Acetazolamide for Treating NPH in Shunt-candidates Patients

Study Overview
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Brief Summary
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Normal pressure hydrocephalus (NPH) consists of a triad of gait disturbance, cognitive deterioration, and urinary incontinence and is characterized by enlarged cerebral ventricles. Current treatment recommendations are based on surgical diversion of Cerebrospinal fluid (CSF), by a ventriculoperitoneal shunt. When patients are appropriately selected, shunting for NPH has a sustained effect in one-half to two-thirds of patients with a reasonable complication rate. However, evidence regarding the efficacy of shunt surgery consists largely of observational studies with relatively short-term follow-up. With regards to the adverse effects of shunting, even though decreased substantially in recent years, shunt complications are still common. Recent studies report ten to twenty-two percent of serious adverse effects following shunt surgery, mainly subdural hematoma (SDH) requiring surgery, infection, and cerebral infarction or hemorrhage. Most complication occur in the first year after the procedure. Many others suffer from adverse events that considered non-serious, such as postural headache and asymptomatic SDH. Since shunt complications are common and potentially severe, there is a need for a better way to identify those patients that will likely benefit from shunting, and find alternative treatments for those unwilling or unable to withstand surgery. Acetazolamide has been shown to reduce the production of CSF in clinical cases of raised intracranial pressure. It is considered the drug of choice for the treatment of idiopathic intracranial hypertension (pseudotumor cerebri). Intuitively, acetazolamide can be effective for the treatment of NPH by reducing the volume of CSF in the brain, and serve as a medical alternative to shunting. Few case reports and small series demonstrated improvement in MRI abnormalities in NPH-patients after administrating the medication. This open-label study will examine the feasibility and effectiveness of acetazolamide in NPH-diagnosed patients who are shunt-candidates. Patients will be treated from time of diagnosis, and gait and cognition will be evaluated after 2-6 weeks. This trial would possibly pave the way to a larger randomized placebo-controlled trials, and perhaps offer a medical alternative to surgery for elderly patients and for patients for which operation is contraindicated.

Official Title
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Acetazolamide for Treating NPH in Shunt-candidates Patients: an Open Label Feasibility Trial

Conditions
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Normal Pressure Hydrocephalus

Intervention / Treatment
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* Drug: Acetazolamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Included will be subjects with a probable diagnosis of NPH. The diagnosis will be based primarily on presence of gait impairment plus at least one other impairment in urinary symptoms, cognition impairment or both. Are 50 years old or older. Patients who meet the criteria for NPH based on: A typical personal history. A typical brain imaging on head CT or MRI. Normal lumbar puncture findings excluding other conditions. Exclusion of other more likely diagnosis. Patients who underwent large-volume spinal tap and subsequently improved clinically by at least 10% in gait function or cognition. Exclusion Criteria: Cirrhosis or marked liver disease or dysfunction. Severe renal disease or dysfunction. Acidosis. Hypersensitivity to acetazolamide, sulfonamides, or any component of the formulation. Decreased sodium and/or potassium levels. Adrenocortical insufficiency. Patients with cognitive impairment who will not be able to give informed consent.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: treatment group<br>patients who met the inclusion criteria will be allocated to the treatment group, and will receive acetazolamide from time of diagnosis until shunt surgery (2-6 weeks). | Drug: Acetazolamide<br>* Patients will be assign and treated by acetazolamide from time of allocation until surgery (2-6 weeks after treatment initiation). The maximal dose of acetazolamide will be the same dose used to treat glaucoma, considering similarity of patients' characteristics, such as age and polypharmacy. We will start at a low dose of 250 mg once a day, and increase it slowly to a maximal dose of 500 mg twice a day. Dose will be individualized according to side-effects and tolerability. Renal and liver function tests will be performed before initiation of treatment, and will be examined again two weeks after treatment had begun.<br>* Other names: Diamox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline Gait | Change from Baseline gait will be evaluated by the neurosurgery department's physiotherapist, using the timed-up-and-go (TUG) test (measured in seconds, higher values represent a worse outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later). | Baseline, week 4 | 
| Change from Baseline Balance | Change from Baseline balance will be evaluated by the neurosurgery department's physiotherapist, using the TINETTI balance assessment score. (0-28 scale, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later). | Baseline, week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline concentration function | concentration function will be evaluated by the neurosurgery department's neuropsychologist using the color trial test (seconds, higher values represent a worse outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later). | Baseline, week 4 | 
| Change from Baseline visuospatial function | visuospatial function will be evaluated by the neurosurgery department's neuropsychologist using the clock drawing test (0-10 scale, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later). | Baseline, week 4 | 
| Change from Baseline verbal fluency | verbal fluency will be evaluated by the neurosurgery department's neuropsychologist using the verbal fluency test (Controlled Oral Word Association Test, number of words in one minute, higher values represent a better outcome). Patients will be evaluated at baseline (before treatment is started) and again before surgery (4 weeks later). | Baseline, week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NPH, Acetazolamide