Brain Advance Access originally published online on June 4, 2008
Brain 2008 131(7):1912-1925; doi:10.1093/brain/awn093
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The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology
1Neurological Clinic, University of Ferrara, 2Neurophysiological Unit, S. Anna General Hospital, Ferrara, 3Neuromuscular Diseases Unit, National Neurological Institute ‘Carlo Besta’, Milan and 4Neurological Clinic, University of Brescia, Italy
Correspondence to: Dr Giuseppe Lauria, Neuromuscular Diseases Unit, National Neurological Institute ‘Carlo Besta’, via Celoria, 11, 20133 Milan, Italy E-mail: glauria{at}istituto-besta.it
Small fibre neuropathy (SFN), a condition dominated by neuropathic pain, is frequently encountered in clinical practise either as prevalent manifestation of more diffuse neuropathy or distinct nosologic entity. Aetiology of SFN includes pre-diabetes status and immune-mediated diseases, though it remains frequently unknown. Due to their physiologic characteristics, small nerve fibres cannot be investigated by routine electrophysiological tests, making the diagnosis particularly difficult. Quantitative sensory testing (QST) to assess the psychophysical thresholds for cold and warm sensations and skin biopsy with quantification of somatic intraepidermal nerve fibres (IENF) have been used to determine the damage to small nerve fibres. Nevertheless, the diagnostic criteria for SFN have not been defined yet and a ‘gold standard’ for clinical practise and research is not available. We screened 486 patients referred to our institutions and collected 124 patients with sensory neuropathy. Among them, we identified 67 patients with pure SFN using a new diagnostic ‘gold standard’, based on the presence of at least two abnormal results at clinical, QST and skin biopsy examination. The diagnosis of SFN was achieved by abnormal clinical and skin biopsy findings in 43.3% of patients, abnormal skin biopsy and QST findings in 37.3% of patients, abnormal clinical and QST findings in 11.9% of patients, whereas 7.5% patients had abnormal results at all the examinations. Skin biopsy showed a diagnostic efficiency of 88.4%, clinical examination of 54.6% and QST of 46.9%. Receiver operating characteristic curve analysis confirmed the significantly higher performance of skin biopsy comparing with QST. However, we found a significant inverse correlation between IENF density and both cold and warm thresholds at the leg. Clinical examination revealed pinprick and thermal hypoesthesia in about 50% patients, and signs of peripheral vascular autonomic dysfunction in about 70% of patients. Spontaneous pain dominated the clinical picture in most SFN patients. Neuropathic pain intensity was more severe in patients with SFN than in patients with large or mixed fibre neuropathy, but there was no significant correlation with IENF density. The aetiology of SFN was initially unknown in 41.8% of patients and at 2-year follow-up a potential cause could be determined in 25% of them. Over the same period, 13% of SFN patients showed the involvement of large nerve fibres, whereas in 45.6% of them the clinical picture did not change. Spontaneous remission of neuropathic pain occurred in 10.9% of SFN patients, while it worsened in 30.4% of them.
Key Words: neuropathy; pain; skin biopsy; quantitative sensory testing; neurophysiology
Abbreviations: CMAP, compound motor action potential; CDT, cold detection threshold; CPT, cold pain thresholds; HPT, heat pain thresholds; IENF, intraepidermal nerve fibres; IGT, impaired glucose tolerance; LEPs, laser evoked potentials; LFN, large fibre neuropathy; MFN, mixed (large and small) fibre neuropathy; MGUS, monoclonal gammopathy of undetermined significance; NCS, nerve conduction study; NRS, numerical rating scale; PT, perceptive thresholds; QST, quantitative sensory testing; ROC, receiver operating characteristic; SFN, small fibre neuropathy; SNAP, sensory nerve action potential; VAS, visual analogue scale; WDT, warm detection threshold
Received January 2, 2008. Revised March 18, 2008. Accepted April 21, 2008.
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