BACKGROUND:
Multiple prospective nonrandomized studies have shown 60% to 70% of patients with idiopathic normal pressure hydrocephalus (iNPH) improve with shunt surgery, but multicenter placebo-controlled trial data are necessary to determine its effectiveness.
OBJECTIVE:
To evaluate the effectiveness of cerebrospinal fluid shunting in iNPH through comparison of open vs placebo shunting groups at 4 months using a pilot study.
METHODS:
Patients were randomized to a Codman Certas Plus valve (Integra LifeSciences) set at 4 (open shunt group) or 8 (“virtual off”; placebo group). Patients and assessors were blinded to treatment group. The primary outcome measure was 10-m gait velocity. Secondary outcome measures included functional scales for bladder control, activities of daily living, depression, and quality of life. Immediately after 4-month evaluation, all shunts were adjusted in a blinded fashion to an active setting and followed to 12 months after shunting.
RESULTS:
A total of 18 patients were randomized. At the 4-month evaluation, gait velocity increased by 0.28 ± 0.28 m/s in the open shunt group vs 0.04 ± 0.17 m/s in the placebo group. The estimated treatment difference was 0.22 m/s ([P = .071], 95% CI −0.02 to 0.46). Overactive Bladder Short Form symptom bother questionnaire significantly improved in open shunt vs placebo (P = .007). The 4-month treatment delay did not reduce the subsequent response to active shunting, nor did it increase the adverse advents rate at 12 months.
CONCLUSION:
This multicenter, randomized pilot study demonstrates the effectiveness, safety, and feasibility of a placebo-controlled trial in iNPH, and found a trend suggesting gait velocity improves more in the open shunt group than in the placebo group.
KEY WORDS: NPH (normal pressure hydrocephalus), Hydrocephalus, Shunting, RCT, Placebo, VPS (ventriculoperitoneal shunting)
ABBREVIATIONS:
- ADL/IADL
activities of daily living/independent activities of daily living
- BDI-II
Beck Depression Inventory, 2nd edition
- ETV
endoscopic third ventriculostomy
- iNPH
idiopathic normal pressure hydrocephalus
- MoCA
Montreal Cognitive Assessment
- NPH
normal pressure hydrocephalus
- OABq-SF
Overactive Bladder Questionnaire, Short Form
- PENS
Placebo-controlled Effectiveness of iNPH Shunting
- SDMT
symbol digit modalities test.
Idiopathic normal pressure hydrocephalus (iNPH) is a syndrome that presents in the elderly with progressive impairment of gait and balance, cognition, and urinary control. The estimated prevalence of iNPH ranges from 300 000 to 700 000 patients in the United States,1-3 and a 2007 study using the Medicare database found that only 25% of patients older than 65 years with the diagnosis of iNPH received shunt surgery. Although iNPH is considered potentially reversible with ventriculoperitoneal shunting (VPS),4 and multiple studies have suggested that 70% to 80% of patients improve with shunt surgery,5-13 concern exists about variable results, durability of benefit, and surgical risks of shunt surgery in the elderly,14 in part due to a lack of evidence from a placebo-controlled trial.15
Unfortunately, surgical placebo-controlled trials are inherently difficult to perform, often with practical and ethical. In addition, 2 previous small-N single-center placebo-controlled trials did not yield convincing proof of effectiveness.16,17 To demonstrate the feasibility of a large multicenter trial, we designed and performed a pilot blinded, placebo-controlled, delayed treatment study in the Adult Hydrocephalus Clinical Research Network.
METHODS
Study Design
This pilot study was a prospective, blinded, randomized, placebo-controlled trial that used a contemporary adjustable shunt system (Codman Certas Plus with the SiphonGuard antisiphon device [Integra LifeSciences]) approved by the Food and Drug Administration and European Commission. Fifteen to 20 patients were planned based on previous pilots. It includes a “virtual off” setting, which allows for noninvasive and reversible adjustment of the shunt setting to assign patients to an open shunt or a placebo group. Institutional review board (IRB) approval was obtained through Johns Hopkins Medicine as the central IRB for US centers (IRB00083576) with sites in Canada (REB17-0306) and Sweden (Ö4-2016). The study was registered with ClinicalTrials.gov (NCT03350750).
The primary outcome measure was gait velocity change from baseline evaluated at 4 months after surgery. Secondary iNPH-related functional measures such as bladder control and neuropsychological function were also evaluated along with functional outcome scales.
The randomization scheme was generated by the Data Coordination Center using randomized blocks of length 2 and 4. Randomization occurred immediately before surgery. Patients were assigned either to the open shunt group (setting 4 at 110 mm H2O) or the placebo group (setting 8 at >400 mm H2O “virtual off”).
The primary outcome evaluation was at 4 months, after which all shunts in the placebo group were changed to an active setting at 4 months (Figure 1). To preserve blinding, the shunts of patients in the open shunt group were mock-adjusted. All patients were evaluated for 12 months after surgery, resulting in 8 months of active shunting for the placebo group and 12 months of active shunting for the open shunt group.
FIGURE 1.
PENS pilot study design. PENS, Placebo-controlled Effectiveness of iNPH Shunting.
Shunt Valve Setting and Blinding
Both blinded group assignment and noninvasive shunt setting change were possible using the Codman Certas Plus with the SiphonGuard device. The placebo group condition was setting 8, with an opening pressure of 400 to 500 mm H2O, known as “virtual off.” The reliability of the “virtual off” setting had been demonstrated previously.18 The open shunt group condition was setting 4, with an opening pressure of approximately 110 mm H2O.
The valve setting was verified preoperatively and at the time of each visit. The assigned setting was not changed until the 4-month primary outcome assessment as described above, unless indicated by the medical needs of the patient. After 4 months of active shunting, the shunt setting could be changed according to clinical indications.
Patient Population
Identification of patients eligible for shunt surgery at each site used testing consistent with the International Guidelines for iNPH diagnosis.7 All patients were ≥60 years old, had ventriculomegaly (Evans ratio ≥0.3), and had a gait velocity <1 m/s at screening. Clinical response to a trial cerebrospinal fluid (CSF) drainage, either lumbar puncture or extended lumbar drainage, was required to identify shunt surgery candidates and potential study subjects. All patients had capacity to consent based on the established criteria of the institution. Patients with previous cranial or hydrocephalus surgery, active stroke, or tumor, or who required anticoagulation therapy were excluded (Supplemental Digital Content 1, http://links.lww.com/NEU/D447 contains detailed criteria).
Some entry criteria were modified based on the initial experience of the trial. Initially, a Montreal Cognitive Assessment (MoCA) score of >18 was required, but this was eliminated. Similarly, patients with a diagnosis of a movement or psychiatric disorder initially were excluded; however, subsequently, patients with these comorbidities were eligible for the study if the site principal investigator judged that the disorder did not interfere with the patient's ability to respond to CSF drainage or shunt surgery.
Outcome Measures
The primary outcome measure was maximum gait velocity over 3 trials for a 10-m walk. Baseline gait velocity was measured within 6 week before surgery and at 4, 8, and 12 months after surgery. Quality control of this measure was ensured by site training and central gait laboratory review of gait test videos. Secondary outcome measures, including the MoCA,19 Symbol Digit Modalities Test,20 the Overactive Bladder Questionnaire, Short Form,21 Beck Depression Inventory-second edition,22 Lawton Activities of Daily Living/Independent Activities of Daily Living Questionnaire,23 and modified Rankin Score scores,24 were administered at similar intervals. All outcome assessments were performed by trained, blinded evaluators. Adverse events collected included surgical complications, falls, and decreased cognitive function, and were monitored by an independent data and safety monitoring board.
Analysis
All effectiveness outcomes were assessed using an analysis of covariance, where a linear regression model was fit with 4-month gait velocity as the dependent outcome variable and assigned treatment arm as a predictor along with baseline gait velocity. Effectiveness evaluations used two-sided testing with type I error of 0.05. Significance assessment for the 2 prespecified secondary outcomes of effectiveness was controlled for multiple comparisons. The effect of delayed shunting (ie, differences between treatment arms in observed improvement after 4 to 8 months of active shunting) was evaluated using linear mixed models for outcome data over time. Complications were analyzed as binary outcomes.
RESULTS
Patient Recruitment and Study Population
Of 240 patients screened between May, 2018, and March, 2020, 37 (15%) were eligible based on inclusion and exclusion criteria. Of eligible patients, 21/37 (57%) consented and 18 were recruited and participated in the study (Figure 2). The most frequent reasons for exclusion were baseline velocity ≥1 m/s (19%), use of anticoagulation (20%), cognitive impairment (27%), and Parkinson's disease (6%). The primary concern expressed by eligible patients who declined participation in the study was the possibility of a 4-month delay before active shunting.
FIGURE 2.
Screening and recruitment workflow. This diagram describes all patients who were screened and approached to participate. aSome participants had multiple exclusion criteria. ETV, endoscopic third ventriculostomy; iNPH, idiopathic normal pressure hydrocephalus.
Patient Characteristics
Demographics, severity of symptoms, comorbidities, ventricular size, and presence of comorbidities are described in Table 1. There were no significant differences between the placebo and open shunt groups. In addition, the severity of the iNPH condition, measured as baseline function (Supplemental Digital Content 2, http://links.lww.com/NEU/D448) and ventricular size, was similar between the 2 groups.
TABLE 1.
Patient Demographics (Randomized Population)
| Traits and comorbidities | Treatment group | ||
|---|---|---|---|
| Placebo (N = 9) | Open shunt (N = 9) | Overall (N = 18) | |
| Age at randomization, y | 74.5 (70.1, 76.5) | 74.0 (73.3, 77.0) | 74.2 (72.1, 76.6) |
| Female | 4 (44%) | 4 (44%) | 8 (44%) |
| Education: at least high school | 9 (100%) | 7 (78%) | 16 (89%) |
| Evans ratio | 0.37 (0.35, 0.42) | 0.36 (0.34, 0.41) | 0.37 (0.34, 0.42) |
| Comorbidities (any) | 7 (78%) | 4 (44%) | 11 (61%) |
| Diabetes | 7 (78%) | 3 (33%) | 10 (56%) |
| Tumor without metastasis | 1 (11%) | 1 (11%) | 2 (11%) |
| Myocardial infarction | 0 (0%) | 1 (11%) | 1 (6%) |
| Peripheral disease | 0 (0%) | 1 (11%) | 1 (6%) |
| Lymphoma | 0 (0%) | 1 (11%) | 1 (6%) |
Outcomes at the 4-Month Primary End Point
The change in gait velocity and secondary outcome measures at 4 months after shunt surgery in the placebo and open shunt groups compared with presurgical baseline are shown in Table 2 and Figure 3. Mean gait velocity increased by 0.28 m/s (±0.28) in the open shunt group compared with 0.04 m/s (±0.17) in the placebo group. Modeling of treatment effect found a statistical trend (P = .07) of a benefit of active shunting. The change in MoCA score showed no treatment difference. However, the Overactive Bladder Short Form symptom bother questionnaire showed significant improvement in the open shunt group (P = .007; significant at the 0.05 level after accounting for multiple secondary effectiveness outcomes).
TABLE 2.
Comparison of Functional Change in the Placebo and Open Shunt Groups 4 Mo After Shunt Surgery
| Outcome variable | Treatment groupc | |||
|---|---|---|---|---|
| Placebo (N = 9)a,d | Open shunt (N = 9)a,d | Treatment difference (95%CI)b | P-valueb | |
| Gait velocity (m/s) | 0.04 ± 0.167 | 0.28 ± 0.284 | 0.22 (−0.02 to 0.46) | .071 |
| MoCA total score | 1.63 ± 1.598 | −0.13 ± 3.643 | −1.44 (−4.57 to 1.68) | .337 |
| OABq-SF | 2.1 ± 17.81 | −23.3 ± 19.89 | −22.93 (−38.13 to −7.72) | .007 |
| SDMT | −0.1 ± 4.02 | −0.3 ± 6.61 | −0.81 (−6.98 to 5.35) | .780 |
| BDI-II | −6.9 ± 10.82 | −6.1 ± 9.03 | −3.26 (−12.51 to 5.99) | .457 |
| Lawton ADL/IADL | 1.4 ± 3.89 | −5.7 ± 6.73 | −3.98 (−10.39 to 2.42) | .201 |
| mRS | −0.13 ± 0.641 | −0.88 ± 1.126 | −0.70 (−1.76 to 0.35) | .172 |
ADL/IADL, activities of daily living/independent activities of daily living; BDI-II, Beck Depression Inventory, 2nd edition; MoCA, Montreal Cognitive Assessment; mRS, modified Rankin Scale; OABq-SF, Overactive Bladder Questionnaire, Short Form; SDMT, Symbol Digit Modalities Test.
Change from baseline to 4 months after shunt surgery.
The results are based on a linear regression model, controlling for baseline assessment values.
Population includes randomized subjects with measured outcomes at baseline and 4 months after shunt surgery.
Change in gait velocity, MoCA, SDMT, and mRS are missing on 2 patients. Change in BDI-II and the Lawton ADL/IADL are missing on 3 patients. Change in OABq-SF is missing on 4 patients.
FIGURE 3.
Improvement from baseline to 4 months. A, Gait velocity in placebo vs active group. B, Total MoCA score in placebo vs active group. C, OAB-q SF in placebo vs active group. Blue = placebo group; red = open shunt group. Error bars indicate standard deviation. MoCA, Montreal Cognitive Assessment; OAB-q SF, Overactive Bladder Short Form symptom bother questionnaire.
Gait Velocity Change With Duration of Active Shunting
After the 4-month primary endpoint assessments, the shunts in both the placebo and the open shunt groups were at active shunt settings for the remainder of the study. Gait velocity and other outcome measures were followed for an additional 8 months after the primary end point, resulting in 12 months of active shunting in the open shunt group and 8 months of active shunting in the placebo group (Supplemental Digital Content 2, http://links.lww.com/NEU/D448). As expected, gait velocity in the placebo group improved after the shunt was changed to an active setting (Figure 4A). When matched for duration of active shunting (Figure 4B), both the open shunt and the placebo groups had the same change in gait velocity after 8 months. Of note, improvement in gait velocity (compared with immediately before active shunting) was statistically significant (P < .05) within each treatment arm at 4 and 8 months, as well as for the entire randomized cohort.
FIGURE 4.
Group gait velocity measures over time. A, Gait velocity changes in 12 months of follow-up from baseline through 12-month postshunt implantation by treatment group. For improvement analysis, the placebo group's baseline of active shunting was 4-month postsurgery compared with the open shunt group's baseline before surgery. A similar significant improvement is shown between both groups in months of active shunting. Cross symbols refer to comparison with baseline (†P < .05, ††P < .01). B, Gait velocity changes from baseline to 12 months of active shunting, group comparison. Gait velocity improved without a significant group difference (not significant NS). Blue = placebo group; red = open shunt group. Symbol represents the mean; the box shows the middle 50% of observations in each group, with the line being the median observation. The whiskers go out to the observations no more than 1.5 times the width of the box. Any observations outside this range are shown individually as symbols (○ and +).
The effect of the 4-month delay until active shunting associated with the placebo condition was quantified using linear mixed models, as shown in Supplemental Digital Content 3, http://links.lww.com/NEU/D449. Specifically, for change in gait velocity, no effect of the 4-month delay was observed (P = .45).
Adverse Events
Adverse events are summarized in Table 3 and shown in detail in Supplemental Digital Content 4, http://links.lww.com/NEU/D450. The risk of adverse events was no different in the open shunt and placebo groups. There were 2 falls in the placebo group during the 4-month placebo condition, but with no adverse medical outcome. Two patients died during the study. The deaths were unrelated to iNPH or to shunt surgery. The details are provided in Table 3.
TABLE 3.
Adverse Events
| Event type | Open shunt | Placebo group | Total |
|---|---|---|---|
| Adverse NPH-related events | |||
| Falls (requiring medical care) | 0 | 2 | 2 |
| Cognitive decline (by MoCA)a | 6 | 1 | 7 |
| Surgical complications | |||
| Subdural hematomas | 0 | 0 | 0 |
| Subdural hygromas | 1 | 0 | 1 |
| Shunt or incisional Infection | 0 | 0 | 0 |
| Cerebral hemorrhage | 0 | 0 | 0 |
| Unrelated morbidity | |||
| Urosepsis | 1 | 0 | 1 |
| Generalized muscular weakness | 1 | 0 | 1 |
| Coagulopathy | 1 | 0 | 1 |
| Crohn's disease (newly diagnosed) | 0 | 1 | 1 |
| Unrelated mortality | |||
| Contralateral stroke | 0 | 1 | 1 |
| Necrotic gallbladder | 1 | 0 | 1 |
MoCA, Montreal Cognitive Assessment; NPH, normal pressure hydrocephalus.
Cognitive decline was defined as a drop in MoCA score greater than or equal 2 points. Although not necessarily an adverse event, any decrease in MoCA score greater than 2 points was assessed by the site investigator for clinical significance. All drops in MoCA score during the study period were transient.
This table summarizes the adverse events and events of interest reported on the study.
DISCUSSION
The purpose of this pilot study was to demonstrate the feasibility of a randomized, placebo-controlled, multicenter study of the effectiveness of shunt surgery in iNPH. The results of this pilot suggest that the “virtual off” setting of the Codman Certas Plus produces an effective placebo condition that is noninvasively reversed, that the method for blinding patients and examiners from the shunt setting is effective, and that the delayed treatment design carries acceptably low risk of harm to patients in the placebo group.
An important concern in placebo-controlled trials involving delayed treatment is the potential of harm to patients resulting from the delay or from disease progression, leading to less clinical response after the placebo period is ended. Patients in the placebo group were not harmed by the 4-month placebo condition, nor did they have worse outcomes, as the gait velocity change with active shunting in the placebo group was similar to the open shunt group at 4 and 8 months of active shunting. Active shunting improved gait velocity to the same extent in both groups by 4 and 8 months. Although 2 falls occurred in the placebo group during the 4-month delay, neither fall resulted in patient harm. These results demonstrate that harm to patients from the delayed treatment design was minimal. Although delay in diagnosis and treatment has been raised as a potential limiter of shunting effectiveness,25 the findings of this pilot study suggest that the 4-month delay until active shunting in the placebo group did not result in worse clinical outcomes.
Change in gait velocity was chosen as the primary outcome measure because it is widely used to select patients for shunt surgery as a response to CSF drainage, and has recently been confirmed to be a robust outcome measure for iNPH.26 The primary outcome finding was the trend to improved gait velocity by 0.28 m/s in the open shunt group compared with 0.04 m/s in the placebo group at 4 months (P = .07). It is recognized that gait changes in iNPH are not limited to velocity and a more complete evaluation of the effect of shunting on motor deficits will also include evaluation of other factors, especially balance. In addition, bladder control was improved in the open shunt group compared with Placebo. Our results are similar to 2 single-center studies. A University of Gothenburg study (n = 14) showed a 30% improvement in gait performance at 3 months in patients with open shunts vs 0.4% in those with ligated shunts.16 A Queen Square study (n = 14) reported a 43% improvement in gait velocity at 3 months in patients with a shunt opening pressure of 5 cmH2O vs 0% in those with a shunt opening pressure of 20 cmH2O.17 Unlike these studies, the method and measurement in this pilot are designed to facilitate a larger patient recruitment, and uses a noninvasive and a more complete, well-blinded placebo.
Other outcome measures, such as those of cognitive function and general functional scales, did not demonstrate significant change. The cognitive decline commonly found in iNPH is generally recognized to be more variable in degree and response to shunting. Although additional enrollment may allow demonstration of cognitive changes, the cognitive screening tools used in the study may be insufficient. A more complete neuropsychological testing battery will be used in a forthcoming study.
Limitations and Generalizability
Although this trial succeeded in demonstrating the feasibility and possible outcomes of a controlled iNPH trial, this pilot study demonstrated several weaknesses that helped us to design a larger clinical trial now initiated. A key vulnerability in the feasibility of a clinical trial is the potential for low enrollment with low patient diversity. Of the potential trial candidates who were screened before CSF testing, 85% failed criteria, most often being excluded because of poor cognitive function, high initial gait velocity, or concurrent treatment with anticoagulants. After review of these excluding factors, in future enrollment, cognitive decline will be accepted if it does not interfere with standard institutional consent criteria or interfere with ability to cooperate and communicate for the testing. Similarly, other comorbidities will be accepted if they are judged to not interfere with the testing process. Because patients with iNPH with comorbidities are accepted in general practice, their inclusion in the forthcoming larger clinical trial will help optimize enrollment, and patient selection will be more closely aligned with general practice.
A recognized barrier to enrollment in clinical trials is refusal by patients to consent to participate. Although the 57% rate of consent observed in this pilot study is encouraging, the main patient concern identified was the potential of a 4-month treatment delay. After review, the potential treatment delay has now been shortened to 3 months. The study group consensus is that this should not affect the study aims but may allow for increased willingness to participate in the upcoming clinical trial. Finally, changes to the study design for the future, larger multicenter clinical trial will allow recruitment from a larger iNPH patient population that will also include an outreach awareness program to reach caregivers and patients in diverse communities, to facilitate an increase in the diversity of participation.
The results of this small pilot study demonstrate the feasibility of a unique study design and have resulted in key methodological changes in measurement and recruitment that will optimize the success of the larger forthcoming clinical trial. This National Institute of Neurological Disorder supported trial titled “Placebo-controlled Effectiveness of iNPH Shunting Trial” (U01NS122764), with 20 centers in the United States, Canada, England, and Sweden, has been initiated. Importantly, evaluation of CSF content, MR imaging, extended neurocognitive, and other gait features are also included in this new clinical trial to investigate their role in diagnosis and shunt-treatment prognosis.
CONCLUSION
This pilot study of a placebo-controlled trial of iNPH shunt effectiveness shows an encouraging trend demonstrating that gait velocity improves with active shunting but not with a placebo condition shunt. The lack of significant harm to subjects in the placebo group from the four-month delay until initiation of active shunting suggests that the design is safe and acceptable from the perspective of research ethics. Future studies will require more complete neuropsychological evaluation and evaluation of other aspects of gait and balance, as well as inclusion of CSF and neuroimaging biomarkers. Based on this pilot and the lessons learned, a larger randomized placebo-controlled trial is feasible and is underway. It will have the potential to significantly change surgical practice in the elderly with iNPH.
Supplementary Material
Acknowledgments
The authors would like to acknowledge our collaborators. Our PENS co-investigators include Michael Meggyesy, MD1, Sevil Yasar, MD1, Seema Gulyani, MD1, Lars-Owe D. Koskinen, MD, PhD3, William Hansson, MD3, Michelle Cecchini, MD3, Nickolas Dasher, PhD4, Mark Bain, MD5. AHCRN site PIs include Jeffrey Wisoff, MD10, Guy McKhann, II, MD10, Richard Edwards, BSc, MBBS, FRCS10, James Golomb, MD10. We would also like to acknowledge those colleagues and team members at the AHCRN and Data Coordinating Center at University of Utah that contributed to the data and analyses in this paper: SallyJo Zuspan2, Cynthia Jones2, Brie Marron2, Caleb Bracken2, and Hailey Jensen2. We opened and kept the study up and running thanks to our staff at the clinical coordinating center at Johns Hopkins: Jessica Wollett1, Lynn Smith1, Cindy Haynes1, Jackie Darrow6, Kallan Dirmeyer1, and Tracey Economas6. At our clinical centers we thank the team members that worked tirelessly to enroll and assess our participants: Cristina Ritter, RN1, Jennell Hedges, RN1, Lacie Manthripragada, RN1, Jenny Larsson3, Kristin Nyman3, Elisa McGee4, Amy Anderson4, Agazit Tecle5, Erica Hennigs5, Mandi Koepsel5, Marcia Leon Rabana5, and Karim Kheniser5, Jarred Dronyk9, and Geberth Urbaneja9.
Footnotes
Supplemental digital content is available for this article at neurosurgery-online.com.
Contributor Information
Richard Holubkov, Email: richard.holubkov@hsc.utah.edu.
Michael A. Williams, Email: maw99@neurosurgery.washington.edu.
Jan Malm, Email: jan.malm@umu.se.
Sean Nagel, Email: nagels@ccf.org.
Abhay Moghekar, Email: am@jhmi.edu.
Anders Eklund, Email: anders.eklund@umu.se.
Thomas Zwimpfer, Email: thomas.zwimpfer@ubc.ca.
Heather Katzen, Email: hkatzen@med.miami.edu.
Daniel F. Hanley, Email: dhanley@jhmi.edu.
Mark G. Hamilton, Email: mghamilton.hydro@gmail.com.
Collaborators: Michael Meggyesy, Sevil Yasar, Seema Gulyani, Lars-Owe D. Koskinen, William Hansson, Michelle Cecchini, Nickolas Dasher, Mark Bain, Jeffrey Wisoff, Guy McKhann, II, Richard Edwards, James Golomb, SallyJo Zuspan, Cynthia Jones, Brie Marron, Caleb Bracken, Hailey Jensen, Jessica Wollett, Lynn Smith, Cindy Haynes, Jackie Darrow, Kallan Dirmeyer, Tracey Economas, Cristina Ritter, Jennell Hedges, Lacie Manthripragada, Jenny Larsson, Kristin Nyman, Elisa McGee, Amy Anderson, Agazit Tecle, Erica Hennigs, Mandi Koepsel, Marcia Leon Rabana, Karim Kheniser, Jarred Dronyk, and Geberth Urbaneja
Funding
This study was supported by Integra LifeSciences, without control of study design, data collection, analysis, or publication. Other support and consultation were provided by the Hydrocephalus Association through the Adult Hydrocephalus Clinical Research Network, the National Center for Advancing Translational Sciences (Grant U24TR001609 in support of the Johns Hopkins‐Tufts Trial Innovation Center) for consultation on recruitment, and the National Institutes of Aging (U19-AG033655) for initial protocol review. Neurosurgery administrative support was also provided to the Johns Hopkins Neurosurgery CSF Disorders Center through George Berry and William Lickle.
Disclosures
Dr Holubkov is on the Data Safety Monitoring Board Service for Pfizer Inc. Dr Moghekar is a nonpaid member of the Medical Advisory Board at the nonprofit Hydrocephalus Association. Dr Hamilton has been paid by Integra Canada and Integra International for general educational lectures at professional meetings not related to the contents of this paper, and receives a one-time consultant fee under $2000 from CereVasc, Inc, for whom he is a current member of the DSMB.
Supplemental Digital Content
Supplemental Digital Content 1. Table. Inclusion and Exclusion Criteria. iNPH = idiopathic normal pressure hydrocephalus; CSF = cerebrospinal fluid; NPH = normal pressure hydrocephalus.
Supplemental Digital Content 2. Table. Baseline and Follow-up Functional Testing. This table shows the raw data of the functional outcomes of the study. In the baseline data there is no difference between the 2 groups. 1The assessment that occurs closest to the lumbar puncture is used as baseline. If the shunt surgery is scheduled more than 6 weeks after the pre-LP assessment, further assessments were performed within 6 weeks of shunt surgery, but not within 2 weeks post-LP. Continuous variables are summarized as N/Mean (SD)/Median [Q1, Q3]/(Min - Max).
Supplemental Digital Content 3. Table. Functional Changes in Open and Closed (Delayed) Groups After Extended Active Shunting. Analysis of the Possible Effect of Delay. 1Patients with the assigned treatment of closed shunt had their shunt activated at 4 months post-op. 2For the open shunt group, this change reflects the change between baseline and 4-month post-op data. For the closed shunt group, this change reflects the change between 4-month post-op (baseline) and 8-month post-op data. 3For the open shunt group, this change reflects the change between baseline and 8-month post-op data. For the closed shunt group this change reflects the change between 4-month post-op (baseline) and 12-month post-op data. 4Results are based on a linear mixed model, controlling for baseline. Continuous variables are summarized as N/Mean (SD)/Median [Q1, Q3]. *P < .05, **P < .01, ***P < .001 for a 1 sample t-test of the hypothesis that this change is significantly different from 0. Small numbers limit interpretation.
Supplemental Digital Content 4. Table. Adverse Events Complete Listing. This is a full detailing of the adverse events. Of note, there were no adverse events that were specifically related to the study itself. Multiple events within a patient are presented in temporal order. MoCA, Montreal Cognitive Assessment; UTI, urinary tract infection.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental Digital Content 1. Table. Inclusion and Exclusion Criteria. iNPH = idiopathic normal pressure hydrocephalus; CSF = cerebrospinal fluid; NPH = normal pressure hydrocephalus.
Supplemental Digital Content 2. Table. Baseline and Follow-up Functional Testing. This table shows the raw data of the functional outcomes of the study. In the baseline data there is no difference between the 2 groups. 1The assessment that occurs closest to the lumbar puncture is used as baseline. If the shunt surgery is scheduled more than 6 weeks after the pre-LP assessment, further assessments were performed within 6 weeks of shunt surgery, but not within 2 weeks post-LP. Continuous variables are summarized as N/Mean (SD)/Median [Q1, Q3]/(Min - Max).
Supplemental Digital Content 3. Table. Functional Changes in Open and Closed (Delayed) Groups After Extended Active Shunting. Analysis of the Possible Effect of Delay. 1Patients with the assigned treatment of closed shunt had their shunt activated at 4 months post-op. 2For the open shunt group, this change reflects the change between baseline and 4-month post-op data. For the closed shunt group, this change reflects the change between 4-month post-op (baseline) and 8-month post-op data. 3For the open shunt group, this change reflects the change between baseline and 8-month post-op data. For the closed shunt group this change reflects the change between 4-month post-op (baseline) and 12-month post-op data. 4Results are based on a linear mixed model, controlling for baseline. Continuous variables are summarized as N/Mean (SD)/Median [Q1, Q3]. *P < .05, **P < .01, ***P < .001 for a 1 sample t-test of the hypothesis that this change is significantly different from 0. Small numbers limit interpretation.
Supplemental Digital Content 4. Table. Adverse Events Complete Listing. This is a full detailing of the adverse events. Of note, there were no adverse events that were specifically related to the study itself. Multiple events within a patient are presented in temporal order. MoCA, Montreal Cognitive Assessment; UTI, urinary tract infection.