Ischemic neuropathy might be a reversible condition, and therapeutic angiogenesis might be an effective treatment. The presence of diabetes does not preclude a response to this therapy.

Objective Phase 2 randomized trial of intramuscular gene transfer using plasmid vascular endothelial growth factor (VEGF) to treat diabetic polyneuropathy. Methods Diabetics with polyneuropathy and no neoplasm or active retinopathy were randomized to receive VEGF:placebo 3:1. Three sets of injections were given at 8 standardized sites adjacent to the sciatic, peroneal and tibial nerves of one leg. Primary outcomes were change in symptom score at 6 months and a prespecified overall clinical and electrophysiologic improvement score. Secondary outcomes were differences in symptoms, examination scores, visual analog pain scale (VAS), nerve conduction and quantitative sensory testing. Results 39 patients received plasmid VEGF and 11, placebo. Mean symptom score improved in both legs at 6 months, favoring VEGF over placebo (–1.2± 0.5 vs. –0.9± 0.5; p<0.01 after adjustment for change in the untreated leg) and compared to the untreated leg (−0.7± 0.5, p=0.02). The region of sensory loss and VAS improved in the treated group (−1.5 vs. −0.5, p=0.01). 12 of 39 VEGF vs. 2 of 11 placebo patients met criterion for overall improvement. Other measures including nerve conduction potentials did not improve. There were 84 adverse events in VEGF patients, 22 serious and 51 events in placebo patients, 2 serious. Interpretation Intramuscular plasmid VEGF gene transfer improved diabetic neuropathic symptoms, meeting primary endpoint criteria for efficacy, but not affecting most secondary measures. Treatment was associated with a higher rate of serious adverse events that did not reach statistical significance. These results are not conclusive but may justify further clinical study.

We performed an open-label, prospective, pilot study of interferon (IFN)-alpha 2a treatment for 6 weeks in 16 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). All patients had failed to improve or relapsed after treatment with at least one conventional therapy (steroids, IV gamma globulin, or plasma exchange). Assessment included MRC strength score, leg sensory score, grip dynanometry, Rankin disability score, electrodiagnostic studies, and serum concentration of tumor necrosis factor-alpha. Nine (56%) improved after IFN-alpha therapy. Mean MRC score increased by 4.2 points (p = 0.01), and mean sensory score improved by 2.3 points (p = 0.02). Five patients improved five or more points on the MRC score, nine had slight improvement or were unchanged, and two worsened. We conclude that IFN-alpha may be effective in some patients with CIDP who relapse or fail to respond to conventional immunomodulating therapy.

There is a predominantly sensory neuropathy associated with chronic and critical limb ischemia. Neuropathic symptoms are often obscured by the effects of ischemia on other tissues. The neurophysiologic changes suggest that the underlying pathophysiology is a distal axonopathy affecting nerve fibers of all sizes. Measures of blood flow in the leg correlate with neurologic symptom scores, examination scores, and electrophysiologic testing.

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