{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:49:28Z","timestamp":1791791368442,"version":"4.3.4"},"reference-count":36,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Euro J of Neurology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background<\/jats:title>\n \n Whipple disease (WD) is a rare, potentially fatal infection caused by\n \n Tropheryma whipplei<\/jats:italic>\n <\/jats:styled-content>\n (TW). Central Nervous System involvement (CNS\u2010WD) is a severe complication of WD with a challenging diagnosis, due to limited data integrating neurological features, imaging, cerebrospinal fluid analysis, PCR, and intestinal histopathology. Prompt recognition and treatment are essential to improve patient outcomes.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n A scoping review of the literature from 2000 to 2025 was conducted, including all CNS\u2010WD case reports and series, to outline its clinical spectrum and diagnostic workup.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Included studies were 89, accounting for 111 CNS\u2010WD cases. Most patients were male (79.8%), with a mean age of 53.6\u2009years. Notably, 13.2% presented with CNS involvement in the absence of systemic WD. Pathognomonic signs were rare (13\/111, 11.7%). Most patients (82.9%, 92\/111) presented with two or more neurological symptoms, the most frequently reported being altered mentation, followed by ataxia, eye movement abnormalities, and other movement disorders. CSF was abnormal in 74.7% (56\/75) of patients and TW PCR was positive in 75% (48\/64); 64% (55\/86) of cases showed intestinal histopathology consistent with WD. TW PCR on gastrointestinal biopsies was positive in 67.9% (19\/28) cases. CNS imaging revealed abnormalities in 85.4% (82\/96) of patients, with no distinctive pattern.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n CNS\u2010WD diagnosis remains challenging due to nonspecific symptoms, variable imaging, and occasional discordance among CSF, TW PCR or biopsy findings. Our review suggests that CNS\u2010WD should be considered in the differential diagnosis of unexplained neurological syndromes, even in patients with atypical clinical or radiological profiles, supporting broader indications for TW testing.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/ene.70772","type":"journal-article","created":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:36:50Z","timestamp":1791790610000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Neurological Manifestations in Whipple's Disease: A Scoping Review of Clinical Features, Laboratory Findings, and Neuroimaging Characteristics of 111 Cases"],"prefix":"10.1111","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6017-1181","authenticated-orcid":false,"given":"Lucia","family":"Moro","sequence":"first","affiliation":[{"name":"Department of Infectious \u2013 Tropical Diseases and Microbiology IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenicantonio","family":"Tropepi","sequence":"additional","affiliation":[{"name":"Neurology Department IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0108-6822","authenticated-orcid":false,"given":"Dora","family":"Buonfrate","sequence":"additional","affiliation":[{"name":"Department of Infectious \u2013 Tropical Diseases and Microbiology IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4561-3447","authenticated-orcid":false,"given":"Cristina","family":"Mazzi","sequence":"additional","affiliation":[{"name":"Department of Infectious \u2013 Tropical Diseases and Microbiology IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1426-2402","authenticated-orcid":false,"given":"Giovanni","family":"Foti","sequence":"additional","affiliation":[{"name":"Radiology Department IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fittipaldo","sequence":"additional","affiliation":[{"name":"Department of Infectious \u2013 Tropical Diseases and Microbiology IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4545-8034","authenticated-orcid":false,"given":"Andrea","family":"Angheben","sequence":"additional","affiliation":[{"name":"Department of Infectious \u2013 Tropical Diseases and Microbiology IRCCS Sacro Cuore \u2013 Don Calabria Hospital Negrar di Valpolicella Verona Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7499-5843","authenticated-orcid":false,"given":"Anna","family":"Beltrame","sequence":"additional","affiliation":[{"name":"Center for Immunization and Infection Research in Cancer (CIRC), H.Lee Moffitt Cancer Center and Research Institute Tampa Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"issue":"6","key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1086\/528693","article-title":"Prevalence of Asymptomatic \n Tropheryma whipplei\n Carriage Among Humans and Nonhuman Primates","volume":"197","author":"Fenollar F.","year":"2008","journal-title":"Journal of Infectious Diseases"},{"issue":"2","key":"e_1_2_10_3_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1007\/s15010-002-3083-0","article-title":"Prevalence of \n Tropheryma whipplei\n DNA in Patients With Various Gastrointestinal Diseases and in Healthy Controls","volume":"31","author":"Amsler L.","year":"2003","journal-title":"Infection"},{"issue":"6","key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"949","DOI":"10.3201\/eid1806.111038","article-title":"Intrafamilial Circulation of \n Tropheryma whipplei\n , France","volume":"18","author":"Fenollar F.","year":"2012","journal-title":"Emerging Infectious Diseases"},{"issue":"4","key":"e_1_2_10_5_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.2217\/fmb-2018-0347","article-title":"Tropheryma whipplei\n Intestinal Colonization in Italian and Migrant Population: A Retrospective Observational Study","volume":"14","author":"Beltrame A.","year":"2019","journal-title":"Future Microbiology"},{"issue":"6","key":"e_1_2_10_6_1","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1128\/AEM.02335-06","article-title":"Tropheryma whipplei\n in the Environment: Survey of Sewage Plant Influxes and Sewage Plant Workers","volume":"73","author":"Sch\u00f6niger\u2010Hekele M.","year":"2007","journal-title":"Applied and Environmental Microbiology"},{"issue":"11","key":"e_1_2_10_7_1","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1111\/1469-0691.12724","article-title":"Prevalence and Risk Factor Assessment of \n Tropheryma whipplei\n in a Rural Community in Gabon: A Community\u2010Based Cross\u2010Sectional Study","volume":"20","author":"Ramharter M.","year":"2014","journal-title":"Clinical Microbiology and Infection"},{"issue":"2","key":"e_1_2_10_8_1","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1128\/CMR.00033-16","article-title":"Clinical Manifestations, Treatment, and Diagnosis of \n Tropheryma whipplei\n Infections","volume":"30","author":"Dolmans R. A.","year":"2017","journal-title":"Clinical Microbiology Reviews"},{"issue":"1","key":"e_1_2_10_9_1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1053\/j.gastro.2009.07.066","article-title":"Impaired Immune Functions of Monocytes and Macrophages in Whipple's Disease","volume":"138","author":"Moos V.","year":"2010","journal-title":"Gastroenterology"},{"issue":"3","key":"e_1_2_10_10_1","first-page":"238","article-title":"Whipple's Disease: A Review of the Literature and Report of Fifteen Patients","volume":"336","author":"Enzinger F. M.","year":"1963","journal-title":"Virchows Archiv f\u00fcr Pathologische Anatomie und Physiologie und f\u00fcr Klinische Medizin"},{"key":"e_1_2_10_11_1","volume-title":"Mayo Clinic Proceedings","author":"Fleming J. L.","year":"1988"},{"issue":"5","key":"e_1_2_10_12_1","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1097\/MD.0b013e3181f204a8","article-title":"Systemic \n Tropheryma whipplei\n : Clinical Presentation of 142 Patients With Infections Diagnosed or Confirmed in a Reference Center","volume":"89","author":"Lagier J. C.","year":"2010","journal-title":"Medicine"},{"issue":"1","key":"e_1_2_10_13_1","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/00002281-200101000-00012","article-title":"Whipple Disease and Arthritis","volume":"13","author":"Pu\u00e9chal X.","year":"2001","journal-title":"Current Opinion in Rheumatology"},{"issue":"8","key":"e_1_2_10_14_1","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1111\/apt.13140","article-title":"Systematic Review: Whipple's Disease (\n Tropheryma whipplei\n Infection) and Its Unmasking by Tumour Necrosis Factor Inhibitors","volume":"41","author":"Marth T.","year":"2015","journal-title":"Alimentary Pharmacology & Therapeutics"},{"issue":"12","key":"e_1_2_10_15_1","doi-asserted-by":"crossref","first-page":"3917","DOI":"10.1128\/JCM.01517-12","article-title":"The Rise of \n Tropheryma whipplei\n : A 12\u2010Year Retrospective Study of PCR Diagnoses in Our Reference Center","volume":"50","author":"Edouard S.","year":"2012","journal-title":"Journal of Clinical Microbiology"},{"issue":"5","key":"e_1_2_10_16_1","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1086\/655677","article-title":"Tropheryma whipplei\n Bacteremia During Fever in Rural West Africa","volume":"51","author":"Fenollar F.","year":"2010","journal-title":"Clinical Infectious Diseases"},{"issue":"2","key":"e_1_2_10_17_1","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3201\/eid1602.090610","article-title":"Tropheryma whipplei\n in Patients With Pneumonia","volume":"16","author":"Bousbia S.","year":"2010","journal-title":"Emerging Infectious Diseases"},{"issue":"5","key":"e_1_2_10_18_1","doi-asserted-by":"crossref","first-page":"776","DOI":"10.3201\/eid1605.091801","article-title":"Tropheryma whipplei\n in Children With Gastroenteritis","volume":"16","author":"Raoult D.","year":"2010","journal-title":"Emerging Infectious Diseases"},{"issue":"6","key":"e_1_2_10_19_1","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1097\/00005792-200211000-00005","article-title":"Neurologic Presentation of Whipple Disease: Report of 12 Cases and Review of the Literature","volume":"81","author":"Gerard A.","year":"2002","journal-title":"Medicine"},{"issue":"3","key":"e_1_2_10_20_1","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/00005792-199705000-00003","article-title":"Whipple Disease: Clinical Review of 52 Cases","volume":"76","author":"Durand D. V.","year":"1997","journal-title":"Medicine"},{"key":"e_1_2_10_21_1","doi-asserted-by":"crossref","first-page":"57","DOI":"10.5334\/tohm.1075","article-title":"Movement Disorders and Oculomotor Abnormalities in Whipple's Disease: An Updated Systematic Review","volume":"15","author":"Maslias E.","year":"2025","journal-title":"Tremor and Other Hyperkinetic Movements"},{"issue":"2","key":"e_1_2_10_22_1","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1007\/s10072-021-05844-5","article-title":"Rapidly Progressive Dementia and Intractable Diarrhea: A Teaching Case Report and a Systematic Review of Cognitive Impairment in Whipple's Disease","volume":"43","author":"Manini A.","year":"2022","journal-title":"Neurological Sciences"},{"issue":"11","key":"e_1_2_10_23_1","doi-asserted-by":"crossref","first-page":"3417","DOI":"10.1111\/ene.15511","article-title":"The Spectrum of Central Nervous System Involvement in Whipple's Disease","volume":"30","author":"Mecklenburg J.","year":"2023","journal-title":"European Journal of Neurology"},{"issue":"6","key":"e_1_2_10_24_1","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1097\/MD.0000000000000010","article-title":"Central Nervous System Involvement in Whipple Disease: Clinical Study of 18 Patients and Long\u2010Term Follow\u2010Up","volume":"92","author":"Compain C.","year":"2013","journal-title":"Medicine"},{"issue":"1","key":"e_1_2_10_25_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1186\/1471-2334-11-171","article-title":"Progressive Dementia Associated With Ataxia or Obesity in Patients With \n Tropheryma whipplei\n Encephalitis","volume":"11","author":"Fenollar F.","year":"2011","journal-title":"BMC Infectious Diseases"},{"issue":"8","key":"e_1_2_10_26_1","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.3174\/ajnr.A2089","article-title":"MR Imaging of Central Nervous System Whipple Disease: A 15\u2010Year Review","volume":"31","author":"Black D. F.","year":"2010","journal-title":"AJNR. American Journal of Neuroradiology"},{"issue":"5","key":"e_1_2_10_27_1","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1111\/j.1572-0241.2005.40128.x","article-title":"Immunosuppressive Therapy in Whipple's Disease Patients Is Associated With the Appearance of Gastrointestinal Manifestations","volume":"100","author":"Mahnel R.","year":"2005","journal-title":"Official Journal of the American College of Gastroenterology | ACG"},{"issue":"9","key":"e_1_2_10_28_1","first-page":"899","article-title":"Long\u2010Term Follow\u2010Up in Cerebral Whipple's Disease","volume":"8","author":"Schnider P. J.","year":"1996","journal-title":"European Journal of Gastroenterology & Hepatology"},{"issue":"1","key":"e_1_2_10_29_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1056\/NEJMra062477","article-title":"Whipple's Disease","volume":"356","author":"Fenollar F.","year":"2007","journal-title":"New England Journal of Medicine"},{"issue":"1","key":"e_1_2_10_30_1","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1186\/s13643-016-0384-4","article-title":"Rayyan\u2014A Web and Mobile App for Systematic Reviews","volume":"5","author":"Ouzzani M.","year":"2016","journal-title":"Systematic Reviews"},{"issue":"5","key":"e_1_2_10_31_1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1086\/590559","article-title":"Value of \n Tropheryma whipplei\n Quantitative Polymerase Chain Reaction Assay for the Diagnosis of Whipple Disease: Usefulness of Saliva and Stool Specimens for First\u2010Line Screening","volume":"47","author":"Fenollar F.","year":"2008","journal-title":"Clinical Infectious Diseases"},{"issue":"2","key":"e_1_2_10_32_1","doi-asserted-by":"crossref","DOI":"10.1128\/jcm.01457-22","article-title":"Contribution of PCR to Differential Diagnosis Between Patients With Whipple Disease and \n Tropheryma whipplei\n Carriers","volume":"61","author":"Meyer S.","year":"2023","journal-title":"Journal of Clinical Microbiology"},{"issue":"11","key":"e_1_2_10_33_1","doi-asserted-by":"crossref","first-page":"3858","DOI":"10.1128\/JCM.01703-13","article-title":"Validation of an rpoB Gene PCR Assay for Detection of \n Tropheryma whipplei\n : 10\u2009Years' Experience in a National Reference Laboratory","volume":"51","author":"Moter A.","year":"2013","journal-title":"Journal of Clinical Microbiology"},{"issue":"6","key":"e_1_2_10_34_1","first-page":"1328","article-title":"MR of Cerebral Whipple Disease","volume":"16","author":"Schnider P.","year":"1995","journal-title":"American Journal of Neuroradiology"},{"issue":"1","key":"e_1_2_10_35_1","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.jns.2010.07.001","article-title":"An Atypical Case of Neuro\u2010Whipple: Clinical Presentation, Magnetic Resonance Spectroscopy and Follow\u2010Up","volume":"297","author":"Pauletti C.","year":"2010","journal-title":"Journal of the Neurological Sciences"},{"issue":"6","key":"e_1_2_10_36_1","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1007\/s00415-008-0597-0","article-title":"Neuro\u2010Whipple Confirmed Five Years After a Presumptive Diagnosis of a Primitive CNS Vasculitis","volume":"255","author":"El Helou J.","year":"2008","journal-title":"Journal of Neurology"},{"issue":"4","key":"e_1_2_10_37_1","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1111\/j.1552-6569.2004.tb00267.x","article-title":"Novel Neuroimaging Findings in a Patient With Cerebral Whipple's Disease: A Magnetic Resonance Imaging and Positron Emission Tomography Study","volume":"14","author":"Galldiks N.","year":"2004","journal-title":"Journal of Neuroimaging"}],"container-title":["European Journal of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.70772","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/ene.70772","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/ene.70772","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:36:56Z","timestamp":1791790616000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/ene.70772"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10]]},"references-count":36,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1111\/ene.70772"],"URL":"https:\/\/doi.org\/10.1111\/ene.70772","archive":["Portico"],"relation":{},"ISSN":["1351-5101","1468-1331"],"issn-type":[{"value":"1351-5101","type":"print"},{"value":"1468-1331","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10]]},"assertion":[{"value":"2026-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70772"}}