{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T03:14:42Z","timestamp":1775618082903,"version":"3.50.1"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T00:00:00Z","timestamp":1682035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007051","name":"Uppsala University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100007051","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Neurosarcoidosis presents a diagnostic challenge in clinical settings, as it has no pathognomonic symptoms or signs and a wide range of differential diagnoses. The aim of this report is to present the pathological features of our group of patients, obtained through a systematic diagnostic approach. This retrospective cohort study enrolled all adult patients primarily diagnosed with neurosarcoidosis at the neurology department of a tertiary center in Sweden over a period of 30\u00a0years, from 1990 to 2021. We identified 90 patients, 54 with possible neurosarcoidosis and 36 with probable neurosarcoidosis. CNS biopsy revealed an alternative diagnosis for 24 patients, who were then excluded. The collected data from medical records included demographic and clinical characteristics, systemic and\/or neurological isolated involvement, various laboratory tests, including cerebrospinal fluid (CSF), serum analysis, imaging studies (MRI, FDG-PET\/CT, and HRCT), nerve conduction studies, electromyography, and pathology reports of central nervous system (CNS), and extra-neural tissue biopsies. Sixty-six patients were included in our cohort. The median age at onset of symptoms was 49\u00a0years, with a similar sex distribution. Cranial neuropathies (38%), motor deficit (32%), headache (16%), and pituitary dysfunction (12%) were the most common presenting features. CSF studies were abnormal in 77% of the patients, who showed lymphocytosis (57%), elevated protein (44%), oligoclonal bands (40%), elevated ACE (28%), and raised T lymphocyte CD4<jats:sup>+<\/jats:sup>\/CD8<jats:sup>+<\/jats:sup> ratios (13%). Strikingly, MRI showed that 17% of the patients presented with isolated pituitary gland lesions. FDG-PET\/CT was performed in 22 patients (33%) and confirmed systemic sarcoidosis in 11. Despite our extensive workup, the final classification for our patients only allowed for a definite diagnosis in 14 patients; the remainder were classified as probable (32) or possible (20) neurosarcoidosis. Since 2007, the employment of a structured laboratory and imaging approach and the increasing number of CNS biopsies have facilitated and improved the process of correct attribution in patients with presumptive neurosarcoidosis, especially in patients with isolated neurological lesions. We highlight a higher frequency of pituitary lesions due to neurosarcoidosis than has been classically described. A detailed laboratory diagnostic workup is included.<\/jats:p>","DOI":"10.1038\/s41598-023-33631-z","type":"journal-article","created":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T10:03:17Z","timestamp":1682071397000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["A comprehensive diagnostic approach in suspected neurosarcoidosis"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2251-5879","authenticated-orcid":false,"given":"Shala Ghaderi","family":"Berntsson","sequence":"first","affiliation":[]},{"given":"Andreas","family":"Elmgren","sequence":"additional","affiliation":[]},{"given":"Olafur","family":"Gudjonsson","sequence":"additional","affiliation":[]},{"given":"Anna","family":"Grabowska","sequence":"additional","affiliation":[]},{"given":"Anne-Marie","family":"Landtblom","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8917-6592","authenticated-orcid":false,"given":"Maria-Francisca","family":"Moraes-Fontes","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,4,21]]},"reference":[{"key":"33631_CR1","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1177\/014107688107400212","volume":"74","author":"JG Scadding","year":"1981","unstructured":"Scadding, J. G. The eponymy of sarcoidosis. J. R. Soc. Med. 74, 147\u2013157 (1981).","journal-title":"J. R. Soc. Med."},{"key":"33631_CR2","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1055\/s-0037-1602845","volume":"38","author":"K Mateyo","year":"2017","unstructured":"Mateyo, K. & Thomeer, M. Sarcoidosis around the Globe. Semin. Respir. Crit. Care Med. 38, 393\u2013403. https:\/\/doi.org\/10.1055\/s-0037-1602845 (2017).","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"33631_CR3","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1093\/oxfordjournals.aje.a009096","volume":"145","author":"BA Rybicki","year":"1997","unstructured":"Rybicki, B. A., Major, M., Popovich, J. Jr., Maliarik, M. J. & Iannuzzi, M. C. Racial differences in sarcoidosis incidence: A 5-year study in a health maintenance organization. Am. J. Epidemiol. 145, 234\u2013241. https:\/\/doi.org\/10.1093\/oxfordjournals.aje.a009096 (1997).","journal-title":"Am. J. Epidemiol."},{"key":"33631_CR4","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s12883-016-0741-x","volume":"16","author":"D Fritz","year":"2016","unstructured":"Fritz, D., van de Beek, D. & Brouwer, M. C. Clinical features, treatment and outcome in neurosarcoidosis: Systematic review and meta-analysis. BMC Neurol. 16, 220. https:\/\/doi.org\/10.1186\/s12883-016-0741-x (2016).","journal-title":"BMC Neurol."},{"key":"33631_CR5","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1093\/qjmed\/92.2.103","volume":"92","author":"JP Zajicek","year":"1999","unstructured":"Zajicek, J. P. et al. Central nervous system sarcoidosis\u2013diagnosis and management. QJM Monthly J. Assoc. Phys. 92, 103\u2013117. https:\/\/doi.org\/10.1093\/qjmed\/92.2.103 (1999).","journal-title":"QJM Monthly J. Assoc. Phys."},{"key":"33631_CR6","doi-asserted-by":"publisher","first-page":"1546","DOI":"10.1001\/jamaneurol.2018.2295","volume":"75","author":"BJ Stern","year":"2018","unstructured":"Stern, B. J. et al. Definition and consensus diagnostic criteria for neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group. JAMA Neurol. 75, 1546\u20131553. https:\/\/doi.org\/10.1001\/jamaneurol.2018.2295 (2018).","journal-title":"JAMA Neurol."},{"key":"33631_CR7","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1097\/MCP.0b013e32833c86df","volume":"16","author":"E Hoitsma","year":"2010","unstructured":"Hoitsma, E., Drent, M. & Sharma, O. P. A pragmatic approach to diagnosing and treating neurosarcoidosis in the 21st century. Curr. Opin. Pulm. Med. 16, 472\u2013479. https:\/\/doi.org\/10.1097\/MCP.0b013e32833c86df (2010).","journal-title":"Curr. Opin. Pulm. Med."},{"key":"33631_CR8","doi-asserted-by":"publisher","first-page":"2153","DOI":"10.1056\/NEJMra071714","volume":"357","author":"MC Iannuzzi","year":"2007","unstructured":"Iannuzzi, M. C., Rybicki, B. A. & Teirstein, A. S. Sarcoidosis. N. Engl. J. Med. 357, 2153\u20132165. https:\/\/doi.org\/10.1056\/NEJMra071714 (2007).","journal-title":"N. Engl. J. Med."},{"key":"33631_CR9","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1016\/j.crad.2015.09.007","volume":"71","author":"G Bathla","year":"2016","unstructured":"Bathla, G., Singh, A. K., Policeni, B., Agarwal, A. & Case, B. Imaging of neurosarcoidosis: Common, uncommon, and rare. Clin. Radiol. 71, 96\u2013106. https:\/\/doi.org\/10.1016\/j.crad.2015.09.007 (2016).","journal-title":"Clin. Radiol."},{"key":"33631_CR10","doi-asserted-by":"publisher","first-page":"576","DOI":"10.3109\/07853890.2015.1093164","volume":"47","author":"C Tana","year":"2015","unstructured":"Tana, C. et al. Challenges in the diagnosis and treatment of neurosarcoidosis. Ann. Med. 47, 576\u2013591. https:\/\/doi.org\/10.3109\/07853890.2015.1093164 (2015).","journal-title":"Ann. Med."},{"key":"33631_CR11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jctube.2017.02.001","volume":"7","author":"KK Shah","year":"2017","unstructured":"Shah, K. K., Pritt, B. S. & Alexander, M. P. Histopathologic review of granulomatous inflammation. J. Clin. Tuberc. Other Mycobact. Dis. 7, 1\u201312. https:\/\/doi.org\/10.1016\/j.jctube.2017.02.001 (2017).","journal-title":"J. Clin. Tuberc. Other Mycobact. Dis."},{"key":"33631_CR12","doi-asserted-by":"publisher","first-page":"146","DOI":"10.1093\/clinids\/23.1.146","volume":"23","author":"A Zumla","year":"1996","unstructured":"Zumla, A. & James, D. G. Granulomatous infections: Etiology and classification. Clin. Infect. Diseases 23, 146\u2013158. https:\/\/doi.org\/10.1093\/clinids\/23.1.146 (1996).","journal-title":"Clin. Infect. Diseases"},{"key":"33631_CR13","doi-asserted-by":"publisher","first-page":"488","DOI":"10.1007\/s00415-005-0043-5","volume":"253","author":"S Marangoni","year":"2006","unstructured":"Marangoni, S., Argentiero, V. & Tavolato, B. Neurosarcoidosis. Clinical description of 7 cases with a proposal for a new diagnostic strategy. J. Neurol. 253, 488\u2013495. https:\/\/doi.org\/10.1007\/s00415-005-0043-5 (2006).","journal-title":"J. Neurol."},{"key":"33631_CR14","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000725","author":"C Otto","year":"2020","unstructured":"Otto, C., Wengert, O., Unterwalder, N., Meisel, C. & Ruprecht, K. Analysis of soluble interleukin-2 receptor as CSF biomarker for neurosarcoidosis. Neurol. Neuroimmunol. Neuroinflamm. https:\/\/doi.org\/10.1212\/NXI.0000000000000725 (2020).","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"33631_CR15","doi-asserted-by":"publisher","first-page":"e331","DOI":"10.1016\/j.lpm.2011.12.017","volume":"41","author":"K Nozaki","year":"2012","unstructured":"Nozaki, K. & Judson, M. A. Neurosarcoidosis: Clinical manifestations, diagnosis and treatment. Presse. Med. 41, e331-348. https:\/\/doi.org\/10.1016\/j.lpm.2011.12.017 (2012).","journal-title":"Presse. Med."},{"key":"33631_CR16","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1055\/s-2007-970332","volume":"28","author":"Y Rosen","year":"2007","unstructured":"Rosen, Y. Pathology of sarcoidosis. Semin. Respir. Crit. Care Med. 28, 36\u201352. https:\/\/doi.org\/10.1055\/s-2007-970332 (2007).","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"33631_CR17","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1007\/s00415-016-8336-4","volume":"264","author":"RT Ibitoye","year":"2017","unstructured":"Ibitoye, R. T., Wilkins, A. & Scolding, N. J. Neurosarcoidosis: A clinical approach to diagnosis and management. J. Neurol. 264, 1023\u20131028. https:\/\/doi.org\/10.1007\/s00415-016-8336-4 (2017).","journal-title":"J. Neurol."},{"key":"33631_CR18","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.rdc.2017.06.008","volume":"43","author":"P Ungprasert","year":"2017","unstructured":"Ungprasert, P. & Matteson, E. L. Neurosarcoidosis. Rheum. Dis. Clin. N. Am. 43, 593\u2013606. https:\/\/doi.org\/10.1016\/j.rdc.2017.06.008 (2017).","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"33631_CR19","doi-asserted-by":"publisher","first-page":"13735","DOI":"10.1038\/s41598-021-92967-6","volume":"11","author":"M Ramos-Casals","year":"2021","unstructured":"Ramos-Casals, M. et al. Clinical characterization and outcomes of 85 patients with neurosarcoidosis. Sci. Rep. 11, 13735. https:\/\/doi.org\/10.1038\/s41598-021-92967-6 (2021).","journal-title":"Sci. Rep."},{"key":"33631_CR20","doi-asserted-by":"publisher","first-page":"e11481","DOI":"10.7759\/cureus.11481","volume":"12","author":"T Blazin","year":"2020","unstructured":"Blazin, T. et al. Hypothalamic-pituitary axis dysfunction, central diabetes insipidus, and syndrome of inappropriate antidiuretic hormone secretion as the first clinical presentation of neurosarcoidosis: Why early diagnosis and treatment is important?. Cureus. 12, e11481. https:\/\/doi.org\/10.7759\/cureus.11481 (2020).","journal-title":"Cureus."},{"key":"33631_CR21","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1093\/qjmed\/hcs121","volume":"105","author":"C Langrand","year":"2012","unstructured":"Langrand, C. et al. Hypothalamo-pituitary sarcoidosis: A multicenter study of 24 patients. QJM Monthly J. Assoc. Phys. 105, 981\u2013995. https:\/\/doi.org\/10.1093\/qjmed\/hcs121 (2012).","journal-title":"QJM Monthly J. Assoc. Phys."},{"key":"33631_CR22","volume-title":"Lymphocytic Hypophysitis","author":"J Naran","year":"2020","unstructured":"Naran, J. & Can, A. S. Lymphocytic Hypophysitis (StatPearls, 2020)."},{"key":"33631_CR23","doi-asserted-by":"publisher","first-page":"15","DOI":"10.4103\/2156-7514.76693","volume":"1","author":"DT Ginat","year":"2011","unstructured":"Ginat, D. T., Dhillon, G. & Almast, J. Magnetic resonance imaging of neurosarcoidosis. J. Clin. Imaging Sci. 1, 15. https:\/\/doi.org\/10.4103\/2156-7514.76693 (2011).","journal-title":"J. Clin. Imaging Sci."},{"key":"33631_CR24","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1007\/s00415-016-8092-5","volume":"263","author":"CA Durel","year":"2016","unstructured":"Durel, C. A. et al. Clinical features and prognostic factors of spinal cord sarcoidosis: A multicenter observational study of 20 BIOPSY-PROVEN patients. J. Neurol. 263, 981\u2013990. https:\/\/doi.org\/10.1007\/s00415-016-8092-5 (2016).","journal-title":"J. Neurol."},{"key":"33631_CR25","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000000722","author":"OC Murphy","year":"2020","unstructured":"Murphy, O. C. et al. Clinical and MRI phenotypes of sarcoidosis-associated myelopathy. Neurol. Neuroimmunol. Neuroinflamm. https:\/\/doi.org\/10.1212\/NXI.0000000000000722 (2020).","journal-title":"Neurol. Neuroimmunol. Neuroinflamm."},{"key":"33631_CR26","doi-asserted-by":"publisher","first-page":"638","DOI":"10.3390\/neurolint14030052","volume":"14","author":"R Liberio","year":"2022","unstructured":"Liberio, R. et al. Relevance of medullary vein sign in neurosarcoidosis. Neurol. Int. 14, 638\u2013647. https:\/\/doi.org\/10.3390\/neurolint14030052 (2022).","journal-title":"Neurol. Int."},{"key":"33631_CR27","doi-asserted-by":"publisher","first-page":"2045","DOI":"10.3174\/ajnr.A5783","volume":"39","author":"C Zamora","year":"2018","unstructured":"Zamora, C., Hung, S. C., Tomingas, C., Atkinson, C. & Castillo, M. Engorgement of deep medullary veins in neurosarcoidosis: A common-yet-underrecognized cerebrovascular finding on SWI. AJNR Am. J. Neuroradiol. 39, 2045\u20132050. https:\/\/doi.org\/10.3174\/ajnr.A5783 (2018).","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"33631_CR28","doi-asserted-by":"publisher","first-page":"1536","DOI":"10.1148\/rg.2018180053","volume":"38","author":"G Akaike","year":"2018","unstructured":"Akaike, G. et al. PET\/CT in the diagnosis and workup of sarcoidosis: Focus on atypical manifestations. Radiographics 38, 1536\u20131549. https:\/\/doi.org\/10.1148\/rg.2018180053 (2018).","journal-title":"Radiographics"},{"key":"33631_CR29","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1053\/j.semnuclmed.2013.06.007","volume":"43","author":"D Sobic-Saranovic","year":"2013","unstructured":"Sobic-Saranovic, D., Artiko, V. & Obradovic, V. FDG PET imaging in sarcoidosis. Semin. Nucl. Med. 43, 404\u2013411. https:\/\/doi.org\/10.1053\/j.semnuclmed.2013.06.007 (2013).","journal-title":"Semin. Nucl. Med."},{"key":"33631_CR30","doi-asserted-by":"publisher","first-page":"1274","DOI":"10.1111\/ene.13975","volume":"26","author":"T Chazal","year":"2019","unstructured":"Chazal, T. et al. The cerebrospinal fluid CD4\/CD8 ratio and interleukin-6 and -10 levels in neurosarcoidosis: A multicenter, pragmatic, comparative study. Eur. J. Neurol. 26, 1274\u20131280. https:\/\/doi.org\/10.1111\/ene.13975 (2019).","journal-title":"Eur. J. Neurol."},{"key":"33631_CR31","doi-asserted-by":"publisher","first-page":"480","DOI":"10.1111\/ane.13297","volume":"142","author":"S Nordstrom","year":"2020","unstructured":"Nordstrom, S., Andersson, B. & Malmestrom, C. Cerebrospinal fluid CD4(+)\/CD8(+) ratio in diagnosing neurosarcoidosis. Acta Neurol. Scand. 142, 480\u2013485. https:\/\/doi.org\/10.1111\/ane.13297 (2020).","journal-title":"Acta Neurol. Scand."},{"key":"33631_CR32","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1136\/practneurol-2019-002349","volume":"20","author":"DP Kidd","year":"2020","unstructured":"Kidd, D. P. Neurosarcoidosis: Clinical manifestations, investigation and treatment. Pract. Neurol. 20, 199\u2013212. https:\/\/doi.org\/10.1136\/practneurol-2019-002349 (2020).","journal-title":"Pract. Neurol."},{"key":"33631_CR33","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1097\/NRL.0b013e31819bcf84","volume":"15","author":"J Khoury","year":"2009","unstructured":"Khoury, J., Wellik, K. E., Demaerschalk, B. M. & Wingerchuk, D. M. Cerebrospinal fluid angiotensin-converting enzyme for diagnosis of central nervous system sarcoidosis. Neurologist 15, 108\u2013111. https:\/\/doi.org\/10.1097\/NRL.0b013e31819bcf84 (2009).","journal-title":"Neurologist"},{"key":"33631_CR34","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/0022-510x(86)90066-3","volume":"73","author":"V Oksanen","year":"1986","unstructured":"Oksanen, V., Gronhagen-Riska, C., Tikanoja, S., Somer, H. & Fyhrquist, F. Cerebrospinal fluid lysozyme and beta 2-microglobulin in neurosarcoidosis. J. Neurol. Sci. 73, 79\u201387. https:\/\/doi.org\/10.1016\/0022-510x(86)90066-3 (1986).","journal-title":"J. Neurol. Sci."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-33631-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-33631-z","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-33631-z.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,21]],"date-time":"2023-04-21T10:13:54Z","timestamp":1682072034000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-023-33631-z"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,21]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["33631"],"URL":"https:\/\/doi.org\/10.1038\/s41598-023-33631-z","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,21]]},"assertion":[{"value":"29 June 2022","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 April 2023","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2023","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"6539"}}