A Randomized Trial of Shunting for Idiopathic Normal-Pressure Hydrocephalus

By Evelyn Ooi, MD

Synopsis: In this randomized, double-blind, placebo-controlled trial, investigators demonstrated that ventriculoperitoneal shunt surgery produces a clinically meaningful improvement in gait (but not in cognition or urinary symptoms) at three months in carefully selected patients with idiopathic normal-pressure hydrocephalus.

Sources: Luciano MG, Williams MA, Hamilton MG, et al. A randomized trial of shunting for idiopathic normal-pressure hydrocephalus. N Engl J Med. 2025;393(22):2198-2209.

Ropper AH. Small steps, big ventricles: Idiopathic normal-pressure hydrocephalus. N Engl J Med. 2025;393(22):2264-2266.

Idiopathic normal-pressure hydrocephalus (iNPH) is a progressive neurologic disorder of older adults characterized by gait and balance impairment, cognitive decline, urinary urgency or incontinence, and ventriculomegaly. Its prevalence increases sharply with age. Untreated disease is associated with worsening disability and increased mortality. Although cerebrospinal fluid (CSF) shunt surgery has been used for decades and is recommended in clinical guidelines, uncertainty has persisted regarding its true effectiveness, durability, and overall risk–benefit profile.

To address these concerns, Luciano et al designed and conducted the Placebo-Controlled Efficacy in iNPH Shunting (PENS) trial, a rigorously executed international, multicenter, double-blind, randomized, placebo-controlled study evaluating the efficacy of shunt surgery in iNPH. Participants met international guideline-based criteria for shunting and were required to demonstrate improvement in gait velocity after temporary CSF drainage, reflecting real-world clinical practice.

Randomization occurred immediately before surgery, with participants assigned to either an open-shunt valve setting or a placebo valve setting using a programmable shunt, allowing blinding of participants and outcome assessors. Outcome measures were standardized, assessors were carefully trained, gait assessments were video recorded for quality control, and data analysis was centralized. The primary outcome was change in maximum gait velocity at three months, an objective and clinically meaningful measure strongly associated with functional independence and fall risk in older adults. Secondary outcomes included measures of balance, cognition, and urinary symptoms, while tertiary outcomes assessed functional status, quality of life, and neuroimaging markers.

At three months, participants in the open-shunt group showed a substantial improvement in gait velocity, whereas those in the placebo group showed essentially no change. The between-group difference exceeded established thresholds for meaningful clinical improvement, with 80% of patients in the open-shunt group achieving a substantial gait response compared with 24% in the placebo group. Balance, as measured by the Tinetti scale, also improved significantly in the open-shunt group, reinforcing the conclusion that shunting provides a clear motor benefit in appropriately selected patients.

In contrast, improvements in cognition and urinary symptoms were modest and did not differ significantly between groups at three months. This finding tempers expectations of rapid improvement across the full symptom triad of iNPH and suggests that early benefits of shunting are most reliably observed in gait and balance. Nevertheless, tertiary outcomes suggested broader effects, including improved quality of life, greater functional independence, and reduced ventricular volume in the open-shunt group.

Shunt-related complications were common. Falls were more frequent in the placebo group, likely reflecting persistent gait impairment, whereas complications related to CSF overdrainage (such as subdural hematomas and positional headaches) were more common in the open-shunt group. Most complications were managed with valve adjustments, although some required additional intervention, and one death occurred in association with surgical hemorrhage. These findings underscore the importance of careful patient selection, postoperative monitoring, and shared decision-making.

The authors acknowledge limitations, including restricted eligibility criteria that may limit generalizability and the relatively short three-month timeframe for the primary outcome. Longer-term outcomes, particularly cognitive effects and durability of gait improvement, remain to be determined. To this end, outcome measures and complications continue to be collected for participants through 12 months, to be supplemented by comprehensive neuropsychological battery, further imaging, and CSF biomarkers.

Commentary

The PENS trial provides a long-overdue, methodologically rigorous response to skepticism surrounding shunt surgery for iNPH. By successfully implementing a double-blind, randomized, placebo-controlled surgical design, Luciano and colleagues address a central critique of prior studies, namely that observed benefits may reflect placebo effects rather than true treatment efficacy.

The execution of this trial alone represents a landmark achievement in iNPH research. Importantly, the study evaluates shunting within the same guideline-based clinical framework most clinicians already use, including demonstrated improvement after temporary CSF drainage. The robust and clinically meaningful improvement in gait seen in the open-shunt group, contrasted with minimal change in the placebo group, strongly supports iNPH as a genuine and treatable condition. For gait (the most reliable and, arguably, most functionally relevant symptom), the evidence now is difficult to dispute.

At the same time, the trial appropriately tempers expectations. The lack of significant short-term improvement in cognition and urinary symptoms mirrors real-world experience and highlights the need for more precise patient counseling. Shunting should not be framed as a global remedy for the full iNPH triad, but rather as an intervention with its strongest and earliest benefits in gait and balance.

The complication profile reinforces the importance of careful patient selection and postoperative management. Although overdrainage-related events were more common in the open-shunt group, most were manageable with valve adjustment, and the higher fall rate in the placebo group underscores the risks of untreated disease. As Dr. Alan Ropper notes in the accompanying editorial, the PENS trial does not resolve all controversies in iNPH, but it decisively elevates the evidentiary standard. In doing so, it provides much-needed clarity and a firmer foundation for both clinical decision-making and future research.

Evelyn Ooi, MD, is Assistant Professor of Clinical Neurology and Assistant Attending Neurologist, NewYork-Presbyterian/Weill Cornell Medical Center.