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Validation of the nerve axon reflex for the assessment of small nerve fibre dysfunction
  1. A Caselli1,
  2. V Spallone1,
  3. G A Marfia2,
  4. C Battista1,
  5. C Pachatz2,
  6. A Veves3,
  7. L Uccioli1
  1. 1Department of Internal Medicine, University of Tor Vergata, Rome, Italy
  2. 2Department of Neurological Sciences, University of Tor Vergata
  3. 3Joslin-Beth Israel Deaconess Foot Center, Department of Surgery, Microcirculation Laboratory, Beth Israel-Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to:
 Dr Antonella Caselli
 Department of Internal Medicine, University of Tor Vergata, Viale Oxford, 81 00133 Rome, Italy; dracaselli{at}; antonella.caselli{at}


Objective: To validate nerve–axon reflex-related vasodilatation as an objective method to evaluate C-nociceptive fibre function by comparing it with the standard diagnostic criteria.

Methods: Neuropathy was evaluated in 41 patients with diabetes (26 men and 15 women) without peripheral vascular disease by assessing the Neuropathy Symptom Score, the Neuropathy Disability Score (NDS), the vibration perception threshold (VPT), the heat detection threshold (HDT), nerve conduction parameters and standard cardiovascular tests. The neurovascular response to 1% acetylcholine (Ach) iontophoresis was measured at the forearm and at both feet by laser flowmetry. An age-matched and sex-matched control group of 10 healthy people was also included.

Results: Significant correlations were observed between the neurovascular response at the foot and HDT (rs = −0.658; p<0.0001), NDS (rs = −0.665; p<0.0001), VPT (rs = −0.548; p = 0.0005), tibial nerve conduction velocity (rs = 0.631; p = 0.0002), sural nerve amplitude (rs = 0.581; p = 0.0002) and autonomic function tests. According to the NDS, in patients with diabetes who had mild, moderate or severe neuropathy, a significantly lower neurovascular response was seen at the foot than in patients without neuropathy and controls. A neurovascular response <50% was found to be highly sensitive (90%), with a good specificity (74%), in identifying patients with diabetic neuropathy.

Conclusion: Small-fibre dysfunction can be diagnosed reliably with neurovascular response assessment. This response is already reduced in the early stages of peripheral neuropathy, supporting the hypothesis that small-fibre impairment is an early event in the natural history of diabetic neuropathy.

  • Ach, acetylcholine
  • AUC, area under the curve
  • HDT, heat detection threshold
  • NDS, Neuropathy Disability Score
  • QSART, Quantitative Sudomotor Axon Reflex Test
  • ROC, receiver-operating characteristic
  • SNP, sodium nitroprusside
  • VPT, vibration perception threshold

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  • Published Online First 19 April 2006

  • Competing interests: None.

  • Ethical approval: The necessary ethics committee approval was secured for the study. The study was approved by the local ethics committee of the Tor Vergata Hospital in Rome and each patient signed a written informed consent.

    Part of the study was presented at the 40th Annual Meeting of the European Association for the Study of Diabetes, Münich, 5–9 September 2004, and published as an abstract ( Diabetologia2004;(Suppl 1):) .