Primary amyloidosis is mainly a disease of older men, the median age at the time of diagnosis being 65 years. In our clinical material, the majority of the patients have had peripheral neuropathy, but this may reflect a referral bias as in other series, less than one-third were so affected (Kyle et al). The neuropathic symptoms and signs are similar to those of hereditary amyloid polyneuropathy discussed further on, but the progress of the disease is considerably more rapid.
The initial syndrome is primarily sensory—numbness, paresthesias, and very often, acral pain—signs that are mainly characteristic of involvement of small-diameter sensory fibers (loss of pain and thermal sensation). It is the painful aspect and the autonomic features discussed later that distinguish this disease from the other paraproteinemic neuropathies and indeed, from most other polyneuropathies. Weakness follows, initially limited to the feet but becoming more extensive as the disease progresses and eventually spreads to the hands and arms. Only later is there loss of mainly large fibers that mediate sensations of touch, pressure, and proprioception. Twenty-five percent of patients have carpal tunnel syndrome from infiltration of the flexor retinaculum. Exceptionally, patterns other than the painful and sensory predominant polyneuropathy have been associated with amyloidosis; preferential involvement of motor nerves, lumbar roots, plexopathy, and amyloidomas involving single nerves (sciatic, facial, trigeminal) have been reported. Unusual cases of mononeuritis multiplex are difficult to explain.
Autonomic involvement can be severe in amyloid neuropathy (familial or primary) and may become evident early in the course of the illness; several of our patients presented with disturbances of gastrointestinal motility such as episodic diarrhea and orthostatic dizziness or erectile dysfunction and bladder disturbances. The pupils may show a slow reaction to light, or there may be a reduction in sweating. An infiltrative amyloid myopathy also occurs as a rare complication of the disease; it presents as an enlargement and induration of many muscles, particularly those of the tongue (macroglossia), pharynx, and larynx.
Progression of the illness is relatively rapid, the mean survival being 12 to 24 months. An indolent neuropathy that evolves over years is unlikely to be a result of amyloidosis, although we have seen such a case. Death is a result of the renal, cardiac, or gastrointestinal effects of amyloid deposits, the manifestations of which are already evident in more than half of the patients who present with neuropathy. A nephrotic syndrome is also characteristic.
Analysis of the serum and urine, searching for an abnormal paraprotein, is the most useful screening test for amyloid neuropathy. Next in value is a microscopic examination of a biopsy of the abdominal fat pad, gingiva, or rectal mucosa for deposition of amyloid in tissue or blood vessels. Biopsy of the sural nerve or of the involved viscera has a high diagnostic yield; muscle tissue gives variable results. The liver biopsy is positive in virtually all cases of primary amyloid and the kidney shows amyloid infiltration in 85 percent. In several of our patients with a clinical syndrome typical of amyloid neuropathy but in whom amyloid was absent in the sural nerve, the diagnosis was established only after sequential biopsy of numerous sites (fat pad, kidney, liver). If the sural nerve is severely depopulated of nerve fibers, the amount of congophilic staining and the characteristic amyloid birefringence may be meager and yield a spuriously negative result. It is also critical to ensure the accuracy of congophilic staining by comparison with positive and negative control tissue from the same laboratory. The CSF has a normal or mildly elevated protein concentration, but this does not distinguish the neuropathic process from many others.