), genitourinary (39%), erectile (67% of men only), vasomotor (26%), or pupillary (25%). Four patients (6%) had no autonomic symptoms. Median CASS scores were 3 for adrenergic and cardiovagal testing and 2 for sudomotor testing. Axonal sensorimotor polyneuropathy was found on nerve conduction studies in 49 of 52 (94%) studied. Overall, five patterns of neuropathy and autonomic failure were disclosed: generalized autonomic failure (GAF) with polyneuropathy and pain (62%); GAF with polyneuropathy without pain (17%); GAF only (11%); polyneuropathy without GAF (6%); and GAF with small-fiber neuropathy (5%). Autonomic testing is warranted in patients with idiopathic polyneuropathy, as abnormal findings may be seen even in the absence of autonomic symptoms, leading to the early diagnosis and treatment of amyloidosis.
"All that glitters is not gold," and not all painful neuropathies with dysautonomia are due to amyloid, even in the presence of amyloid on biopsy.1 Amyloid neuropathy was initially diagnosed in a 66-year-old woman with a 19-year history of progressive gait difficulties and painful distal paresthesiae. Bilateral Adie's pupils indicated autonomic involvement, but she denied dryness of the mouth or eyes, orthostatic hypotension, abnormal sweating, or other autonomic dysfunction. Periumbilical fat aspiration biopsy was positive for amyloid, resulting in initial misdiagnosis, but sural nerve biopsy ultimately ruled out an acquired amyloid neuropathy, and nucleotide sequencing demonstrated a Thr95Met mutation in the myelin protein zero (MPZ) gene, seen with CMT1B. Axonal MPZ gene mutations can perfectly mimic amyloid neuropathy.
1. Briani C, Adami F, Cavallaro T, et al. Axonal neuropathy due to myelin protein zero mutation misdiagnosed as amyloid neuropathy. Muscle Nerve 2008;38:921-923.