Current Treatment for Central Nervous System Involvement in Children with Hemophagocytic Lymphohistiocytosis

Hemophagocytic lymphohistiocytosis (HLH) is a severe life-threatening clinical syndrome with hyperinflammation rather than an isolated disease. It is classified as primary HLH and secondary HLH. Primary HLH is associated with HLH-related gene mutations, whereas secondary HLH occurs after severe infections, tumors, connective tissue diseases, etc.[1] Regardless of primary or secondary HLH, 30–73% of patients have central nervous system (CNS) involvement.[2] Among adults with HLH in China, 38.4% of patients have neurological symptoms at the onset, and there are up to 89.6% with neurological symptoms during the entire course of the disease.[3] However, it has not been clearly reported about the CNS involvement in children with HLH.

In this issue of CMJ, Zhao et al.[4] reported a retrospective single-institution study evaluating the involvement of CNS in 179 children with HLH. It was found that 21.2% of HLH children had neurological symptoms at the onset, 50% had cranial imaging changes, and 14.7% had cerebrospinal fluid (CSF) abnormal. In total, 60.3% of the children with HLH had CNS involvement including one of the presences such as CNS symptoms, imaging abnormalities, and changes in CSF. The results suggested that children with HLH suffering from CNS involvement had a poor prognosis. Therefore, clinical attention should be paid to the presence of HLH children with CNS involvement. Early diagnosis and timely treatment is particularly important to improve its outcome. Cranial magnetic resonance imaging (MRI) and CSF examinations are necessary for all HLH children diagnosed according to the HLH-2004 protocol.[5] Importantly, this study found that the clinical symptoms combined CSF abnormality had more prognostic significance than simple CNS imaging changes.

How to treat patients with HLH complicated with CNS involvement? The HLH-94/04 protocol is the basic regimen, supplemented with intrathecal injection of methotrexate and glucocorticoid. In the case of primary HLH, hematopoietic stem cell transplantation (HSCT) is suggested to perform as soon as possible after induction of remission. For secondary HLH, induction of remission should be followed by treatment of the underlying diseases. If the HLH still could not be controlled, high-dose steroid pulse therapy, anti-CD52 monoclonal antibody (alemtuzumab), or new biological agents (such as anti-interferon-γ antibody or ruxolitinib) should be administered. Salvage therapy or HSCT could be considered for the HLH patients who failed to the above treatment.[6,7,8] In clinical practice, the treatment regimen will be adjusted according to patient's conditions. The appropriate treatment plan is crucial for the children with HLH, especially for whom have CNS involvement.

In conclusion, HLH is a lethal syndrome triggered by an inflammatory cytokine storm. The presence of CNS involvement is a poor prognostic sign and should be carefully investigated for the neurological symptoms, brain MRI with multifocal white matter abnormalities and CSF examinations. Early diagnosis of CNS involvement will apparently increase timely and appropriate treatment to improve the prognosis of children with HLH.