Evidence-based Links between Sympathetic Vascular Dysfunction and C-fiber Neuropathy
Researchers have long suspected a connection between sympathetic vascular dysfunction and small fiber neuropathy in diabetic patients. This is of special significance regarding the plantar skin of the foot where many diabetic complications arise. Several studies have found reduced vasomotor control to this skin in diabetics with diabetic peripheral neuropathy (DPN). Although the underlying mechanisms behind these observations remain to be elucidated, the connection appears consistent across varying patient populations and test protocols. The most prevalent hypothesis is that lack of proper neurological control results in abnormal vasomotor responses in the microcirculation of the skin.
In particular, the normal vasoconstriction reflex present in healthy skin seen in response to external stimuli such as cold (1, 2), inspiratory gasp (3, 4) and dependent position (5, 6) has been shown to be muted or absent in patients with neuropathy. It has been suggested that small fiber neuropathy explains these findings; specifically, the C-fiber autonomic nerves responsible for controlling skin microcirculation. Studies investigating the vasomotor effects of the external stimuli noted above revealed an approximately 40% transient drop in skin blood flow consistent with vasoconstriction in healthy patients. This contrasts with observations in DPN patients where a muted or absent vasoconstriction reflex was recorded.
The results of these studies have led researchers to posit various hypothetical explanations for the pathophysiological processes at work. Most of these point to the deep and complementary interplay of microangiopathic and neuropathic changes that occur in diabetes. Among other conclusions, their findings have direct implications for diabetic wound healing. Others studying microcirculatory dysfunction in diabetes have concluded that these difficult to heal wounds are functionally ischemic due to deficits in skin microcirculation (7). Some have also concluded that measurement of the vasoconstriction reflex could be a valid diagnostic method of quantifying small nerve fiber dysfunction. In particular, Bornmyr et al. (1, 2) have proposed a vasoconstriction index (VAC index*) as a test for small fiber nerve function in response to cold challenge. This approach would have the benefit of being non-invasive, objective and quantitative. Such a measurement would be welcome in clinical practice as small fiber neuropathy is notoriously difficult to quantify at point-of-care.
*Vasoconstriction Index (healthy skin) = Skin blood flow after cold exposure/Skin blood flow before cold exposure = 0.6 average
VAC Indices approaching 1.0 indicate impaired vasomotor response to cold exposure.
- Bornmyr S, Svensson H, Söderström T, Sundkvist G, Wollmer P. Finger skin blood flow in response to indirect cooling in normal subjects and in patients before and after sympathectomy. Clin Physiol. 1998 Mar;18(2):103-7.
- Holmlund F, Freccero C, Bornmyr S, Castenfors J, Johansson AM, Nordquist J, Sundkvist G, Svensson H, Wollmer P. Sympathetic skin vasoconstriction–further evaluation using laser Doppler techniques. Clin Physiol. 2001 May;21(3):287-91.
- Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care. 2007 Mar;30(3):655-9.
- Aso Y, Inukai T, Takemura Y. Evaluation of skin vasomotor reflexes in response to deep inspiration in diabetic patients by laser Doppler flowmetry. A new approach to the diagnosis of diabetic peripheral autonomic neuropathy. Diabetes Care. 1997 Aug;20(8):1324-8.
- Midttun M, Snorgaard O. Heat-washout -an objective method for diagnosing neuropathy and atherosclerosis in diabetic patients.Clin Physiol Funct Imaging. 2013 Jul;33(4):302-6.
- Midttun M, Azad BB, Broholm R, Jensen LT, Svarer C, Jensen PE. Heat-washout measurements compared to distal blood pressure and perfusion in orthopaedic patients with foot ulcers. Clin Physiol Funct Imaging. 2017 Jan;37(1):79-83.
- Hamdy O, Abou-Elenin K, LoGerfo FW, Horton ES, Veves A. Contribution of nerve-axon reflex-related vasodilation to the total skin vasodilation in diabetic patients with and without neuropathy. Diabetes Care. 2001 Feb;24(2):344-9.