Diagnosing and dEtermining the contribution of small FIbre NEuropathy to pain in FibroMyalgia Syndrome (DEFINE-FMS)

We hypothesise that the rapid non-invasive diagnostic imaging technique of corneal confocal microscopy (CCM) can detect small fibre neuropathy in people with fibromyalgia syndrome (FMS) as accurately as the current reference standard of small fibre quantification by skin biopsy.

We also aim to evaluate if specific small nerve fibre structural alterations detected by CCM are directly related to dysfunction (hyperexcitability) of small nerve fibres and pain phenotypes.

If successful, CCM has huge potential in rapidly and accurately identifying patients with small fibre neuropathy and CCM may predict those who may benefit from targeted therapy. The patient and societal benefits are considerable if the projected outcomes from this study are met. FMS affects ~5-6% of the European population, and is characterised by chronic widespread musculoskeletal pain (1).

FMS shares features of neuropathic pain and several studies in recent years have demonstrated significant small fibre neuropathy in approximately 35-75% of individuals with FMS (2-10). Indeed, our study shows a prevalence of ~50% of small fibre neuropathy in FMS (11).

Other studies have also shown clear abnormalities in pain-evoked potentials, somatosensory abnormalities during quantitative sensory testing and evidence of pain with small fibre neuropathy (2,3). Currently, skin biopsy is considered the reference standard for the assessment of small fibre neuropathy (12).

However, as well as being invasive, laboratory availability for undertaking intra-epidermal nerve fibre quantification in skin biopsies is severely limited in the UK.

CCM is a technique that allows direct visualisation of the small nerve fibres in the cornea which represent the same type of nerves that are involved in neuropathic pain elsewhere.

This technique is a real−time, non−invasive, time−efficient and a repeatable method of imaging small nerve fibres. It allows for detailed quantification without the need of complex laboratory analysis as with skin biopsy.

CCM has been extensively used to identify small fibre pathology in diabetic neuropathy (13,14) and a range of other peripheral neuropathies (15-17). We have shown CCM has comparable diagnostic ability to skin biopsy in people with diabetic neuropathy (18).

Furthermore, people with small fibre neuropathy and peripheral neuropathy with neuropathic pain show greater corneal nerve loss compared to healthy people (15,17,19-22).

Microneurography provides a direct means of recording action potentials and detection of diseased small nerve fibres (nociceptors) (23) and therefore information on pathogenesis of the painful symptoms in small fibre neuropathy.

In a seminal study of microneurography, majority of people with FMS had abnormal C-nociceptors with silent nociceptor hyperexcitability resembling that of small fibre neuropathy (23).

Fifty healthy-volunteer controls and seventy-seven people with FMS will undergo detailed evaluation of small nerve fibre structure and function along with neuropathic pain phenotyping.

Small nerve fibre pathology will be quantified through CCM and skin biopsy with a comparative evaluation by receiver-operator curve analyses to define the ability of each technique to delineate small fibre neuropathy.

In addition, microneurography will be undertaken in 10 healthy-volunteer controls, 10 people with FMS and no small nerve fibre neuropathy and 10 people with FMS with small nerve fibre neuropathy.