Idiopathic normal pressure hydrocephalus: from pathophysiological mechanisms to precision diagnosis and optimized therapeutic outcomes

Background Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder of older adults, characterized by the classic triad of gait disturbance, cognitive impairment, and urinary incontinence. Despite its treatable nature, iNPH remains widely underdiagnosed, and the prediction of shunt responsiveness and optimization of therapeutic outcomes remain major clinical challenges. Methods We conducted a narrative review informed by a structured PubMed search of studies published between January 2017 and June 2026. Forty-eight original clinical studies, including randomized controlled trials (RCTs), prospective and retrospective cohort studies, and cross-sectional studies addressing the pathophysiology, diagnosis, treatment, or prognosis of iNPH, were selected for synthesis; foundational trials and guidelines published before 2017 were cited for context. Results Emerging, largely correlational evidence links iNPH to impaired glymphatic function, perivascular aquaporin-4 loss, and delayed cerebrospinal fluid (CSF) tracer clearance, although causality remains unproven. Instrumented gait analysis, MRI volumetry, and refined CSF tap test protocols may improve the objectivity of patient evaluation, but most of these tools have been validated only in small single-center cohorts. The first large placebo-controlled RCT (PENS) confirmed gait improvement after shunt surgery, extending earlier evidence from the Japanese SINPHONI and SINPHONI-2 studies, whereas acetazolamide showed no benefit in the DRAIN trial. Adjuvant rehabilitation may enhance gait recovery and reduce fall risk. Multiple clinical, imaging, and neuropsychological predictors of shunt responsiveness have been reported, but no single biomarker achieves sufficient predictive accuracy, and heterogeneity in diagnostic criteria, outcome measures, and follow-up limits comparisons across studies. Conclusion Shunt surgery is now supported by randomized evidence for gait outcomes, whereas most diagnostic and prognostic biomarkers remain investigational. Priorities include standardized diagnostic pathways, prospective external validation of multimodal prognostic models, incorporation of patient-reported and caregiver outcomes, and equitable access to specialized care.