Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis
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ORIGINAL ARTICLE
Neuroinflammatory Disease as an Isolated Manifestation of Hemophagocytic Lymphohistiocytosis Annaliesse Blincoe 1,2 & Maximilian Heeg 3,4,5 & Patrick K. Campbell 6 & Melissa Hines 7 & Amer Khojah 8 & Marisa Klein-Gitelman 8,9 & Julie-An Talano 10 & Carsten Speckmann 3,11 & Fabien Touzot 1 & Arjan Lankester 12 & Geertje E. Legger 13 & Jacques G. Rivière 14,15 & Marina Garcia-Prat 14,15 & Laura Alonso 16 & Maria C. Putti 17 & Kai Lehmberg 18 & Sarah Maier 18 & Yasmine El Chazli 19 & Marwa Abd Elmaksoud 20 & Itziar Astigarraga 21 & Natalja Kurjane 22,23 & Inita Bulina 22,24 & Viktorija Kenina 23,25 & Yenan Bryceson 26 & Jelena Rascon 27,28 & Anne Lortie 29 & Gal Goldstein 30 & Claire Booth 31 & Austen Worth 31 & Evangeline Wassmer 32 & Erica G. Schmitt 33 & Julia T. Warren 33 & Jeffrey J. Bednarski 33 & Salah Ali 34 & Kuang-Yueh Chiang 34,35 & Joerg Krueger 34,35 & Michael M. Henry 36 & Steven M. Holland 37 & Rebecca A. Marsh 38 & Stephan Ehl 3 & Elie Haddad 1 Received: 27 March 2020 / Accepted: 25 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Isolated neuroinflammatory disease has been described in case reports of familial hemophagocytic lymphohistiocytosis (FHL), but the clinical spectrum of disease manifestations, response to therapy and prognosis remain poorly defined. We combined an international survey with a literature search to identify FHL patients with (i) initial presentation with isolated neurological symptoms; (ii) absence of cytopenia and splenomegaly at presentation; and (iii) systemic HLH features no earlier than 3 months after neurological presentation. Thirty-eight (20 unreported) patients were identified with initial diagnoses including acute demyelinating encephalopathy, leukoencephalopathy, CNS vasculitis, multiple sclerosis, and encephalitis. Median age at presentation was 6.5 years, most commonly with ataxia/gait disturbance (75%) and seizures (53%). Diffuse multifocal white matter changes (79%) and cerebellar involvement (61%) were common MRI findings. CSF cell count and protein were increased in 22/ 29 and 15/29 patients, respectively. Fourteen patients progressed to systemic inflammatory disease fulfilling HLH-2004 criteria at a mean of 36.9 months after initial neurological presentation. Mutations were detected in PRF1 in 23 patients (61%), RAB27A in 10 (26%), UNC13D in 3 (8%), LYST in 1 (3%), and STXBP2 in 1 (3%) with a mean interval to diagnosis of 28.3 months. Among 19 patients who underwent HSCT, 11 neurologically improved, 4 were stable, one relapsed, and 3 died. Among 14 nontransplanted patients, only 3 improved or had stable disease, one relapsed, and 10 died. Isolated CNS-HLH is a rare and often overlooked cause of inflammatory brain disease. HLH-directed therapy followed by HSCT seems to improve survival and outcome. Keywords Familial hemophagocytic lymphohistiocytosis . CNS disease . CNS inflammation . therapy
Annaliesse Blincoe, Maximilian Heeg, Stephan Ehl and Elie Haddad contributed equally to this work. Electronic su
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