1. Neuroinflammatory disease as an isolated manifestation of hemophagocytic lymphohistiocytosis
- Author
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Salah Ali, Yenan T. Bryceson, Marina Garcia-Prat, Maximilian Heeg, Jeffrey J. Bednarski, Carsten Speckmann, Jelena Rascon, Viktorija Kenina, Annaliesse Blincoe, Melissa Hines, Rebecca A. Marsh, Elie Haddad, Julie-An Talano, Anne Lortie, Patrick Campbell, Natalja Kurjane, Geertje E. Legger, Amer Khojah, Fabien Touzot, yasmine El Chazli, Julia T. Warren, Erica G. Schmitt, Marisa Klein-Gitelman, Stephan Ehl, Laura C. Alonso, Austen Worth, Maria C. Putti, Joerg Krueger, Evangeline Wassmer, Jacques G. Rivière, Kai Lehmberg, Itziar Astigarraga, Gal Goldstein, Kuang-Yueh Chiang, Inita Bulina, Claire Booth, Arjan C. Lankester, Michael M. Henry, Sarah Maier, Marwa Abd El-Maksoud, and Steven M. Holland
- Subjects
Male ,PRF1 ,Biopsy ,CHILDREN ,Gastroenterology ,Leukoencephalopathy ,Immunology and Allergy ,Age of Onset ,Child ,CNS disease ,Hematopoietic Stem Cell Transplantation ,NERVOUS-SYSTEM INVOLVEMENT ,Familial Hemophagocytic Lymphohistiocytosis ,Magnetic Resonance Imaging ,PERFORIN ,Phenotype ,Child, Preschool ,Disease Progression ,Female ,GENOTYPE-PHENOTYPE ,Symptom Assessment ,medicine.symptom ,Encephalitis ,Adult ,medicine.medical_specialty ,Ataxia ,Adolescent ,Genotype ,Immunology ,Neuroimaging ,FREQUENCY ,Lymphohistiocytosis, Hemophagocytic ,Young Adult ,MUNC13-4 ,Internal medicine ,Familial hemophagocytic lymphohistiocytosis ,medicine ,Humans ,Genetic Predisposition to Disease ,UNC13D ,Alleles ,Cytopenia ,Hemophagocytic lymphohistiocytosis ,SPECTRUM ,therapy ,business.industry ,MUTATIONS ,Multiple sclerosis ,Infant ,medicine.disease ,CNS inflammation ,Mutation ,ONSET ,business ,Biomarkers - 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 non-transplanted 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.
- Published
- 2020