@article{EgenolfAltenschildescheKressetal.2021,
  author    = {Egenolf, Nadine and Altenschildesche, Caren Meyer zu and Kreß, Luisa and Eggermann, Katja and Namer, Barbara and Gross, Franziska and Klitsch, Alexander and Malzacher, Tobias and Kampik, Daniel and Malik, Rayaz A. and Kurth, Ingo and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Diagnosing small fiber neuropathy in clinical practice: a deep phenotyping study},
  series = {Therapeutic Advances in Neurological Disorders},
  volume    = {14},
  journal   = {Therapeutic Advances in Neurological Disorders},
  issn      = {1756-2864},
  doi       = {10.1177/17562864211004318},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-232019},
  year      = {2021},
  abstract  = {Background and aims: Small fiber neuropathy (SFN) is increasingly suspected in patients with pain of uncertain origin, and making the diagnosis remains a challenge lacking a diagnostic gold standard. Methods: In this case-control study, we prospectively recruited 86 patients with a medical history and clinical phenotype suggestive of SFN. Patients underwent neurological examination, quantitative sensory testing (QST), and distal and proximal skin punch biopsy, and were tested for pain-associated gene loci. Fifty-five of these patients additionally underwent pain-related evoked potentials (PREP), corneal confocal microscopy (CCM), and a quantitative sudomotor axon reflex test (QSART). Results: Abnormal distal intraepidermal nerve fiber density (IENFD) (60/86, 70\%) and neurological examination (53/86, 62\%) most frequently reflected small fiber disease. Adding CCM and/or PREP further increased the number of patients with small fiber impairment to 47/55 (85\%). Genetic testing revealed potentially pathogenic gene variants in 14/86 (16\%) index patients. QST, QSART, and proximal IENFD were of lower impact. Conclusion: We propose to diagnose SFN primarily based on the results of neurological examination and distal IENFD, with more detailed phenotyping in specialized centers.},
  language  = {en}
}
@phdthesis{Klitsch2021,
  author    = {Klitsch, Alexander},
  title     = {Corneal and cutaneous factors contributing to small fiber pathology in fibromyalgia syndrome},
  doi       = {10.25972/OPUS-22439},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-224398},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2021},
  abstract  = {We examined 143 patients suffering from FMS, a syndrome characterized by chronic widespread pain, sleep disturbances, and fatigue. Etiology and pathophysiology of FMS are scarcely understood. In recent years abnormalities of small Aδ- and C-nerve fibers have been found in subgroups of FMS patients. It is yet unclear how such SFP is caused in FMS patients and how it contributes to FMS symptoms. We used CCM to analyze corneal small nerve fibers and associated LC, comparing FMS patients' results to those from 65 healthy controls and 41 disease controls suffering from SFN. We, further, assessed expression levels of mRNA and miRNA in keratinocytes taken from skin punch biopsies of FMS patients and healthy controls kept as monocellular cell cultures. A screening was performed using NGS in a small cohort of 12 FMS patients and 5 healthy controls. Results were validated in larger cohorts by qRT-PCR. As in previous studies IENFD and CNFD were reduced in a subgroup of FMS patients. We found identical LC densities in FMS patients, healthy controls, and SFN patients. The subpopulation of dLCfiber contact in FMS and SFN patients was lower than in healthy controls. Our RNA expression analysis revealed one mRNA that was expressed higher in FMS patients than in controls: PRSS21. We conclude that reduced neurotrophic signaling of LC may contribute to SFP in the cornea. Epidermal PRSS21 expression and dLCfiber contact density are promising biomarker candidates for FMS diagnosis.},
  subject      = {Fibromyalgie},
  language  = {en}
}
@article{KlitschEvdokimovFranketal.2020,
  author    = {Klitsch, Alexander and Evdokimov, Dimitar and Frank, Johanna and Thomas, Dominique and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Sisignano, Marco and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}{\c{c}}eyler, Nurcan},
  title     = {Reduced association between dendritic cells and corneal sub-basal nerve fibers in patients with fibromyalgia syndrome},
  series = {Journal of the Peripheral Nervous System},
  volume    = {25},
  journal   = {Journal of the Peripheral Nervous System},
  number    = {1},
  doi       = {10.1111/jns.12360},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214150},
  pages     = {9-18},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}
@article{EvdokimovFrankKlitschetal.2019,
  author    = {Evdokimov, Dimitar and Frank, Johanna and Klitsch, Alexander and Unterecker, Stefan and Warrings, Bodo and Serra, Jordi and Papagianni, Aikaterini and Saffer, Nadine and Meyer zu Altenschildesche, Caren and Kampik, Daniel and Malik, Rayaz A. and Sommer, Claudia and {\"U}ceyler, Nurcan},
  title     = {Reduction of skin innervation is associated with a severe fibromyalgia phenotype},
  series = {Annals of Neurology},
  volume    = {86},
  journal   = {Annals of Neurology},
  number    = {4},
  doi       = {10.1002/ana.25565},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-206168},
  pages     = {504-516},
  year      = {2019},
  abstract  = {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.},
  language  = {en}
}