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

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.

CD4 + T Cells Orchestrate Lethal Immune Pathology despite Fungal Clearance during Cryptococcus neoformans Meningoencephalitis

“…Clinical evidence increasingly suggests that the host inflammatory response, rather than pathogen burden, may lead to the development of pathology, neuronal injury, and deteriorating status, especially in IRIS and PIIRS patients (28,30,32,33,(36)(37)(38)(39)(40). Thus, our next goal was to evaluate CNS pathology during the progression of C. neoformans infection and to determine a possible link to the accumulation of a cellular inflammatory response within the CNS.…”

Choroid plexus and the blood–cerebrospinal fluid barrier in disease

“…It appears that invasion into the brain occurs via the BBB from among cortical capillaries but not through the CP [167][168][169]. However, co-occurrence of CP plexitis and ependymitis in HIV patients reflecting immune activation in the CP has been shown via magnetic resonance imaging (MRI) [170,171]. Finding CP plexitis in the MRI in immunocompromised patients may indicate a diagnosis of CNS cryptococcosis [172].…”

Chemokine receptor CXCR3 is required for lethal brain pathology but not pathogen clearance during cryptococcal meningoencephalitis

“…Recent clinical and animal studies indicate that the host inflammatory response is, in part, responsible for neurological deficits in patients with IRIS and PIIRS (4,7). We sought to determine whether the CXCR3 pathway contributes to the pathogenesis of CM.…”

“…The high prevalence of the cryptococcal disease in immune-deficient human patients (such as HIV/AIDS) supported the view that uncontrolled fungal invasion because of immunodeficiency is a major factor leading to disease pathology. Unexpectedly, recent studies have shown that strong anticryptococcal inflammatory responses are linked to severe neurological sequelae and mortality in a subset of patients with CM (4)(5)(6)(7)(8). Patients with AIDS with treated CM who undergo combination antiretroviral therapy can experience acute neurological deterioration caused by a paradoxical cryptococcal immune reconstitution inflammatory syndrome (c-IRIS) (9,10).…”