TY - JOUR A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Klitsch, Alexander A1 - Unterecker, Stefan A1 - Warrings, Bodo A1 - Serra, Jordi A1 - Papagianni, Aikaterini A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üceyler, Nurcan T1 - Reduction of skin innervation is associated with a severe fibromyalgia phenotype JF - Annals of Neurology N2 - 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 (MDP: 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. KW - fibromyalgia Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206168 VL - 86 IS - 4 ER - TY - JOUR A1 - Klitsch, Alexander A1 - Evdokimov, Dimitar A1 - Frank, Johanna A1 - Thomas, Dominique A1 - Saffer, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Sisignano, Marco A1 - Kampik, Daniel A1 - Malik, Rayaz A. A1 - Sommer, Claudia A1 - Üçeyler, Nurcan T1 - Reduced association between dendritic cells and corneal sub‐basal nerve fibers in patients with fibromyalgia syndrome JF - Journal of the Peripheral Nervous System N2 - 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. KW - corneal confocal microscopy KW - fibromyalgia syndrome KW - Langerhans cells KW - pain KW - small fiber neuropathy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-214150 VL - 25 IS - 1 ER - TY - THES A1 - Meyer zu Altenschildesche, Caren T1 - Genetische Variationen bei Patienten mit idiopathischer Small fiber Neuropathie T1 - Genetic variations in patients with idiopathic small fibre neuropathy N2 - Die Literatur beschreibt unter Patienten mit idiopathischer Small fiber Neuro-pathie (SFN) einen Anteil von etwa ein Fünftel bis Drittel mit Variationen unkla-rer pathogenetischer Relevanz in Schmerz-assoziierten Genen. Dies bestätig-te sich im Rahmen unserer klinischen Studie: Über die Zeit von Mai 2015 bis Januar 2020 konnten bei 13 von 66 (21%) eingeschlossenen Patienten mit klinischem Verdacht auf SFN genetische Variationen in Schmerz-assoziierten Genen detektiert werden. Solche Veränderungen können über Gain- oder Loss-of-Function-Mechanismen die Funktion codierter nozizeptiver Signalpro-teine modulieren und so potentiell zur SFN-Symptomatik führen. Im Rahmen der Studie erfolgte neben der genetischen Diagnostik eine umfangreiche Un-tersuchung der Teilnehmer. In der Diagnostik stachen die potentiell geneti-schen SFN-Patienten nicht heraus und auch klinisch fielen nur dezente Unter-schiede zu den übrigen Patienten auf: Wir zeigten, dass die Betroffenen häufi-ger von äußeren Einflussfaktoren getriggerte Schmerzattacken erleiden und eine tendenziell weitläufigere Symptommanifestation aufwiesen. Dies ähnelt der Klinik anderer hereditärer neuropathischer Schmerzsyndrome wie der pa-roxysmalen extremen Schmerzstörung (PEPD) oder den familiären episodi-schen Schmerzsyndromen (FEPS). Die potentiell genetische Grundlage führte bei unseren Patienten zu einer stärkeren Limitation im täglichen und berufli-chen Alltag und minderte die Lebensqualität der Betroffenen deutlich. Mögli-che Ursache hierfür war auch die herausfordernde Therapie der Patienten mit Genvariationen: Für den gleichen Behandlungserfolg mussten die Patienten mit potentiell genetischer SFN deutlich mehr Wirkstoffe einnehmen und über-haupt versuchen. Obwohl nur minimale klinische Hinweise eine potentiell ge-netische Genese andeuten, sollten diese frühzeitig durch eine strukturierte Anamnese erkannt werden. Die Sammlung von Daten zu betroffenen Familien kann die pathogenetische Relevanz der Variationen erhärten. Auch wird im Feld der genetischen Schmerzforschung rasant an zielgerichteten Analgetika gearbeitet, die fehlregulierte Rezeptoren blockieren sollen. Damit könnte Be-troffenen künftig gezielt geholfen werden. Wir empfehlen auf Grundlage unse-rer Studie bei Vorliegen genannter hinweisender Charakteristika eine geneti-sche Testung und Beratung zusätzlich zur weiteren ätiologischen Diagnostik. Das zu untersuchende Panel sollte möglichst viele Schmerz-assoziierte Gene umfassen – vorrangig die Gene codierend für die spannungsabhängigen Nat-riumkanäle SCN9A, -10A und 11A und die TRP-Kanalproteine TRPA1, TRPV1 und -3. N2 - In literature, eyery fifth to third patient with idiopathic small fiber neuropathy (SFN) shows a variation of unclear pathogenetic relevance in a pain-associated gene. This was confirmed in our clinical study: Over the time period from May 2015 to January 2020, genetic variations in pain-associated genes were detected in 13 of 66 (21%) patients with symptoms suspicious for SFN. Those genetical changes can modulate the function of encoded nociceptive signaling proteins via gain- or loss-of-function mechanisms and potentially lead to SFN symptoms. In addition to genetic diagnostics, the study included a full assessment of the participants. In terms of diagnostics, the potentially genetic SFN patients did not stand out, and there were only subtle differences regarding the clinical picture: We showed that patients with genetic SFN more frequently suffered from triggered pain attacks and a more extensive symptom distribution . This is similar to other hereditary neuropathic pain syndromes such as the paroxysmal extreme pain disorder (PEPD) or familial episodic pain syndromes (FEPS). The potentially genetic background led to a higher limitation in our patients' daily and professional life and significantly reduced their quality of life. Additionally, this could base on the challenging therapy of the patients with gene variations: For the same treatment success, patients with potentially genetic SFN had to take and try more analgetic drugs than patients with idiopathic SFN. Although only minimal clinical characteristics indicate a potential genetic etiology, they should be recognized early with a complete anamnesis. The collection of data from affected families can substantiate the pathogenetic relevance of the variations. In pain research, they work rapidly on targeted analgetics that are intended to block dysregulated receptors. In this way, those affected could be helped in a targeted manner in the future. Based on our study, we recommend genetic testing in addition to further etiological diagnostics especially if the clinical characteristics are present. The panel to be examined should include as many pain-associated genes as possible - primarily the genes coding for the voltage-dependent sodium channels SCN9A, -10A and 11A and the TRP channel proteins TRPA1, TRPV1 and -3. KW - Neuropathie KW - Kleinfaserneuropathie Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-282742 ER - TY - JOUR A1 - Jänsch, Sarah A1 - Evdokimov, Dimitar A1 - Egenolf, Nadine A1 - Meyer zu Altenschildesche, Caren A1 - Kreß, Luisa A1 - Üçeyler, Nurcan T1 - Distinguishing fibromyalgia syndrome from small fiber neuropathy: a clinical guide JF - Pain Reports N2 - 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. KW - fibromyalgia syndrome KW - small fiber neuropathy KW - clinical phenotype KW - pain pattern KW - differential diagnosis Y1 - 2024 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350306 VL - 9 IS - 1 ER -