Central Nervous System Involvement in Children with Hemophagocytic Lymphohistiocytosis: an HLH-2004 Study Report

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome with an inherited (Mendelian) form (primary HLH, pHLH), of which familial HLH (FHL) is most prevalent, and an acquired (non-Mendelian) form (secondary HLH, sHLH); both potentially rapidly fatal. As more patients survive, evaluating long-term morbidity, especially neurological complications, is important. Here we report on CNS involvement at onset, its impact on mortality and morbidity, and long-term follow-up in 365 children aged <18 years enrolled in the prospective multinational HLH-2004 study. This treatment included etoposide, dexamethasone, cyclosporin A, and, for selected patients, intrathecal methotrexate/prednisolone, followed by hematopoietic stem cell transplantation (HSCT) for pHLH. At diagnosis, 33% had neurological symptoms and 57% abnormal CSF; 33% and 73% in children with verified FHL, respectively. Elevated CSF protein was associated with inferior survival in univariate analyses, and multivariate analyses revealed reduced survival in children with both neurological symptoms and abnormal CSF. Altogether 32% of long-term survivors post-HSCT had neurological symptoms at last follow-up, more often in children with abnormal CSF at diagnosis; psychomotor retardation affected 25%, seizures 11%, and ADHD/autism 10% (at least). Seizures and psychomotor retardation were detected pre-HSCT in about half of the transplanted children, but, notably, at least 3 years post-HSCT in one third. The median time for reporting ADHD/autism was 5 years post-HSCT. Late neurological complications were reported in 7% of long-term survivors without HSCT. In conclusion, late neurological complications remain a major concern in pHLH, CSF evaluation at diagnosis is valuable, and long follow-up is important since complications may be diagnosed late. NCT00426101.