Background
Idiopathic normal pressure hydrocephalus, often abbreviated iNPH, is a brain disorder that mainly affects older adults. It is caused by an abnormal buildup of cerebrospinal fluid, which leads to enlarged brain ventricles while measured pressure may remain normal. The classic symptom triad includes gait disturbance, cognitive slowing, and urinary urgency or incontinence. Because these symptoms can overlap with other age-related conditions, diagnosis can be challenging, but the condition is important to recognize because it may improve with treatment.
At present, ventriculoperitoneal shunt surgery is the standard treatment and can improve walking and other symptoms in selected patients. However, surgery carries risks such as infection, bleeding, shunt malfunction, and the need for later revision. For that reason, interest has remained high in non-surgical treatments that might improve symptoms before surgery or reduce the need for it. Acetazolamide, a carbonic anhydrase inhibitor, lowers cerebrospinal fluid production and has been used in several neurologic and ophthalmic conditions. This study tested whether low-dose acetazolamide could improve gait in people with iNPH who were waiting for shunt surgery.
Study Design
This was an investigator-initiated, randomized, double-blind, placebo-controlled phase 2 trial called DRAIN, conducted at Uppsala University Hospital in Sweden. Adults aged 50 to 82 years were eligible if they met international criteria for probable idiopathic normal pressure hydrocephalus and had characteristic brain imaging findings, such as ventriculomegaly with a narrow callosal angle or disproportionately enlarged subarachnoid space hydrocephalus.
Participants also needed reasonably preserved cognition, defined as either a Mini-Mental State Examination score greater than 20 or a cognitive-domain score on the idiopathic normal pressure hydrocephalus grading scale greater than 30. These criteria were used to identify patients who were still appropriate candidates for shunt evaluation and able to complete repeated gait testing.
A total of 119 patients were screened, and 50 were randomly assigned in a 1:1 ratio to acetazolamide or matching placebo using computer-generated block randomization. The drug was given orally after individual titration up to 250 mg twice daily. Treatment continued until admission for shunt surgery or for a maximum of 9 months. The main outcome was change in a composite gait score from baseline to the end-of-treatment visit. The composite score combined three standard walking tests: the 10-meter walk, the Timed Up and Go test, and the 3-meter backward walk.
Safety was assessed throughout the study by tracking adverse events, treatment discontinuations, and laboratory monitoring. The efficacy analysis used a modified intention-to-treat population, meaning only participants with baseline and at least one follow-up gait assessment were included in the primary analysis.
Participants
Of the 50 randomized patients, 41 were included in the modified intention-to-treat analysis: 20 in the acetazolamide group and 21 in the placebo group. The median age was 76 years, and most participants were men. This population reflects the typical demographic of idiopathic normal pressure hydrocephalus, which is most common in older adults.
The median time from randomization to the end-of-treatment visit was 121 days in the acetazolamide group and 187 days in the placebo group. The shorter duration in the acetazolamide group likely reflects treatment discontinuation or earlier progression to surgery rather than a planned shorter course for that group.
Main Findings
Acetazolamide did not improve gait compared with placebo. At the end of treatment, the adjusted between-group difference in change in the composite gait score was 0.09 units, with a 95% confidence interval from -3.61 to 3.79 and a p value of 0.96. In practical terms, this means there was essentially no detectable difference between the drug and placebo groups.
Because gait impairment is often the most functionally disabling symptom of iNPH and is also the symptom most likely to improve after shunt surgery, this negative result is clinically important. The trial provides evidence that acetazolamide, at the studied low dose and in this patient population, should not be expected to meaningfully improve walking while patients await surgery.
Safety and Tolerability
Adverse events were more common in the acetazolamide group. At least one adverse event occurred in 20 of 25 patients taking acetazolamide, compared with 15 of 25 receiving placebo. More importantly, treatment discontinuation due to adverse events occurred in 9 patients in the acetazolamide group versus 2 in the placebo group.
This difference suggests that even though acetazolamide is a familiar medication, it was not particularly well tolerated in this older neurologic population. Acetazolamide can cause side effects such as fatigue, appetite loss, paresthesia, taste changes, dizziness, metabolic acidosis, kidney-related complications, and electrolyte disturbances. In patients with iNPH, who are often frail and may already have balance or cognitive problems, these adverse effects can be especially problematic because they may worsen mobility or reduce adherence.
Four serious adverse events occurred in total: urinary tract infection and venous thrombosis in the acetazolamide group, and pulmonary embolism with pneumonia plus a transient loss of consciousness in the placebo group. None of these events was judged to be related to the study treatment.
Interpretation
In this randomized, double-blind, placebo-controlled phase 2 trial, low-dose acetazolamide did not improve gait in patients with idiopathic normal pressure hydrocephalus awaiting shunt surgery. The drug also caused more side effects and led to more treatment discontinuations than placebo.
The findings do not support acetazolamide as routine pharmacological treatment for iNPH. This is important because the condition has long lacked an evidence-based medical therapy, and there has been understandable interest in a medication that could reduce cerebrospinal fluid production without surgery. However, this study suggests that acetazolamide is not an effective substitute for established surgical evaluation and treatment.
Clinical Context
Idiopathic normal pressure hydrocephalus remains a potentially reversible cause of disability in older adults. When it is correctly identified, shunt surgery can lead to meaningful improvement, especially in gait. Yet patient selection is critical, and not everyone benefits equally. The search for medical therapies has therefore continued.
This trial adds to that evidence base by showing that simply reducing cerebrospinal fluid production with acetazolamide is not enough to produce clinically relevant gait improvement in this setting. It also highlights a broader principle in geriatric neurology: even commonly used medications can cause disproportionate harm in older patients if the expected benefit is small or uncertain.
For clinicians, the message is straightforward. Acetazolamide should not be used routinely to treat idiopathic normal pressure hydrocephalus outside a research setting. For patients, the study reinforces the importance of timely specialist assessment for possible shunt surgery rather than relying on medication alone.
Study Strengths and Limitations
One strength of the DRAIN trial is its randomized, double-blind, placebo-controlled design, which reduces bias and makes the comparison between groups more reliable. The use of objective gait measures is another strength, since walking impairment is a core symptom of iNPH and can be measured reproducibly.
The study also had limitations. The sample size was modest, as expected for a phase 2 trial, which means small treatment effects could have been missed. The modified intention-to-treat analysis included 41 of the 50 randomized participants, so some data were not available for the primary endpoint. In addition, the treatment duration varied, and participants proceeded to surgery at different times, which may have influenced the timing of outcome assessment.
Another limitation is that the study tested low-dose acetazolamide only. It remains theoretically possible that a different dose, a different schedule, or a more selected subgroup might respond differently, but this trial does not provide evidence to support such use in routine practice.
Bottom Line
In older adults with probable idiopathic normal pressure hydrocephalus awaiting shunt surgery, acetazolamide did not improve gait and was less well tolerated than placebo. The results do not support using acetazolamide as standard medical treatment for this disorder.
For now, careful diagnosis, appropriate imaging, and referral for neurosurgical evaluation remain the key steps in managing idiopathic normal pressure hydrocephalus.