Methods: This is a prospective research protocol involving human patients. Eligibility criteria include (1) adults ages 18-75 years, (2) clinically indicated need for continuous ICP monitoring for the diagnosis of hydrocephalus, idiopathic intracranial hypertension (IIH), or shunt malfunction, or (3) clinically indicated need for cerebral spinal fluid (CSF)-infusion testing for the diagnosis of hydrocephalus or IIH. Invasive ICP methods include (1) spinal catheter insertion and fluid-coupled external transducers for patients with hydrocephalus, IIH, and (2) CSF-infusion testing, which will use a standardized automated system, Likvor Celda System ( http://www.likvor.com ) that has been validated in clinical use in Sweden. Noninvasive ICP methods include the TMD method and DPOAE.

Key Findings: In subjects evaluated during CSF infusion testing, as ICP increases, systematic and significant changes in the DPOAE measurements are seen. In particular, for frequencies from 800 to 1700 Hz the DPOAE angle shows significant increases when ICP is ~12 mm Hg above baseline. Statistical analysis of TMD results during infusion testing suggest a relationship between Vm and ICP; however, the subject population had impaired hearing which places the reliability of some measurements into question. Specifically, if the subject's acoustic reflex threshold is too high, then the acoustic stimulus required for the TMD will not be strong enough (in dB) to elicit a consistent tympanic membrane reflex. Re-analysis with subjects sorted according to acoustic reflex threshold is in progress.

Impact: The DPOAE results confirm that changes in DPOAE angle and magnitude seen with change in ICP are physiologically based, and suggest that it should be possible to detect pathological ICP elevation using noninvasive DPOAE measurements. The TMD results may be promising, and in general are consistent with the studies performed by other groups; however, further subgroup analysis is required. Neither the DPOAE nor the TMD method is capable of providing a numeric estimate of ICP, but should be capable of showing relatively large changes in ICP. Furthermore, both methods require sampling over a period of 60 to ~120 seconds, and thus, at best, provide an estimate of the mean ICP during the sampling period, but do not provide information about the variability of ICP during the sampling period, which is a notable shortcoming because the same mean ICP can be seen in subjects with either normal or abnormal intracranial compliance. Additionally, neither method is suitable for noninvasive ICP monitoring during sleep, which is when pathologic ICP waveforms are most likely to appear in subjects with disorders of ICP. Should TMD or DPOAE not reveal significant changes in ICP during awake measurements on astronauts on the International Space Station (ISS), it will not be possible to conclude that ICP is normal on the ISS. Such a conclusion can be reached with continuous ICP monitoring during sleep using a method that is capable of sampling fast enough to permit analysis of beat-to-beat variability in ICP, which is necessary to provide a reliable estimation of whether intracranial compliance is normal or abnormal.

Methods: This is a prospective research protocol involving human patients. Eligibility criteria include (1) adults ages 18-75 years, (2) clinically indicated need for continuous ICP monitoring for the diagnosis of hydrocephalus, IIH, or shunt malfunction, or (3) clinically indicated need for CSF-infusion testing for the diagnosis of hydrocephalus or IIH. Invasive ICP methods include (1) spinal catheter insertion and fluid-coupled external transducers for patients with hydrocephalus, IIH, (2) insertion of a 25-gauge needle into the shunt reservoir and fluid-coupled external transducers for patients with shunt malfunction, and (3) CSF-infusion testing, which will use a standardized automated system, Likvor Celda System ( http://www.likvor.com ) that has been validated in clinical use in Sweden. Noninvasive ICP methods include TMD method and DPOAE.

Key Findings: To date, 15 subjects have been evaluated during CSF infusion testing in Umea, Sweden. Statistical analysis of both DPOAE and TMD results in relation to invasive ICP is in progress. Visual analysis of the raw data suggests that a linear relationship between invasive ICP and the noninvasive ICP methods may exist, but significant inter-individual variation exists. No conclusions should be reached regarding the accuracy or precision of the noninvasive ICP methods until the statistical analysis is complete.

Impact: If, after statistical analysis is completed, a linear relationship between either DPOAE or TMD and invasive ICP is demonstrated, then either method may have the potential to detect change in ICP noninvasively.

Proposed Research Plan for Year 3: The team in Baltimore plans to recruit 5 or 6 subjects in Year 3 for recording of spontaneous ICP to determine whether DPOAE and TMD can detect naturally-occurring ICP changes in sleep and wakefulness in patients with disorders of CSF pressure. The entire research team will complete the statistical analysis of the DPOAE and TMD data and submit the resulting manuscripts for peer-reviewed publication.

The investigators encountered hardware/software incompatibility with the Marchbanks TMD device in the first week that resulted in incomplete data collection on some subjects. With input from Rob Marchbanks and the engineering team in Umea, we resolved the incompatibility by the beginning of the second week, and data collection for TMD and DPOAE methods proceeded. The nature of this incompatibility and its "fix" were shared with other NSBRI and NASA investigators using the same device. The TMD instrument was returned to the UK for repairs and upgrades, and then sent back to the PI. The PI returned to Umea and enrolled an additional 7 subjects between March 17 and March 28, 2014. Data analysis was begun in May 2014 and another software incompatibility with the Marchbanks device was discovered, rendering the machine unable to display on the video monitor except in "Safe Mode", which could not be used to run the instrument. Eventually the Marchbanks team sent a software fix, which, again, was shared with other NSBRI and NASA investigators using the same device. Processing of the TMD and DPOAE data from the Swedish subjects was completed before the ICP data was unblinded. The research team is presently running statistical analysis on both the TMD and DPOAE data sets. Working drafts of 2 manuscripts have been started.

In Year 3, the team in Baltimore plans to recruit 5 or 6 subjects in Year 3 for recording of spontaneous ICP to determine whether DPOAE and TMD can detect naturally-occurring ICP changes in sleep and wakefulness in patients with disorders of CSF pressure.

Primary Objective: Determine the validity, reliability, accuracy, and precision of two noninvasive methods of ICP measurement (tympanic membrane displacement [TMD, Marchbanks Measurements Systems, UK] and distortion product otoacoustic emissions [DPOAE]) in comparison to a reference standard, invasive ICP measurement, in human subjects undergoing diagnostic ICP monitoring.

Methods: This is a prospective research protocol involving human patients. Eligibility criteria include (1) adults ages 18-65 years, (2) clinically indicated need for continuous ICP monitoring for the diagnosis of hydrocephalus, IIH, or shunt malfunction, or (3) clinically indicated need for CSF-infusion testing for the diagnosis of hydrocephalus or IIH. Invasive ICP methods include (1) spinal catheter insertion and fluid-coupled external transducers for patients with hydrocephalus, IIH, (2) insertion of a 25-gauge needle into the shunt reservoir and fluid-coupled external transducers for patients with shunt malfunction, and (3) CSF-infusion testing, which will use a standardized automated system, Likvor Celda System ( http://www.likvor.com ) that has been validated in clinical use in Sweden.

Noninvasive ICP methods include TMD method and DPOAE.

Protocols: (1) Continuous ICP Monitoring. Simultaneous measurement of invasive and noninvasive ICP will be made in the following conditions: (a) Awake in the supine, sitting, standing, and 6-degree head-down position, (b) Asleep in the patient's preferred position, which will be either supine or with slight elevation of the head of the bed. Data will be analyzed in intervals that correspond to the shortest amount of time necessary for each noninvasive method to provide reliable data. (2) CSF-Infusion Testing. CSF-infusion testing will use the continuous-pressure method, in which ICP is regulated to 6 predetermined pressure levels in steps of 3 mmHg. Noninvasive ICP will be measured at each pressure level, allowing controlled, identical pressure range for evaluation in each patient.

Significance: This proposal specifically addresses NASA's High Priority Research Area in Visual Impairment and Intracranial Pressure. The validation of noninvasive ICP methods is of utmost importance for the goal of measuring ICP in spaceflight, which is essential for the health and safety of astronauts in long-duration spaceflight. The noninvasive methods must be shown to be accurate over the pressure ranges expected in normal individuals (0-15 mmHg) and in those with an IIH-like presentation post-flight (15-40 mmHg). Without validation in the physiologic range expected in normal individuals and those with intracranial hypertension, noninvasive ICP measurement methods cannot be selected for advancement through Technology Readiness Levels to be designed for use in an exploration mission (TRL-6).

Equipment Acquisition: We obtained 1) Grason-Stadler GSI 39 Auto Tymp tympanometer, 2) Mimosa Acoustics HearID Auditory Diagnostic System to measure DPOAE, and 3) Marchbanks MMS-12 TMD Cerebral and Cochlear Fluid Pressure Analyzer, which was not received until June 11, 2013. Per discussions with NSBRI, we have purchased a second Marchbanks MMS-12 headset and a second ER10 probe for the Mimosa System for backup purposes.

IRB Application, Finalization of Protocols, and Creation of Case Report Forms: We obtained IRB determination of nonsignificant risk status for the Marchbanks MMS-12, and IRB approval for the Continuous ICP Monitoring Subprotocol. A protocol to test the noninvasive devices on healthy human subjects is pending IRB approval. All protocols have been finalized and all case report forms have been created and are being edited. The continuous ICP monitoring subprotocol was registered (NCT01863381) on the ClinicalTrials.gov ( http://clinicaltrials.gov/ ) website, and a notice was placed on our website. We are planning to place notices on the Hydrocephalus Association and the Intracranial Hypertension Research Foundation websites.

Subject Recruitment: Because of delays in equipment acquisition, and the addition of a protocol to test the noninvasive devices on healthy human subjects, subject recruitment, which was expected to begin at Month 9, has not begun as of the time of this report.

Investigator Training: Investigators met in Baltimore on June 17, 2013 to train in the use of TMD and DPOAE, which included a site visit by Robert Marchbanks. Training in Likvor Celda CSF infusion testing is scheduled for September 17-21, 2013 at the University of Umeå Hospital.

IDE Application to the FDA for the Likvor CELDA: The application process has taken longer than anticipated. A 1470 page IDE application was submitted and after a teleconference with FDA staff, an amended IDE was submitted. We received a Decision Letter on July 22, 2013 indicating disapproval of the application pending response to numerous technical concerns. After extensive discussion with Likvor, we concluded that we cannot address the FDA's concerns within the time frame of the grant. With NSBRI input, we have revised our plan so that the PI will travel to Umea, Sweden to perform the TMD and DPOAE noninvasive ICP on subjects who are undergoing the CELDA infusion for clinical purposes.

Primary Objective: Determine the validity, reliability, accuracy, and precision of two noninvasive methods of ICP measurement (tympanic membrane displacement [TMD, Marchbanks Measurements Systems, UK] and distortion product otoacoustic emissions [DPOAE]) in comparison to a reference standard, invasive ICP measurement, in human subjects undergoing diagnostic ICP monitoring.

Methods: This is a prospective research protocol involving human patients. Eligibility criteria include (1) adults ages 18–65 years, (2) clinically indicated need for continuous ICP monitoring for the diagnosis of hydrocephalus, IIH, or shunt malfunction, or (3) clinically indicated need for CSF-infusion testing for the diagnosis of hydrocephalus or IIH.

Invasive ICP methods include (1) spinal catheter insertion and fluid-coupled external transducers for patients with hydrocephalus, IIH, (2) insertion of a 25-gauge needle into the shunt reservoir and fluid-coupled external transducers for patients with shunt malfunction, and (3) CSF-infusion testing, which will use a standardized automated system, Likvor Celda® System ( http://www.likvor.com ) that has been validated in clinical use in Sweden.

Noninvasive ICP methods include TMD method and DPOAE.

Protocols: (1) Continuous ICP Monitoring. Simultaneous measurement of invasive and noninvasive ICP will be made in the following conditions: (a) Awake in the supine, sitting, standing, and 6-degree head-down position, (b) Asleep in the patient’s preferred position, which will be either supine or with slight elevation of the head of the bed. Data will be analyzed in intervals that correspond to the shortest amount of time necessary for each noninvasive method to provide reliable data. (2) CSF-Infusion Testing. CSF-infusion testing will use the continuous-pressure method, in which ICP is regulated to 6 predetermined pressure levels in steps of 3 mmHg. Noninvasive ICP will be measured at each pressure level, allowing controlled, identical pressure range for evaluation in each patient.

Significance: This proposal specifically addresses NASA’s High Priority Research Area in Visual Impairment and Intracranial Pressure. The validation of noninvasive ICP methods is of utmost importance for the goal of measuring ICP in spaceflight, which is essential for the health and safety of astronauts in long-duration spaceflight. The noninvasive methods must be shown to be accurate over the pressure ranges expected in normal individuals (0–15 mmHg) and in those with an IIH-like presentation post-flight (15–40 mmHg). Without validation in the physiologic range expected in normal individuals and those with intracranial hypertension, noninvasive ICP measurement methods cannot be selected for advancement through Technology Readiness Levels to be designed for use in an exploration mission (TRL-6).