{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T16:58:43Z","timestamp":1781456323043,"version":"3.54.1"},"reference-count":41,"publisher":"SAABRON PRESS","issue":"1","license":[{"start":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T00:00:00Z","timestamp":1771459200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperimmune condition triggered by the pathological activation of T-cells, natural killer cells, and macrophages leading to a cytokine storm with widespread hyperinflammation affecting multiple organ systems, including the brain. This retrospective chart review characterizes the central nervous system (CNS) features in 22 pediatric HLH patients at a single center. CNS involvement was determined based on symptoms, exam, abnormal cerebrospinal fluid (CSF) studies, neuroimaging, and electroencephalogram (EEG) findings. Twenty-two children with HLH were analyzed, classifying them into primary HLH (pHLH) and secondary HLH (sHLH) based on genetic testing. Of 20 patients who underwent genetic testing, 6 (30%) had pathogenic pHLH mutations, while 14 were sHLH (8 with variants of unknown significance, 6 with no variants). CNS involvement was noted in 17 (77.2%) patients. Symptoms included generalized weakness, altered sensorium, seizures, and headaches. MRI abnormalities included patchy T2 FLAIR prolongation (85%) with and without contrast enhancement and subdural collection, diffuse brain atrophy (40%), microhemorrhages (15%) and diffusion restriction (15%) patients. CSF studies showed higher WBC counts in pHLH . Therapies amongst this cohort varied, with 47% receiving dexamethasone, etoposide and cyclosporine, and 29% undergoing HSCT. Mortality in the first year was 18%, with 75% of deaths involving patients with CNS involvement of HLH. Mean survival at six months was 167 days, with no further deaths in the 12-year follow-up. We conclude that frequent neurological abnormalities are noted in children with HLH highlighting the role for active surveillance of CNS involvement in this group of patients.<\/jats:p>","DOI":"10.46989\/001c.155719","type":"journal-article","created":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T01:01:33Z","timestamp":1771462893000},"source":"Crossref","is-referenced-by-count":0,"title":["Central nervous system involvement in pediatric hemophagocytic lymphohistiocytosis: A single-center descriptive study of clinical features, neurodiagnostic findings, and outcomes"],"prefix":"10.46989","volume":"8","author":[{"given":"Manan","family":"Nath","sequence":"first","affiliation":[{"name":"Division of Pediatric Neurology, Arkansas Children\u2019s Hospital, Little Rock, AR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anshul","family":"Vagrecha","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Cohen Children\u2019s Medical Center, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie H.","family":"Roliz","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Cohen Children\u2019s Medical Center, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yash D.","family":"Shah","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Our Lady of the Lake Children\u2019s Hospital, Baton Rouge, LA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Varughese","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Cohen Children\u2019s Medical Center, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramya","family":"Trietel","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Cohen Children\u2019s Medical Center, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Neuroradiology, Northwell Health, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Fein-Levy","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Cohen Children\u2019s Medical Center, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjeev V.","family":"Kothare","sequence":"additional","affiliation":[{"name":"Division of Pediatric Neurology, Cohen Children\u2019s Medical Center, New Hyde Park, NY, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"26435","published-online":{"date-parts":[[2026,2,19]]},"reference":[{"issue":"6","key":"ref1","doi-asserted-by":"publisher","first-page":"2266","DOI":"10.1182\/blood-2002-04-1030","article-title":"Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carryingPRF1 mutations","volume":"100","author":"R. Clementi","year":"2002","journal-title":"Blood"},{"issue":"3","key":"ref2","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1111\/bjh.12386","article-title":"Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens","volume":"162","author":"D. Chellapandian","year":"2013","journal-title":"Br J Haematol"},{"issue":"8","key":"ref3","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1097\/MPH.0b013e3180f61be3","article-title":"Use of Rituximab in Conjunction With Immunosuppressive Chemotherapy as a Novel Therapy for Epstein Barr Virus-associated Hemophagocytic Lymphohistiocytosis","volume":"29","author":"N. J. Balamuth","year":"2007","journal-title":"J Pediatr Hematol Oncol"},{"issue":"7","key":"ref4","doi-asserted-by":"publisher","first-page":"859","DOI":"10.1080\/08035250310003631","article-title":"Epstein-Barr virus-associated haemophagocytic lymphohistiocytosis in Wiskott-Aldrich syndrome","volume":"92","author":"S. Pasic","year":"2003","journal-title":"Acta Paediatr"},{"issue":"7","key":"ref5","first-page":"1248","article-title":"CNS involvement of virus-associated hemophagocytic syndrome: MR imaging appearance","volume":"21","author":"K. P. Forbes","year":"2000","journal-title":"AJNR Am J Neuroradiol"},{"issue":"1","key":"ref6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s11940-017-0439-4","article-title":"How to Treat Involvement of the Central Nervous System in Hemophagocytic Lymphohistiocytosis?","volume":"19","author":"A. Horne","year":"2017","journal-title":"Curr Treat Options Neurol"},{"issue":"2","key":"ref7","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1016\/S0046-8177(84)80057-X","article-title":"Neuropathology of familial erythrophagocytic lymphohistiocytosis","volume":"15","author":"M. Akima","year":"1984","journal-title":"Hum Pathol"},{"issue":"6","key":"ref8","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1007\/s00247-003-0894-9","article-title":"Imaging characteristics of hemophagocytic lymphohistiocytosis","volume":"33","author":"N. E. Fitzgerald","year":"2003","journal-title":"Pediatr Radiol"},{"issue":"3","key":"ref9","doi-asserted-by":"publisher","first-page":"802","DOI":"10.2214\/ajr.170.3.9490981","article-title":"Brain CT and MR imaging in familial hemophagocytic lymphohistiocytosis","volume":"170","author":"M. M. Munoz Ruano","year":"1998","journal-title":"American Journal of Roentgenology"},{"key":"ref10","article-title":"Diffusion-Weighted Cranial MR Imaging Findings in a Patient with Hemophagocytic Syndrome","author":"B. Ozgen"},{"issue":"2","key":"ref11","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1007\/s00431-006-0258-1","article-title":"Familial and acquired hemophagocytic lymphohistiocytosis","volume":"166","author":"G. E. Janka","year":"2006","journal-title":"Eur J Pediatr"},{"issue":"5","key":"ref12","doi-asserted-by":"publisher","first-page":"810","DOI":"10.1002\/pbc.23405","article-title":"Neuroradiologic findings and follow-up with magnetic resonance imaging of the genetic forms of haemophagocytic lymphohistiocytosis with CNS involvement","volume":"58","author":"I. Rego","year":"2012","journal-title":"Pediatr Blood Cancer"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1227\/01.NEU.0000146210.13318.E8","article-title":"Isolated central nervous system hemophagocytic lymphohistiocytosis: case report","author":"J. Shinoda","year":"2005","journal-title":"Neurosurgery"},{"issue":"3","key":"ref14","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1002\/art.22442","article-title":"Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl","volume":"56","author":"D. Moshous","year":"2007","journal-title":"Arthritis Rheum"},{"issue":"01","key":"ref15","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1055\/s-2004-815791","article-title":"CNS Disease as the Main Manifestation of Hemophagocytic Lymphohistiocytosis in Two Children","volume":"35","author":"K. Rostasy","year":"2004","journal-title":"Neuropediatrics"},{"issue":"8785","key":"ref16","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/0140-6736(92)91008-V","article-title":"Cerebromeningeal haemophagocytic lymphohistiocytosis","volume":"339","author":"J. I. Henter","year":"1992","journal-title":"The Lancet"},{"issue":"08","key":"ref17","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1017\/S0012162201001001","article-title":"Acute encephalopathy as a primary manifestation of haemophagocytic lymphohistiocytosis","volume":"43","author":"M. Kieslich","year":"2001","journal-title":"Dev Med Child Neurol"},{"issue":"4","key":"ref18","doi-asserted-by":"publisher","first-page":"273","DOI":"10.5045\/kjh.2012.47.4.273","article-title":"Central nervous system (CNS) involvement is a critical prognostic factor for hemophagocytic lymphohistiocytosis","volume":"47","author":"M. M. Kim","year":"2012","journal-title":"Korean J Hematol"},{"issue":"17","key":"ref19","doi-asserted-by":"publisher","first-page":"4577","DOI":"10.1182\/blood-2011-06-356261","article-title":"Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol","volume":"118","author":"H. Trottestam","year":"2011","journal-title":"Blood"},{"issue":"3","key":"ref20","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1002\/pbc.22239","article-title":"Frequency and development of CNS involvement in Chinese children with hemophagocytic lymphohistiocytosis","volume":"54","author":"S. Yang","year":"2010","journal-title":"Pediatr Blood Cancer"},{"issue":"3","key":"ref21","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1016\/j.pediatrneurol.2013.10.014","article-title":"Central Nervous System Involvement in Hemophagocytic Lymphohistiocytosis: A Single-Center Experience","volume":"50","author":"A. Jovanovic","year":"2014","journal-title":"Pediatr Neurol"},{"issue":"4","key":"ref22","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/j.1651-2227.1991.tb11878.x","article-title":"Incidence in Sweden and Clinical Features of Familial Hemophagocytic Lymphohistiocytosis","volume":"80","author":"J. Henter","year":"1991","journal-title":"Acta Paediatr"},{"issue":"3","key":"ref23","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1111\/j.1365-2141.2007.06922.x","article-title":"Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis","volume":"140","author":"A. Horne","year":"2008","journal-title":"Br J Haematol"},{"key":"ref24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.608492","article-title":"Novel Therapeutic Approaches to Familial HLH (Emapalumab in FHL)","volume":"11","author":"P. Merli","year":"2020","journal-title":"Front Immunol"},{"issue":"4","key":"ref25","doi-asserted-by":"publisher","first-page":"e743","DOI":"10.1542\/peds.2005-1789","article-title":"Hematopoietic Stem Cell Transplantation in Hemophagocytic Lymphohistiocytosis: A Single-Center Report of 48 Patients","volume":"117","author":"M. Ouachee-Chardin","year":"2006","journal-title":"Pediatrics"},{"issue":"3","key":"ref26","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1378\/chest.11-2717","article-title":"Hemophagocytic Lymphohistiocytosis Mimicking Septic Shock","volume":"141","author":"S. Besset","year":"2012","journal-title":"Chest"},{"key":"ref27","series-title":"Pediatric Critical Care","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/978-3-319-96499-7_14","article-title":"Secondary Hemophagocytic Lymphohistiocytosis, Macrophage Activation Syndrome, and Hyperferritinemic Sepsis-Induced Multiple-Organ Dysfunction Syndrome in the Pediatric ICU","author":"J. A. Carcillo","year":"2019"},{"issue":"4","key":"ref28","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1378\/chest.11-0619","article-title":"Hemophagocytic Lymphohistiocytosis","volume":"140","author":"R. A. Raschke","year":"2011","journal-title":"Chest"},{"issue":"7","key":"ref29","doi-asserted-by":"publisher","first-page":"2367","DOI":"10.1182\/blood-2002-01-0172","article-title":"Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation","volume":"100","author":"J. I. Henter","year":"2002","journal-title":"Blood"},{"issue":"7","key":"ref30","doi-asserted-by":"publisher","first-page":"2658","DOI":"10.1182\/blood-2004-09-3590","article-title":"Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity","volume":"105","author":"J. Feldmann","year":"2005","journal-title":"Blood"},{"issue":"3","key":"ref31","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/S0022-3476(97)70196-3","article-title":"Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis","volume":"130","author":"J. I. Henter","year":"1997","journal-title":"J Pediatr"},{"issue":"3","key":"ref32","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1093\/ajcp\/aqaa248","article-title":"Cytomorphologic Features Found in Cerebrospinal Fluid Specimens of Hemophagocytic Lymphohistiocytosis Patients","volume":"156","author":"S. Shyu","year":"2021","journal-title":"Am J Clin Pathol"},{"issue":"2","key":"ref33","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1002\/pbc.25308","article-title":"Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden","volume":"62","author":"M. Meeths","year":"2015","journal-title":"Pediatr Blood Cancer"},{"issue":"5","key":"ref34","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1016\/j.neurobiolaging.2005.03.026","article-title":"White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study","volume":"27","author":"D. Medina","year":"2006","journal-title":"Neurobiol Aging"},{"issue":"6","key":"ref35","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.1182\/blood.V89.3.794","article-title":"Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis","volume":"162","author":"E. Haddad","year":"1997","journal-title":"Blood"},{"issue":"3","key":"ref36","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1007\/BF00443367","article-title":"Familial hemophagocytic lymphohistiocytosis","volume":"140","author":"G. E. Janka","year":"1983","journal-title":"Eur J Pediatr"},{"issue":"15","key":"ref37","doi-asserted-by":"publisher","first-page":"4041","DOI":"10.1182\/blood-2011-03-278127","article-title":"How I treat hemophagocytic lymphohistiocytosis","volume":"118","author":"M. B. Jordan","year":"2011","journal-title":"Blood"},{"issue":"25","key":"ref38","doi-asserted-by":"publisher","first-page":"2728","DOI":"10.1182\/blood-2017-06-788349","article-title":"Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study","volume":"130","author":"E. Bergsten","year":"2017","journal-title":"Blood"},{"issue":"2","key":"ref39","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1002\/pbc.21039","article-title":"HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis","volume":"48","author":"J. I. Henter","year":"2007","journal-title":"Pediatr Blood Cancer"},{"issue":"1","key":"ref40","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1182\/blood-2017-11-814244","article-title":"Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis","volume":"132","author":"I.K. Chinn","year":"2018","journal-title":"Blood"},{"issue":"1","key":"ref41","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/humu.20274","article-title":"Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses ofPRF1, UNC13D, STX11, andRAB27A","volume":"27","author":"U. Zur Stadt","year":"2006","journal-title":"Hum Mutat"}],"container-title":["Clinical Hematology International"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chi.scholasticahq.com\/article\/155719-central-nervous-system-involvement-in-pediatric-hemophagocytic-lymphohistiocytosis-a-single-center-descriptive-study-of-clinical-features-neurodiag","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,14]],"date-time":"2026-06-14T16:28:00Z","timestamp":1781454480000},"score":1,"resource":{"primary":{"URL":"https:\/\/chi.scholasticahq.com\/article\/155719-central-nervous-system-involvement-in-pediatric-hemophagocytic-lymphohistiocytosis-a-single-center-descriptive-study-of-clinical-features-neurodiag"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,19]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026]]}},"URL":"https:\/\/doi.org\/10.46989\/001c.155719","relation":{},"ISSN":["2590-0048"],"issn-type":[{"value":"2590-0048","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,19]]}}}