Cerebrospinal fluid biomarkers of brain injury, inflammation and synaptic autoimmunity predict long-term neurocognitive outcome in herpes simplex encephalitis

Gabriel Westman,Elisabeth Aurelius,Clas Ahlm,Kaj Blennow,Kristina Eriksson,Liza Lind,Silvia Schliamser,Fredrik Sund,Henrik Zetterberg,Marie Studahl

doi:10.1016/j.cmi.2020.09.031

Abstract

ObjectivesThe aim was to investigate the correlation between biomarkers of brain injury and long-term neurocognitive outcome, and the interplay with intrathecal inflammation and neuronal autoimmunity, in patients with herpes simplex encephalitis (HSE). MethodsA total of 53 adult/adolescent HSE patients were included from a prospective cohort in a randomized placebo-controlled trial investigating the effect of a 3-month follow-up treatment with valaciclovir. Study subjects underwent repeated serum/cerebrospinal fluid (CSF) sampling and brain magnetic resonance imaging in the first 3 months along with cognitive assessment using the Mattis Dementia Rating Scale (MDRS) at 24 months. CSF samples were analysed for biomarkers of brain injury, inflammation and synaptic autoimmunity. The predefined primary analysis was the correlation between peak CSF neurofilament protein (NFL), a biomarker of neuronal damage, and MDRS at 24 months. ResultsImpaired cognitive performance significantly correlated with NFL levels (rho = –0.36, p = 0.020). Development of IgG anti-N-methyl-D-aspartate receptor (NDMAR) antibodies was associated with a broad and prolonged proinflammatory CSF response. In a linear regression model, lower MDRS at 24 months was associated with previous development of IgG anti-N-methyl-D-aspartate receptor (NMDAR) (beta = –0.6249, p = 0.024) and age (z-score beta = –0.2784, p = 0.024), but not CSF NFL, which however significantly correlated with subsequent NMDAR autoimmunization (p = 0.006). DiscussionOur findings show that NFL levels are predictive of long-term neurocognitive outcome in HSE, and suggest a causative chain of events where brain tissue damage increases the risk of NMDAR autoimmunisation and subsequent prolongation of CSF inflammation. The data provides guidance for a future intervention study of immunosuppressive therapy administered in the recovery phase of HSE.

Highlights

Herpes simplex encephalitis (HSE) affects approximately two to four individuals per million each year and often results in severe neurocognitive sequelae in spite of antiviral therapy [1e5]
We show that the long-term neurocognitive outcome after HSE correlates with Cerebrospinal fluid (CSF) biomarkers of brain injury, inflammation and synaptic autoimmunity
The predefined primary statistical analysis shows a significant correlation between NFL levels in CSF and long-term cognitive performance as measured by Mattis Dementia Rating Scale (MDRS) after 24 months of follow-up

Summary

Introduction

Herpes simplex encephalitis (HSE) affects approximately two to four individuals per million each year and often results in severe neurocognitive sequelae in spite of antiviral therapy [1e5]. Aciclovir (ACV) treatment greatly improves clinical outcome but far from all patients reach full neurocognitive recovery [3,7]. In line with radiological findings and clinical outcome, several biomarkers of brain injury are elevated and patients often present with long-term intrathecal inflammation [10e13]. Markers of astroglial cell damage, glial fibrillary acidic protein (GFAP) and S100B are greatly elevated but reach their peak already in the first week of disease [14]. The response in neurodegeneration-related biomarkers such as the synaptic protein neurogranin (Ng) and the astroglial marker YKL-40 (chitinase 3-like protein 1) has not previously been characterized in HSE but correlates with negative outcome in other neuroinflammatory diseases [15,16]

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