Choroid Plexitis and Ependymitis by Magnetic Resonance Imaging are Biomarkers of Neuronal Damage and Inflammation in HIV-negative Cryptococcal Meningoencephalitis

Dima A. Hammoud,Bibi Bielakova,Irini Sereti,Peter R. Williamson,Anil A. Panackal,Eman Mahdi,John E. Bennett,Paul Wakim,Virginia Sheikh

doi:10.1038/s41598-017-09694-0

Abstract

CNS cryptococcal meningoencephalitis in both HIV positive (HIV+) and HIV negative (HIV−) subjects is associated with high morbidity and mortality despite optimal antifungal therapy. We thus conducted a detailed analysis of the MR imaging findings in 45 HIV− and 11 HIV+ patients to identify imaging findings associated with refractory disease. Ventricular abnormalities, namely ependymitis and choroid plexitis were seen in HIV− but not in HIV+ subjects. We then correlated the imaging findings in a subset of HIV− subjects (n = 17) to CSF levels of neurofilament light chain (NFL), reflective of axonal damage and sCD27, known to best predict the presence of intrathecal T-cell mediated inflammation. We found that ependymitis on brain MRI was the best predictor of higher log(sCD27) levels and choroid plexitis was the best predictor of higher log(NFL) levels. The availability of predictive imaging biomarkers of inflammation and neurological damage in HIV− subjects with CNS cryptococcosis may help gauge disease severity and guide the therapeutic approach in those patients.

Highlights

Assessing responsiveness to immunosuppressive agents including corticosteroids[6] creates a need for readily available clinical biomarkers of inflammation and neuronal damage that can be used in combination with microbiological biomarkers, such as early fungicidal activity[7, 8], to individualize and guide therapy
The present studies seek to identify imaging biomarkers that would be most predictive of CSF lymphocytic activation and inflammation patterns in the HIV− population, by correlating MRI findings with cerebrospinal fluid (CSF) levels of neurofilament light chain (NFL) and a soluble marker of T-cell activation, sCD27, recently shown to best predict the presence of intrathecal T-cell mediated inflammation compared to other biomarkers[27]
CNS cryptococcosis in previously healthy HIV− subjects accounts for almost a third of the cases in developed countries[3] and is associated with significant (~30%) mortality despite optimal therapy[2, 4, 5]

Summary

Introduction

Assessing responsiveness to immunosuppressive agents including corticosteroids[6] creates a need for readily available clinical biomarkers of inflammation and neuronal damage that can be used in combination with microbiological biomarkers, such as early fungicidal activity[7, 8], to individualize and guide therapy. There has been no direct comparison of imaging findings between the two populations and no attempts at correlating MR imaging findings with CSF indicators of inflammation and lymphocyte activation. The present studies seek to identify imaging biomarkers that would be most predictive of CSF lymphocytic activation and inflammation patterns in the HIV− population, by correlating MRI findings with cerebrospinal fluid (CSF) levels of NFL and a soluble marker of T-cell activation, sCD27, recently shown to best predict the presence of intrathecal T-cell mediated inflammation compared to other biomarkers[27]. To provide a broader clinical context, we compared these imaging manifestations to those of HIV+ subjects presenting with CM to better understand differences in disease pathophysiology between the two populations

Methods

Results

Conclusion