Pathophysiology of intracranial hypertension in cryptococcal meningoencephalitis

Cryptococcal meningoencephalitis (CME) is a major cause of death and disability, and intracranial hypertension is a leading, treatable contributor to mortality and neurologic sequelae. Across CME cohorts, markedly elevated cerebrospinal fluid (CSF) opening pressure is common and often occurs despite minimal ventriculomegaly or diffuse edema on neuroimaging. This review synthesizes clinical, microbiological, imaging, pathological, and experimental evidence to define priorities for mechanistic research. Intracranial pressure (ICP) physiology predicts that once intracranial compliance is exhausted, small volume changes can produce rapid pressure increases, making CSF dynamics central to many intracranial hypertension syndromes. In CME, the frequent, rapid improvement after therapeutic CSF drainage, followed by pressure re-accumulation, supports a CSF outflow-limited mechanism for ICP. Convergent observations, including correlations between opening pressure and fungal/capsular polysaccharide burden and postmortem localization of organisms and polysaccharide at candidate CSF efflux sites, support a model of increased CSF outflow resistance. Potential modifiers include cryptococcal phenotypes (e.g., capsule size/architecture, aggregation), host immune and osmotic states, and disruption of perivascular ("glymphatic") transport that may alter clearance and compliance. Alternative dominant mechanisms (e.g., mass effect, obstructive hydrocephalus, venous sinus thrombosis, or inflammatory edema in immune reconstitution inflammatory syndrome/post-infectious inflammatory response syndrome) likely account for a minority of cases but remain clinically important. Current ICP control relies on invasive CSF drainage, and empiric pharmacologic approaches have not translated well, meaning progress will depend on both clinical and basic science research that link fungal and host factors to ICP trajectories, quantify efflux-site burden, directly measure outflow resistance, and explore adjunctive therapeutics that address CSF efflux and fungal clearance.