Autonomic Small-Fiber Pathology in Patients With Fibromyalgia.

In this clinical and skin biopsy study, we aimed to investigate whether fibromyalgia-associated small-fiber pathology (SFP), consisting of an intraepidermal nerve fiber loss, implies damage of dermal autonomic nerve fibers and how this damage is associated with autonomic symptoms that patients with fibromyalgia syndrome experience. Using skin biopsy, we investigated intraepidermal nerve fiber density, piloerector muscle, and sweat gland nerve fiber density (SGNFD) in 138 participants, that is, 58 patients with fibromyalgia syndrome, 48 healthy subjects, and 32 patients with small-fiber neuropathy. In patients with fibromyalgia-associated SFP, we also investigated how the different skin biopsy variables correlated with autonomic symptoms, as assessed with the Composite Autonomic Symptom Score 31 questionnaire. We found that in patients with fibromyalgia-associated SFP, the piloerector muscle and SGNFD were lower than that in healthy subjects. However, the autonomic small-fiber damage had no correlation with autonomic symptoms severity. In patients with SFP, the intraepidermal, piloerector muscle, and SGNFD were higher than that in patients with small-fiber neuropathy. Our clinical and skin biopsy study shows that patients with fibromyalgia have a reduction of dermal autonomic small fibers paralleling the intraepidermal nerve fiber loss, thus indicating that SFP also implies autonomic small nerve fiber damage. However, the autonomic small-fiber damage we found had no correlation with the severity of autonomic symptoms, and thus its clinical impact is still undetermined. PERSPECTIVE: In patients with fibromyalgia, SFP also affects autonomic fibers. These novel data provide additional insights into the pathophysiology of fibromyalgia syndrome, highlighting the complex role of small-fiber damage in the clinical picture of fibromyalgia.

Quantitative sensory testing and skin biopsy findings in late-onset ATTRv presymptomatic carriers: Relationships with predicted time of disease onset (PADO).

INTRODUCTION: Hereditary transthyretin amyloidosis polyneuropathy (ATTRv-PN) presymptomatic carriers often show preclinical abnormalities at small fiber-related diagnostic tests. However, no validated biomarker is currently available to use for presymptomatic carriers' follow-up, thus helping therapeutic decision making. Our study aimed at assessing nerve conduction study (NCS), quantitative sensory testing (QST), and skin biopsy parameters in a large cohort of late-onset ATTRv presymptomatic carriers and to evaluate whether they correlated with predicted age of disease onset (PADO). METHODS: Late-onset ATTRv presymptomatic carriers were consecutively enrolled and underwent NCS, QST, and skin biopsy with intraepidermal nerve fiber density (IENFD) evaluation from a distal and a proximal site. Douleur Neuropathique-4 (DN4) and Small Fiber Neuropathy-Symptoms Inventory (SFN-SIQ) were used to assess painful and small fiber neuropathy-related symptoms. PADO and time-to-PADO (delta-PADO) were estimated for each carrier, and correlations with diagnostic test measures were analyzed. RESULTS: Forty presymptomatic ATTRv subjects were enrolled. Twenty carriers (50%) had distal IENFD reduction, with a non-length-dependent distribution in 73% of cases. Eleven subjects (27.5%) had cold and/or warm detection threshold (CDT and/or WDT) abnormalities at QST. Delta-PADO positively correlated with sural sensory nerve action potential (SNAP) amplitude (r = .416, p = .004), and z-values of QST parameters like CDT (r = .314, p = .028), WDT (r = -.294, p = .034), and mechanical detection threshold (MDT; r = -.382, p = .012). Simple linear regression models showed a linear relation between delta-PADO and sural SAP, CDT, and MDT. CONCLUSIONS: Our findings confirm that IENFD reduction and QST abnormalities may occur early in ATTRv presymptomatic carriers, often with a non-length-dependent pattern. However, only sural SAP amplitude and QST parameters correlated with delta-PADO, suggesting that serial combined QST and NCS evaluation could be useful in ATTRv presymptomatic carriers' follow-up.

Small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and small-fibre neuropathy.

BACKGROUND: In this clinical and psychophysical study, we aimed to verify whether patients with fibromyalgia with and without small-fibre pathology and patients with pure small-fibre neuropathy share common sensory phenotypes. METHODS: Using an algorithm based on quantitative sensory testing variables, we grouped 64 consecutive patients with fibromyalgia (20 with small-fibre pathology, 44 without) and 30 patients with pure small-fibre neuropathy into different sensory phenotypes: sensory loss, thermal hyperalgesia, mechanical hyperalgesia and healthy phenotypes. RESULTS: We found that the frequency of the different sensory phenotypes differed markedly between patients with fibromyalgia and patients with small-fibre neuropathy. In patients with fibromyalgia, with and without small-fibre pathology, healthy and hyperalgesia phenotypes (both thermal and mechanical) were similarly represented, whilst sensory loss and mechanical hyperalgesia phenotypes were the most frequent phenotypes in patients with small-fibre neuropathy. CONCLUSIONS: Our findings indicate that small-fibre damage is associated with distinct sensory phenotypes in patients with fibromyalgia and in patients with small-fibre neuropathy. The lack of phenotype differences between patients with fibromyalgia with and without small-fibre pathology and the relatively high frequency of the healthy phenotype in these patients highlight a complex relationship between small-fibre pathology and pain in patients with fibromyalgia.

Functional and morphometric assessment of small-fibre damage in late-onset hereditary transthyretin amyloidosis with polyneuropathy: the controversial relation between small-fibre-related symptoms and diagnostic test findings.

INTRODUCTION: We aimed at investigating whether functional and morphometric tests assessing small-fibre damage, ie quantitative sensory testing, Sudoscan and skin biopsy, reliably reflect neuropathic pain and autonomic symptoms in patients with late-onset hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN). METHODS: In 30 patients with late-onset ATTRv-PN, we collected quantitative sensory testing, Sudoscan and skin biopsy with assessment of intraepidermal, piloerector muscle and sweat gland nerve fibre density. We then correlated these functional and morphometric parameters with neuropathic pain and autonomic symptoms as assessed with the Neuropathic Pain Symptom Inventory (NPSI) and Composite Autonomic Symptom Score-31 (COMPASS-31). RESULTS: 50% of patients showed small-fibre damage in the form of a pure small-fibre neuropathy, 47% in the context of a mixed fibre neuropathy with small and large fibre involvement. All patients complained of at least one autonomic symptom and 60% had neuropathic pain. Whereas quantitative sensory testing and Sudoscan parameters correlated with neuropathic pain and autonomic symptoms as assessed by NPSI and COMPASS-31, intraepidermal, piloerector muscle and sweat gland nerve fibre density quantification did not. CONCLUSIONS: Our findings indicate that functional test parameters reliably reflect neuropathic pain and autonomic symptoms related to small-fibre damage. These findings might help to identify clinically useful biomarkers to assess patient follow-up.

The diagnostic accuracy of the small fiber neuropathy symptoms inventory questionnaire (SFN-SIQ) for identifying pure small fiber neuropathy.

A definite diagnosis of pure small fiber neuropathy (SFN) relies on specific diagnostic testing, such as skin biopsy, quantitative sensory testing (QST), and nociceptive evoked potentials, which require considerable resources that may not be widely available. Accordingly, diagnostic tools with easy implementation in non-specialist centers are warranted to identify patients who require second-level diagnostic tests. In this study, we aimed to test the accuracy of the Small Fiber Neuropathy Symptoms Inventory Questionnaire (SFN-SIQ) in diagnosing pure SFN. We enrolled 86 patients with suspected pure SFN. In these patients, we calculated the diagnostic accuracy of the SFN-SIQ using a combination of clinical examination, QST, and skin biopsy as a reference standard. We found that the SFN-SIQ showed an excellent ability to discriminate between patients with and without pure SFN, with 86% sensitivity and 70% specificity in the diagnosis of pure SFN. Our study providing the diagnostic yield of the SFN-SIQ for pure SFN diagnosis suggests that this questionnaire might be used to screen patients with suspected SFN and identify those requiring second-level diagnostic tests such as QST, skin biopsy, or nociceptive evoked potentials.

Unravelling the role of unmyelinated nerve fibres in trigeminal neuralgia with concomitant continuous pain.

OBJECTIVE: In this clinical and neurophysiological study, we aimed to test trigeminal nerve fibre function in patients with trigeminal neuralgia, with and without concomitant continuous pain. METHODS: We enrolled 65 patients with a definite diagnosis of primary trigeminal neuralgia. Patients were grouped according to whether they experienced purely paroxysmal pain (36) or also had concomitant continuous pain (29). All participants underwent trigeminal reflex testing to assess the function of large non-nociceptive myelinated fibres and laser-evoked potentials to assess the function of small myelinated Aδ and unmyelinated C fibres. Neurophysiological examiners were blinded to the affected side. RESULTS: The only neurophysiological abnormality distinguishing the two groups of patients was the side asymmetry of C fibre-related laser-evoked potential amplitude (p = 0.005), which was higher in patients with concomitant continuous pain than in patients with purely paroxysmal pain (indicative of a reduced C fibre-related laser-evoked potential amplitude in the affected side of patients with concomitant continuous pain). CONCLUSIONS: Our clinical and neurophysiological study indicates that in patients with trigeminal neuralgia concomitant continuous pain is associated with unmyelinated C fibre damage as assessed with laser-evoked potentials. SIGNIFICANCE: Our findings suggest that concomitant continuous pain is related to unmyelinated C fibre loss, possibly triggering abnormal activity in denervated trigeminal second-order neurons.