Cerebrospinal fluid cyto-/chemokine profile during acute herpes simplex virus induced anti-N-methyl-d-aspartate receptor encephalitis and in chronic neurological sequelae

AimTo examine the cytokine/chemokine profile of cerebrospinal fluid (CSF) during acute herpes simplex virus-induced N-methyl-d-aspartate receptor (NMDAR) autoimmunity and in chronic/relapsing post-herpes simplex virus encephalitis (HSE) neurological syndromes. MethodWe measured longitudinal serial CSF cyto-/chemokines (n=34) and a glial marker (calcium-binding astroglial protein, S100B) in one patient during acute HSE and subsequent anti-NMDAR encephalitis, and compared the results with those from two patients with anti-NMDAR encephalitis without preceding HSE. We also compared cyto-/chemokines in cross-sectional CSF samples from three children with previous HSE who had ongoing chronic or relapsing neurological symptoms (2yr 9 mo-16y after HSE) with those in a group of children having non-inflammatory neurological conditions (n=20). ResultsAcute HSE showed elevation of a broad range of all T-helper-subset-related cyto-/chemokines and S100B whereas the post-HSE anti-NMDAR encephalitis phase showed persistent elevation of two of five T-helper-1 (chemokine [C-X-C motif] ligand 9 [CXCL9], CXCL10), three of five predominantly B-cell (CXCL13, CCL19, a proliferation-inducing ligand [APRIL])-mediated cyto-/chemokines, and interferon-. The post-HSE anti-NMDAR encephalitis inflammatory response was more pronounced than anti-NMDAR encephalitis. All three chronic post-HSE cases showed persistent elevation of CXCL9, CXCL10, and interferon-, and there was histopathological evidence of chronic lymphocytic inflammation in one biopsied case 7 years after HSE. Two of three chronic cases showed a modest response to immune therapy. InterpretationHSE-induced anti-NMDAR encephalitis is a complex and pronounced inflammatory syndrome. There is persistent CSF upregulation of cyto-/chemokines in chronic or relapsing post-HSE neurological symptoms, which may be modifiable with immune therapy. The elevated cyto-/chemokines may be targets of monoclonal therapies. What this paper adds Inflammatory response is higher in anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis if is it preceded by herpes simplex encephalitis (HSE). Aggressive immune treatment in acute post-HSE anti-NMDAR illness improves the chances of a good outcome. Children with previous HSE and ongoing neurological symptoms may have persistent immune activation and chronic encephalitis. Persistent cerebrospinal fluid upregulation of cyto-/chemokines may be modifiable with immune therapy. This article is commented on by Ellul and Griffiths on pages 776-777 of this issue.