This study assessed whether painful diabetic neuropathy is associated with abnormal sympathetic nervous function in the affected limbs. Nine patients with diabetes (four men, five women; age 61 ± 7 years) and painful peripheral neuropathy of the feet, but without evidence of generalized autonomic neuropathy, underwent intravenous infusion of tritiated norepinephrine (NE) and sampling of arterial and venous blood in both feet and in one arm to quantify the rate of entry of NE into the local venous plasma (NE spillover). In the same patients, positron emission tomography (PET) scanning after intravenous injection of the sympathoneural imaging agent 6-[18F]fluorodopamine was used to visualize sympathetic innervation and after intravenous [13N]ammonia to visualize local perfusion. The results were compared with those in the feet of normal volunteers and in an unaffected foot of patients with unilateral complex regional pain syndrome (CRPS). In addition, neurochemical results obtained in painful diabetic neuropathy were compared with those obtained in diabetic control patients with painless neuropathy and diabetic control patients without neuropathy. Local arteriovenous difference in plasma NE levels (ΔNEAV) and NE spillover in the arms did not differ across the groups. However, ΔNEAV in the feet was significantly less in the group with painful diabetic neuropathy than in the control groups. Also NE spillover in the feet tended to be lower in painful neuropathy. ΔNEAV of diabetic control patients without neuropathy (n = 6) resembled values in the control groups without diabetes, whereas patients with painless diabetic neuropathy (n = 6) had evidence suggesting partial loss of sympathetic innervation. PET scanning revealed decreased flow-corrected 6-[18F]fluorodopamine-derived radioactivity in patients with painful diabetic neuropathy, compared with values in normal volunteers and patients with CRPS. The results provide neurochemical and neuroimaging evidence for regionally selective sympathetic denervation in the painful feet of patients with diabetic neuropathy.
Address correspondence and reprint requests to Dr. Cees J. Tack, Division of General Internal Medicine, University Hospital, PO Box 9101, 6500 HB Nijmegen, The Netherlands. E-mail:.
Received for publication 29 May 2002 and accepted in revised form 13 September 2002.
BP, blood pressure; CRPS, complex regional pain syndrome; DHPG, dihydroxyphenolglycol; DOPA, dihydroxyphenylalanine; ΔDOPAAV, l-dihydroxyphenylalanine; 18F:13N ratio, 6-[18F]fluorodopamine-derived radioactivity divided by [13N]-ammonia-derived radioactivity; FBF, forearm blood flow; LBF, leg blood flow; NE, norepinephrine; NE spillover, rate of entry of NE into the local venous plasma; ΔNEAV, arteriovenous difference in plasma NE levels; NIH, National Institutes of Health; PET, positron emission tomography; RSD, reflex sympathetic dystrophy.