{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T09:58:25Z","timestamp":1782899905552,"version":"3.54.5"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T00:00:00Z","timestamp":1589760000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"M\u00e4rta and Erik Karberg Foundation for Medical Research","award":["Schwannomatosis"],"award-info":[{"award-number":["Schwannomatosis"]}]},{"name":"Bundesverband Neurofibromatose","award":["Schwannomatose"],"award-info":[{"award-number":["Schwannomatose"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16\/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13\/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.<\/jats:p>","DOI":"10.3390\/ijms21103569","type":"journal-article","created":{"date-parts":[[2020,5,18]],"date-time":"2020-05-18T11:34:14Z","timestamp":1589801654000},"page":"3569","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["C-Fiber Loss as a Possible Cause of Neuropathic Pain in Schwannomatosis"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3596-5932","authenticated-orcid":false,"given":"Said","family":"Farschtschi","sequence":"first","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0597-2648","authenticated-orcid":false,"given":"Tina","family":"Mainka","sequence":"additional","affiliation":[{"name":"Department of Neurology, Charit\u00e9 University Medicine, 10117 Berlin, Germany"},{"name":"Berlin Institute of Health, 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Glatzel","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena","family":"Hannekum","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hauck","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Department of Neurophysiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"Gelderblom","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0518-0824","authenticated-orcid":false,"given":"Christian","family":"Hagel","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reinhard","family":"Friedrich","sequence":"additional","affiliation":[{"name":"Department of Maxillofacial Surgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schuhmann","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University Medical Center T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Schulz","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany"},{"name":"MVZ Human Genetics, 99084 Erfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Morrison","sequence":"additional","affiliation":[{"name":"Leibniz Institute on Aging, Fritz Lipmann Institute, 07745 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hildegard","family":"Kehrer-Sawatzki","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, University of Ulm, 89081 Ulm, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Luhmann","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Gerloff","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bendszus","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, University Medical Center Heidelberg, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"B\u00e4umer","sequence":"additional","affiliation":[{"name":"Department of Neuroradiology, University Medical Center Heidelberg, 69120 Heidelberg, Germany"},{"name":"Department of Radiology, German Cancer Research Center, 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor-Felix","family":"Mautner","sequence":"additional","affiliation":[{"name":"Department of Neurology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1212\/01.WNL.0000163982.78900.AD","article-title":"Diagnostic criteria for schwannomatosis","volume":"64","author":"MacCollin","year":"2005","journal-title":"Neurology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1136\/jnnp-2018-318538","article-title":"Schwannomatosis: A genetic and epidemiological study","volume":"89","author":"Evans","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1634\/theoncologist.2012-0162","article-title":"Clinical features of schwannomatosis: A retrospective analysis of 87 patients","volume":"17","author":"Merker","year":"2012","journal-title":"Oncologist"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.1212\/WNL.46.4.1072","article-title":"Schwannomatosis: A clinical and pathologic study","volume":"46","author":"MacCollin","year":"1996","journal-title":"Neurology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1212\/01.wnl.0000201190.89751.41","article-title":"Increasing the specificity of diagnostic criteria for schwannomatosis","volume":"66","author":"Baser","year":"2006","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1086\/513207","article-title":"Germline mutation of INI1\/SMARCB1 in familial schwannomatosis","volume":"80","author":"Hulsebos","year":"2007","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5239","DOI":"10.1093\/hmg\/dds370","article-title":"Expression of SMARCB1 (INI1) mutations in familial schwannomatosis","volume":"21","author":"Smith","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1038\/ng.2855","article-title":"Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas","volume":"46","author":"Piotrowski","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00401-014-1311-1","article-title":"Whole exome sequencing reveals that the majority of schwannomatosis cases remain unexplained after excluding SMARCB1 and LZTR1 germline variants","volume":"128","author":"Hutter","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/s00439-016-1753-8","article-title":"The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis","volume":"136","author":"Farschtschi","year":"2017","journal-title":"Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1002\/ajmg.a.35760","article-title":"Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria","volume":"161","author":"Plotkin","year":"2013","journal-title":"Am. J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/j.1529-8027.2010.00271.x","article-title":"Intraepidermal nerve fiber density at the distal leg: A worldwide normative reference study","volume":"15","author":"Lauria","year":"2010","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1111\/bpa.12780","article-title":"Distinctive low epidermal nerve fiber density in schwannomatosis patients provides a major parameter for diagnosis and differential diagnosis","volume":"30","author":"Farschtschi","year":"2020","journal-title":"Brain Pathol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","article-title":"The hospital anxiety and depression scale","volume":"67","author":"Zigmond","year":"1983","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1185\/030079906X132488","article-title":"painDETECT: A new screening questionnaire to identify neuropathic components in patients with back pain","volume":"22","author":"Freynhagen","year":"2006","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_16","unstructured":"Fahrenberg, J., and Hampel, R. (2001). Das Freiburger Pers\u00f6nlichkeitsinventar (FPI). Revidierte Fassung. Handanweisung, Hogrefe. [7th ed.]."},{"key":"ref_17","unstructured":"Franke, G.H. (2002). SCL-90-R, Symptom-Checkliste von L.R. Derogatis, Deutsche Version. Manual, Beltz Test GmbH. [2nd ed.]."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1016\/0277-9536(95)00115-N","article-title":"German translation and psychometric testing of the SF-36 Health Survey: Preliminary results from the IQOLA Project. International Quality of Life Assessment","volume":"41","author":"Bullinger","year":"1995","journal-title":"Soc. Sci. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/j.pain.2006.01.041","article-title":"Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values","volume":"123","author":"Rolke","year":"2006","journal-title":"Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.pain.2010.07.026","article-title":"Reference data for quantitative sensory testing (QST): Refined stratification for age and a novel method for statistical comparison of group data","volume":"151","author":"Magerl","year":"2010","journal-title":"Pain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"16307","DOI":"10.1038\/s41598-017-13633-4","article-title":"Acupuncture analgesia involves modulation of pain-induced gamma oscillations and cortical network connectivity","volume":"7","author":"Hauck","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1215\/15228517-2008-011","article-title":"Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1","volume":"10","author":"Mautner","year":"2008","journal-title":"Neuro Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1007\/s00415-012-6581-8","article-title":"Accumulation of non-compressive fascicular lesions underlies NF2 polyneuropathy","volume":"260","author":"Mautner","year":"2013","journal-title":"J. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/j.1468-1331.2010.03023.x","article-title":"European Federation of Neurological Societies\/Peripheral Nerve Society Guideline on the use of skin biopsy in the diagnosis of small fiber neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society","volume":"17","author":"Lauria","year":"2010","journal-title":"Eur. J. Neurol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1016\/j.pain.2013.05.047","article-title":"Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus","volume":"154","author":"Backonja","year":"2013","journal-title":"Pain"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/ana.24753","article-title":"Multifocal nerve lesions and LZTR1 germline mutations in segmental schwannomatosis","volume":"80","author":"Farschtschi","year":"2016","journal-title":"Ann. Neurol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.neucli.2003.10.009","article-title":"Clinical usefulness of laser-evoked potentials","volume":"33","author":"Treede","year":"2003","journal-title":"Neurophysiol. Clin."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2147\/JPR.S4860","article-title":"C-fiber-related EEG-oscillations induced by laser radiant heat stimulation of capsaicin-treated skin","volume":"2","author":"Domnick","year":"2009","journal-title":"J. Pain Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0304-3959(95)00161-1","article-title":"Topical capsaicin selectively attenuates heat pain and A delta fiber-mediated laser-evoked potentials","volume":"65","author":"Beydoun","year":"1996","journal-title":"Pain"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s00221-007-0863-x","article-title":"Duration of the cue-to-pain delay increases pain intensity: A combined EEG and MEG study","volume":"180","author":"Hauck","year":"2007","journal-title":"Exp. Brain Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1002\/mus.10181","article-title":"Small-fiber neuropathy","volume":"26","author":"Lacomis","year":"2002","journal-title":"Muscle Nerve"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1055\/a-0648-0450","article-title":"Small-Fiber-Neuropathien","volume":"86","author":"Sommer","year":"2018","journal-title":"Fortschr. Neurol. Psychiatr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1111\/bpa.12125","article-title":"Schwannomas and Their Pathogenesis","volume":"24","author":"Hilton","year":"2014","journal-title":"Brain Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1212\/01.WNL.0000035638.74084.F4","article-title":"Evaluation of clinical diagnostic criteria for neurofibromatosis 2","volume":"59","author":"Baser","year":"2002","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Carney, J.A.Y.W. (1992). Primary Pigmented Nodular Adrenocortical Disease and Its Associated Conditions, Lippincott Williams & Wilkins.","DOI":"10.1097\/00019616-199201000-00003"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1002\/(SICI)1096-8628(19980616)78:1<76::AID-AJMG16>3.0.CO;2-L","article-title":"Multiple schwannomas, multiple nevi, and multiple vaginal leiomyomas: A new dominant syndrome","volume":"78","author":"Gorlin","year":"1998","journal-title":"Am. J. Med. Genet."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s00256-013-1626-3","article-title":"Schwannoma in neurofibromatosis type 1: A pitfall for detecting malignancy by metabolic imaging","volume":"42","author":"Ahlawat","year":"2013","journal-title":"Skelet. Radiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1002\/mus.20641","article-title":"Hereditary neuropathy with liability to pressure palsy combined with schwannomas of the median and medial plantar nerves","volume":"35","author":"Heckmann","year":"2007","journal-title":"Muscle Nerve"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.expneurol.2017.06.006","article-title":"Neuropathies in the setting of Neurofibromatosis tumor syndromes: Complexities and opportunities","volume":"299","author":"Schulz","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_40","first-page":"e136","article-title":"Pain as a symptom of peripheral nerve sheath tumors: Clinical significance and future therapeutic directions","volume":"3","author":"Sughrue","year":"2008","journal-title":"J. Brachial Plex. Peripher. Nerve Inj."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/0306-4522(96)00127-3","article-title":"Schwann cells produce tumor necrosis factor alpha: Expression in injured and non-injured nerves","volume":"73","author":"Wagner","year":"1996","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7947","DOI":"10.1073\/pnas.1331358100","article-title":"Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2","volume":"100","author":"Abbadie","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1007\/978-981-32-9636-7_22","article-title":"Schwann Cells as Crucial Players in Diabetic Neuropathy","volume":"1190","author":"Naruse","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.amjsurg.2006.08.026","article-title":"Effects of collagen nerve guide on neuroma formation and neuropathic pain in a rat model","volume":"193","author":"Tyner","year":"2007","journal-title":"Am. J. Surg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3569\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:30:01Z","timestamp":1760175001000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/10\/3569"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,18]]},"references-count":44,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["ijms21103569"],"URL":"https:\/\/doi.org\/10.3390\/ijms21103569","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,18]]}}}