From the past to the present: evolving theories in the pathophysiology of normal pressure hydrocephalus.

Abstract

Over recent decades, various hypotheses and theoretical frameworks have been advanced to elucidate the aetiology of normal pressure hydrocephalus (NPH). This reversible neurological condition, characterised by the classical clinical triad of gait disturbance, urinary incontinence and cognitive impairment, represents a multifactorial interplay of pathophysiological processes that co-occur, rather than originating from a single, defined cause. Despite extensive research efforts, the precise aetiology and underlying pathophysiological pathways remain indeterminate. Contributory factors such as dysfunction of the glymphatic system, diminished arterial pulsatility, metabolic and osmotic dysregulation, astrogliosis and neuroinflammatory processes are acknowledged as critical in the pathogenesis of NPH. Recent advancements in the understanding of these pathophysiological aberrations have substantially refined the conceptualisation of the NPH phenotype, enhancing the predictive accuracy for cerebrospinal fluid diversion interventions. This review addresses the definition and classification of NPH and emphasises future research directions aimed at further elucidating the molecular and physiological mechanisms underlying the disease. A comprehensive understanding of this syndrome is critical for informed clinical decision-making and optimising therapeutic outcomes. With the global increase in ageing populations, accurately differentiating NPH from other neurodegenerative disorders and managing overlapping comorbidities has become increasingly significant.