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The peripheral neuropathy seen with necrotizing angiopathy is said to begin classically as a mononeuritis multiplex, usually associated with polyarteritis nodosa, rheumatoid arthritis, or systemic lupus erythematosus. Our experience, however, suggests that a large number of these patients do not have a well-defined collagen vascular disease or the typical clinical pattern. In 350 consecutive nerve biopsies (sural or superficial radial), 16 patients showed a necrotizing angiopathy in the epineurial blood vessels. Six of these 16 patients had a distal symmetrical sensorimotor polyneuropathy. The remaining 10 had a mononeuritis multiplex, although in 8 overlapping nerve involvement somewhat obscured the picture of mononeuritis. In 12 patients, no specific underlying collagen vascular disease could be diagnosed by accepted criteria despite extensive clinical, radiological, and serological evaluations. The peripheral neuropathy was the only objective evidence of vasculitis in 7 of these 12 patients. Our findings suggest that patients with a peripheral neuropathy secondary to necrotizing angiopathy often do not have a definable collagen vascular disease. In fact, peripheral neuropathy may be the sole manifestation of vasculitis. Furthermore, the neuropathy was found to be a distal symmetrical sensorimotor neuropathy in a higher proportion of cases than has been documented previously.

Delayed relaxation of muscle following voluntary contraction was an unusual feature of a mild chronic sesorimotor peripheral neuropathy in an adult. This abnormality resulted from rapid repetitive discharges in motor nerves occurring only in response to passing impulses; there was no spontaneous nerve discharge. Voluntary contraction of affected muscles generated involuntary high-frequency discharges of motor unit potentials, which persisted briefly after attempted relaxation. Nerve blocks localized independent zones of hyperexcitability in distal and proximal sections of nerve from which such repetitive discharges could be triggered. Intravenous administration of phenytoin diminished the discharge. Examination of intramuscular nerve bundles revealed loss of myelinated nerve fibers with numberous sprouting and remyelinating axons. These findings, along with muscle biopsy changes of neurogenic atrophy and type grouping, strongly favor an axonal neuropathy. An explanation for the repetitive nerve discharge is slow waning of heightened excitability of a motor nerve after passage of an impulse.

Phenytoin has been implicated as a causative agent in peripheral neuropathy, although structural changes in nerve have not been characterized. A 47-year-old man was seen with clinical and electrophysiological signs of peripheral neuropathy after 30 years of phenytoin administration. Despite a modest dose of phenytoin (300 mg/day) blood levels were 31 to 38 micrograms/ml. A sural nerve biopsy showed a loss of large myelinated nerve fibers and a nonrandom clustered distribution of segmental demyelination and remyelination. The latter findings were accompanied by axonal shrinkage. Sixteen months after phenytoin was stopped, the patient's clinical and electrophysiological findings reflected improvement. These data indicate that long-term phenytoin administration can cause a reversible neuropathy characterized by axonal shrinkage and secondary demyelination.

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