Acetazolamide in hydrocephalus management: Mechanistic insights and clinical challenges

Hydrocephalus is a heterogeneous neurological disorder characterized by impaired cerebrospinal fluid (CSF) dynamics, resulting in ventriculomegaly, neurological dysfunction, and substantial morbidity across pediatric and adult populations. Surgical CSF diversion remains the standard treatment but risks infection, shunt malfunction, and lifelong dependency, underscoring the need for potential nonsurgical adjuncts. Acetazolamide, a carbonic anhydrase inhibitor, has been investigated as a pharmacological approach to reduce CSF production, lower intracranial pressure, and modulate cerebral blood flow. More recently, acetazolamide has also been implicated in regulating aquaporin-mediated water transport and enhancing brain glymphatic clearance function mechanisms, particularly relevant to the pathophysiology of idiopathic normal pressure hydrocephalus. These emerging mechanistic insights have renewed interest in evaluating its potential in hydrocephalus management. Experimental studies and selective clinical applications suggest possible benefits; however, conclusive evidence remains at large across hydrocephalus subtypes. Beyond exploratory treatment strategies, acetazolamide has also been applied diagnostically, including in cerebrovascular reactivity testing and as a predictor of CSF shunt responsiveness. This review appraises the critical mechanistic rationale, experimental findings, and clinical evidence regarding acetazolamide in hydrocephalus management, highlighting current uncertainties and limitations. Well-designed, subtype-specific clinical trials are needed to clarify whether the modulation of CSF and glymphatic pathway functions can be translated into safe, consistent, and durable clinical benefit.