[Sequence variants of unknown significance in small fiber neuropathy : Characterization of a heterogeneous patient population]. / Sequenzvarianten unklarer Signifikanz bei Small-Fiber-Neuropathie : Charakterisierung einer heterogenen PatientInnenpopulation.

BACKGROUND: In almost half of patients suffering from small fiber neuropathies (SFN), the etiology remains elusive. For these patients with "idiopathic SFN", symptomatic analgesic therapy is the only option. Reports on a potential genetic background of neuropathic pain syndromes are increasing and particularly in SFN patients, several genetic variants were found mainly located in genes encoding voltage-gated sodium channels. Although up to 30% of SFN patients show genetic alterations, most of these remain of "unknown pathogenic significance" and little is known about "genetic SFN". OBJECTIVES: The study aimed to determine clinical characteristics of SFN patients carrying a rare genetic variant of unknown significance in pain-associated genes. MATERIALS AND METHODS: From 2015 to 2020, 66 patients with primarily idiopathic SFN were examined and rare gene variants of unknown significance detected in 13/66 (20%) of these. A detailed medical history with focus on pain was recorded and patients filled in standardized questionnaires to assess physical and emotional burden due to pain. RESULTS: The authors found 13/66 (20%) patients with rare variants of unknown significance located in pain-associated genes who reported pain refractory to analgesic treatment, a higher number of external factors influencing clinical symptoms, and a higher level of physical impairment and emotional stress due to pain compared with patients without such genetic variants. CONCLUSIONS: Early genetic assessment is recommended to optimize the management of patients with potentially hereditary SFN. Early access to rehabilitation and mental support as well as a consequent elimination of external triggering factors should be granted.

Reduction of skin innervation is associated with a severe fibromyalgia phenotype.

OBJECTIVE: To assess patterns and impact of small nerve fiber dysfunction and pathology in patients with fibromyalgia syndrome (FMS). METHODS: One hundred seventeen women with FMS underwent neurological examination, questionnaire assessment, neurophysiology assessment, and small fiber tests: skin punch biopsy, corneal confocal microscopy, microneurography, quantitative sensory testing including C-tactile afferents, and pain-related evoked potentials. Data were compared with those of women with major depressive disorder and chronic widespread pain (MD-P) and healthy women. RESULTS: Intraepidermal nerve fiber density (IENFD) was reduced at different biopsy sites in 63% of FMS patients (MD-P: 10%, controls: 18%; p < 0.001 for each). We found 4 patterns of skin innervation in FMS: normal, distally reduced, proximally reduced, and both distally and proximally reduced (p < 0.01 for each compared to controls). Microneurography revealed initial activity-dependent acceleration of conduction velocity upon low frequencies of stimulation in 1A fibers, besides 1B fiber spontaneous activity and mechanical sensitization in FMS patients. FMS patients had elevated warm detection thresholds (p < 0.01), impaired C-tactile afferents (p < 0.05), and reduced amplitudes (p < 0.001) of pain-related evoked potentials compared to controls. Compared to FMS patients with normal skin innervation, those with generalized IENFD reduction had higher pain intensity and impairment due to pain, higher disease burden, more stabbing pain and paresthesias, and more anxiety (p < 0.05 for each). FMS patients with generalized IENFD reduction also had lower corneal nerve fiber density (p < 0.01) and length (p < 0.05). INTERPRETATION: The extent of small fiber pathology is related to symptom severity in FMS. This knowledge may have implications for the diagnostic classification and treatment of patients with FMS. ANN NEUROL 2019;86:504-516.

Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome.

In our study, we aimed at investigating corneal langerhans cells (LC) in patients with fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) as potential contributors to corneal small fiber pathology. We enrolled women with FMS (n = 134) and SFN (n = 41) who underwent neurological examination, neurophysiology, prostaglandin analysis in tear fluid, and corneal confocal microscopy (CCM). Data were compared with those of 60 age-matched female controls. After screening for dry eye disease, corneal LC were counted and sub-classified as dendritic (dLC) and non-dendritic (ndLC) cells with or without nerve fiber association. We further analyzed corneal nerve fiber density (CNFD), length (CNFL), and branch density (CNBD). Neurological examination indicated deficits of small fiber function in patients with SFN. Nerve conduction studies were normal in all participants. Dry eye disease was more prevalent in FMS (17%) and SFN (28%) patients than in controls (5%). Tear fluid prostaglandin levels did not differ between FMS patients and controls. While corneal LC density in FMS and SFN patients was not different from controls, there were fewer dLC in association with nerve fibers in FMS and SFN patients than in controls (P < .01 each). Compared to controls, CNFL was lower in FMS and SFN patients (P < .05 each), CNFD was lower only in FMS patients (P < .05), and CNBD was lower only in SFN patients (P < .001). There was no difference in any CCM parameter between patients with and without dry eyes. Our data indicate changes in corneal innervation and LC distribution in FMS and SFN, potentially based on altered LC signaling.

Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide.

Introduction: Fibromyalgia syndrome (FMS) and small fiber neuropathy (SFN) are distinct pain conditions that share commonalities and may be challenging as for differential diagnosis. Objective: To comprehensively investigate clinical characteristics of women with FMS and SFN to determine clinically applicable parameters for differentiation. Methods: We retrospectively analyzed medical records of 158 women with FMS and 53 with SFN focusing on pain-specific medical and family history, accompanying symptoms, additional diseases, and treatment. We investigated data obtained using standardized pain, depression, and anxiety questionnaires. We further analyzed test results and findings obtained in standardized small fiber tests. Results: FMS patients were on average ten years younger at symptom onset, described higher pain intensities requiring frequent change of pharmaceutics, and reported generalized pain compared to SFN. Pain in FMS was accompanied by irritable bowel or sleep disturbances, and in SFN by paresthesias, numbness, and impaired glucose metabolism (P < 0.01 each). Family history was informative for chronic pain and affective disorders in FMS (P < 0.001) and for neurological disorders in SFN patients (P < 0.001). Small fiber pathology in terms of skin denervation and/or thermal sensory threshold elevation was present in 110/158 (69.7 %) FMS patients and 39/53 (73.6 %) SFN patients. FMS patients mainly showed proximally reduced skin innervation and higher corneal nerve branch densities (p<0.001) whereas SFN patients were characterized by reduced cold detection and prolonged electrical A-delta conduction latencies (P < 0.05). Conclusions: Our data show that FMS and SFN differ substantially. Detailed pain, drug and family history, investigating blood glucose metabolism, and applying differential small fiber tests may help to improve diagnostic differentiation and targeted therapy.