24-Hour IOP Telemetry in the Nonhuman Primate: Implant System Performance and Initial Characterization of IOP at Multiple Timescales

Abstract

Purpose.: IOP is the most common independent risk factor for development and progression of glaucoma, but very little is known about IOP dynamics. Continuous IOP telemetry was used in three nonhuman primates to characterize IOP dynamics at multiple time scales for multiple 24-hour periods.

Methods.: An existing implantable telemetric pressure transducer system was adapted to monitoring anterior chamber IOP. The system records 500 IOP, ECG, and body temperature measurements per second and compensates for barometric pressure in real time. The continuous IOP signal was digitally filtered for noise and dropout and reported using time-window averaging for 19, 18, and 4 24-hour periods in three animals, respectively. Those data were analyzed for a nycthemeral pattern within each animal.

Results.: Ten-minute time-window averaging for multiple 24-hour periods showed that IOP fluctuated from 7 to 14 mm Hg during the day, and those changes occurred frequently and quickly. Two-hour time-window averages of IOP for multiple 24-hour periods in three animals showed a weak nycthemeral trend, but IOP was not repeatable from day-to-day within animals.

Conclusions.: The measured IOP was successfully measured continuously by using a new, fully implantable IOP telemetry system. IOP fluctuates as much as 10 mm Hg from day to day and hour to hour in unrestrained nonhuman primates, which indicates that snapshot IOP measurements may be inadequate to capture the true dynamic character of IOP. The distributions, magnitudes, and patterns of IOP are not reproducible from day to day within animals, but IOP tends to be slightly higher at night when IOP data are averaged across multiple 24-hour periods within animals.

IOP and patient age are the most frequently identified independent risk factors for development and progression of glaucoma in the major prospective clinical trials. ^{1 –5} Lowering IOP is the only clinical treatment that has been shown to retard the onset and progression of glaucoma, but once damaged, the optic nerve head (ONH) is thought to be more susceptible to further glaucomatous progression, even after intervention has lowered IOP to epidemiologically determined normal levels. ^6,7 In addition to data from prospective trials in glaucoma and ocular hypertension, every population-based survey conducted to date has demonstrated a strong relationship between the prevalence of glaucoma and advancing age, ⁸ even though most studies show little or no change in IOP with age, ^{9 –13} except in black patients. ^14,15 Furthermore, normal-tension glaucoma is frequently seen in elderly individuals, ^16,17 but is not seen in children or young adults other than in a few isolated cases. ¹⁸  

We have previously interpreted these findings to mean that the aging ONH becomes increasingly vulnerable to glaucomatous injury at similar levels of mean IOP and that IOP and aging are truly independent risk factors for glaucoma. Although there is evidence that the aged eye is more susceptible to damage at all levels of mean IOP, ¹⁹ unmeasured components of IOP may also be playing a role. High-frequency IOP fluctuations become larger as IOP increases, presumably driven by stretching and stiffening of the ocular coats, which reduces elastic damping. In addition, we and others have shown that the ocular coats stiffen with age in monkeys and humans ^{20 –22} and stiffen after exposure to chronically elevated IOP in a monkey model of glaucoma. ^23,24 From these data we could conclude that IOP fluctuations will be larger in both elderly and glaucomatous eyes in which the ocular coats have stiffened due to age-related changes and/or IOP-induced remodelling. We therefore hypothesize that there are unknown age- and disease-related components of IOP (such as greater IOP fluctuation) that independently contribute to the onset and progression of glaucoma in those at-risk populations. 

Very little is known about IOP dynamics, as IOP is typically measured clinically with a snapshot method (Goldmann), which is repeated every 3 to 12 months during clinic hours. IOP fluctuation has been calculated in some studies as the intervisit variation in IOP (monthly) or as diurnal or 24-hour curves (hourly). In the intervisit IOP studies, the evidence for long-term IOP fluctuation as a risk factor for visual field progression in glaucoma is inconclusive. ^{7,25 –27} Diurnal/nycthemeral IOP fluctuations with more frequent measurements (hourly) have been considered a risk factor for progression, but again, results are inconclusive. ^{28 –30} The most recent evidence suggests that while a nycthemeral IOP rhythm is present in humans, the IOP curves are not reproducible within individuals. ^31,32  

The Pascal dynamic contour tonometer is capable of measuring IOP continuously for short periods in humans, ^33,34 but it relies on corneal contact and requires the patient to remain still and avoid eye movements and blinks, both of which are major sources of IOP fluctuation. ³⁵ Some studies have shown that IOP is much more dynamic than can be measured by a snapshot device. ^35,36 A recent study of a new contact lens–based IOP telemetry system has shown promising results in patients and shows that IOP is very dynamic. ³⁷ The contact lens–based IOP telemetry systems for humans measure the relative change in IOP in arbitrary units, which cannot easily be translated to absolute IOPs. Several studies have reported the results of IOP telemetry in rabbits ^{38 –40} and rodents, ⁴¹ but the devices used therein (DSI, St. Paul, MN) cannot be used for long-term studies because of their short service life. Also, although the pressure telemetry systems used in these studies (DSI) are appropriate for rabbit and rodent work, they are not suitable for use in nonhuman primates because of their very short signal transmission range (≤18 in.) and the fact that the transducer cannot be located on or near the monitored eye, a design that lends itself to hydrostatic pressure errors with head tilt. 

To begin investigating IOP dynamics and their relationship to glaucomatous onset and progression in the primate, we developed a fully implantable telemetry system that allows continuous wireless monitoring of IOP measured in the anterior chamber, ECG, and body temperature, with measurements obtained 500 times per second, 24 h/d, 7 d/wk, for up to 9 months. The purpose of the present study is to report the initial performance specifications of this system and to characterize the dynamics of IOP over multiple time scales for multiple 24-hour periods in three normal nonhuman primates. 

Materials and Methods

Animals

All animals were treated in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research under a protocol approved and monitored by our Institutional Animal Care and Use Committee. Three young adult female rhesus macaques, 4 to 7 years old, weighing 5.5 to 7.5 kg and having no ocular abnormality or previous ocular surgery, were used for the study. After implantation, the animals were kept on a 7 AM-to-7 PM light–dark cycle and fed at approximately 8 AM and 5 PM daily. Water was provided via continuous feed and was always available. Food and water intake were not measured. 

The Telemetric IOP Monitoring System

The current version of the IOP telemetry implant is based on an existing, commercially available, battery-powered, implantable pressure monitor of proven design ⁴² (T30F-13B; Konigsberg Instruments, Pasadena, CA). To enable IOP telemetry, a standard P4 pressure transducer (Konigsberg Instruments) was integrated into a custom-designed silicone baseplate that is secured into the orbital wall with bone screws and connected to the anterior chamber via a 35-mm-long, 23-gauge silicone aqueous transduction tube (Fig. 1). 

Figure 1.

 

(A) A typical T30F total implant system (Konigsberg Instruments, Pasadena, CA) showing the battery/transmitter module, radio frequency (RF) ring antenna for on/off, transmission antenna, a pressure transducer, and two ECG electrodes plus ground. (B) The extraorbital surface of the custom IOP transducer housing, which was secured within a 1/4-in. hole in the lateral orbital wall with bone screws, as shown in (C). A 23-gauge silicone tube delivered aqueous from the anterior chamber to a fluid reservoir on the intraorbital side of the transducer (partially hidden from view in B); The tube (with appropriate slack to allow for eye movement) was trimmed, inserted into the anterior chamber, sutured to the sclera using the integral scleral tube anchor plate, and covered with a scleral patch graft (not shown).

The P4-based IOP transducer consists of a thin, deformable, 4.0-mm-diameter titanium membrane, hermetically laser-welded into a titanium housing. When the titanium membrane is placed in contact with a fluid, it deforms with the fluctuations in pressure of that fluid. Strain gauges on the back of the transducer membrane register these deformations, and the resulting electrical responses of the gauges are fed to the transmitter electronics package via silicone-encased, helically wound, braided, stainless steel lead wires. The implant's transmitter electronics package transmits a multiplexed analog signal to an antenna up to 3 m away that is connected to a signal processor (TD-14 Basestation; RMISS, Wilmington, DE). The processor digitally samples the IOP, ECG, and body temperature measurements 500 times per second and adjusts for barometric pressure in real time by subtracting the ambient air pressure from the IOP signal (Fig. 2). As the eye and the transducer housing are closed pressure vessels, this adjustment ensures that the recorded values represent the true pressures in the eye, over and above the ambient atmospheric pressure. Once decoded and corrected for ambient air pressure, the IOP data are streamed to a dual-redundant industrial data-acquisition system (CA Recorder; DISS, Dexter, MI) that stores the data and allows for visualization and initial processing (Fig. 2). The IOP data are then sent to the Ocular Biomechanics Laboratory server for upload and further in-house custom postprocessing. 

Figure 2.

 

The IOP telemetry system.

Surgical Implantation of the IOP Telemetry Implant System

Each monkey received preprocedural IM analgesics (2.2 mg/kg ketoprofen) for 24 hours before surgery, to alleviate pain during the procedure. On the morning of the surgery, under ketamine/xylazine anesthesia, each animal was shaved and intubated, given IM antibiotics (5 mg/kg Baytril; Bayer Animal Health, Bayer, AG, Leverkusen, Germany), and transferred to a sterile surgical suite where isoflurane anesthesia and fentanyl continuous drip analgesia were initiated. The animal was ventilated, and blood pressure and oxygen saturation were monitored throughout the procedure. The abdomen, head, and skin overlying the SC course of wires (between the abdomen and orbit) was prepped and draped in a sterile fashion. 

Because the transducer can be damaged by intraoperative cautery, the procedure was staged as follows. First, with bipolar cautery used to maintain hemostasis, the lateral orbital wall was isolated and a ¼-in.-diameter hole was drilled through the bone with a sterile flex-shaft drill. The animal was then repositioned on its back beneath an operating microscope, allowing the eye and lateral orbital wall to be prepped and draped. A 6-0 Vicryl traction suture was passed through the superotemporal peripheral cornea, and the eye was rotated until the superotemporal quadrant was centered in the operative field. Lidocaine and epinephrine were injected beneath Tenon's fascia 8 mm posterior to the limbus. An 8-mm incision was made through the conjunctiva and Tenon's to bare sclera, followed by dissection of these layers to the limbus. A small, curved hemostat was passed into the wound posteriorly until the hole in the lateral orbital wall was reached and the orbital fascia gently protruded. An assistant carefully cut through the orbital tissues until a 4-0 nylon suture could be placed into the working end of the hemostat, after which the hemostat was withdrawn through the conjunctival incision, leaving the suture to mark the future passage of the 23-gauge aqueous tube of the transducer. All cautery was then removed from the surgical field. 

The transceiver module was then inserted through a 5 cm abdominal wall incision into a pocket between the peritoneum and abdominal wall muscles created by blunt dissection. The ECG leads were routed via SC blunt dissection to their appropriate locations on the chest wall and sutured in place. The ocular transducer baseplate (placed in a protective bonnet to avoid contamination and damage) and attached leadwire were threaded SC via blunt dissected tunnels from the abdomen to the back, up the posterior torso and neck, and over the ear to the temple in a serpentine pattern that provides sufficient slack to accommodate subsequent animal movement. Multiple incisions through the skin were opened and closed to pass the transducer. 

With the animal on its back, the ocular end of the 4-0 nylon suture was again grasped by the hemostat and used to gently pull the hemostat tips through the orbital wall hole. Then, the scleral anchor plate on the anterior chamber end of the aqueous transduction tube (Fig. 1B) was grasped between the hemostat tips gently pulled back through the hole into the sub-Tenon's space between the superior and lateral rectus muscles. A loose loop of redundant tube located between the transducer housing and the scleral anchor plate was pushed back into the orbit to accommodate subsequent eye movement (Figs. 1C, 2). 

The transducer aqueous reservoir was then placed into the orbital bone window, and the transducer baseplate was secured to the orbital wall with three size 000 × 3/32-in. stainless steel bone screws (Fig. 1C). The aqueous transduction tube was then trimmed and inserted through the sclera into the anterior chamber, just superior and parallel to the iris via a 23-gauge needle hole, with care taken to position the tube as close to the iris surface as possible. The aqueous transduction tube was sutured to the sclera with two 8-0 nylon sutures secured through the tube's integrated scleral anchor plate, plus an additional butterfly mattress suture. The tube and its fixation plate were then covered with transgraft human donor sclera. The conjunctiva and Tenon's fascia were closed in a single layer with a running locked 8-0 Vicryl suture. A sub-Tenon's injection of dexamethasone, gentamicin, and cefazolin was given in the inferior fornix. The muscles and fascia around the orbital entrance site were closed with deep and superficial 3-0 Prolene sutures, and the skin was closed SC with buried 5-0 Vicryl sutures. All wounds were coated with antibiotic ointment. Each animal was monitored until it regained a swallow reflex, and then it was extubated and taken back to its cage for recovery. 

Each animal received IM antibiotics (5 mg/kg Baytril; Bayer Animal Health) once daily and postoperative IM pain medications (0.02 mg/kg buprenorphine) twice daily for a minimum of 5 days and was examined in its cage each postoperative day for 1 week. Examination at the slit lamp and the first calibration test were performed at postoperative days 5 to 7, depending on how each animal recovered from anesthesia and surgery. Slit lamp examinations occurred approximately every 2 weeks thereafter (at each IOP transducer calibration test; see below) for the remainder of the study. 

IOP Transducer Calibration

Approximately every 2 weeks, each animal was placed under isoflurane anesthesia, and the implanted eye was cannulated with a 27-gauge needle placed through the cornea into the anterior chamber. The needle was connected to a bottle of sterile isotonic saline solution via a sterile infusion set, and the connecting tube was fitted with an in-line, digital pressure gauge (XPi; Crystal Engineering, San Luis Obispo, CA). The manometer bottle was lowered to a level such that the in-line pressure gauge read 5 mm Hg and was allowed to stabilize. The telemetric IOP reading from the implanted transducer was then recorded for comparison. The manometer-controlled IOP was raised in increments of 5 mm Hg up to 45 mm Hg, and the telemetric IOP reading was compared to that from the digital in-line pressure gauge at each step. The telemetric and gauge IOP values were recorded and compared, to quantify IOP transducer signal accuracy and drift. The calibration file was updated on the signal processor (TD-14 Basestation; RMISS) after each IOP calibration check, such that the transducer IOP read accurately in the system. 

IOP Data Acquisition

All analog IOP data were decoded, adjusted for ambient barometric pressure in real-time, digitally sampled at 500 Hz, and stored on the data-acquisition system computers (CA Recorder; DISS). The system is limited to recording a maximum of 99 hours of data in each session, but it is recommended that only 24-hour increments be collected to minimize the possibility of write-to-disc errors. Hence, data were recorded in 24-hour blocks starting at 9 AM, several days per week, generally every other week. This schedule was maintained as closely as possible, but was periodically interrupted for IOP transducer calibration tests and ocular examinations, where the anesthesia and/or anterior chamber cannulation disrupted normal IOP. Data collection was avoided for at least 24 hours after these events, to allow IOP to recover to baseline levels. Hence, while the system is capable of recording IOP continuously, we captured data in 24-hour blocks approximately 6 days per month. 

Digital Filtering and Noise Elimination

After collection and real-time barometric pressure compensation, the IOP signal was extracted from the file and adjusted according to the data from the IOP calibration tests. The IOP signal was assumed to have drifted linearly between transducer calibration tests, and the data from each acquisition session were continually offset by the drift calculated for that period. For example, if the IOP data were acquired at day 7 of the 14-day period that ended in a transducer calibration test indicating that the IOP transducer signal had drifted +2 mm Hg away from reference in 14 days, then from 0.86 to 1.0 mm Hg was subtracted from the signal for that day (i.e., a 2-mm Hg drift over 14 days equals a 0.14-mm Hg drift per day, equating to an 0.86-mm Hg drift at the start of day 7 and a 1.0-mm Hg at the end). 

The continuous IOP signal is subject to signal noise and loss when the animal moves too far from the antenna or orients its body in a way that the signal has to pass through most of the animal's body to reach the antenna. As a result, the data were digitally filtered to eliminate noise and signal dropout. IOP data were flagged as suspicious if the transducer read less than 0 mm Hg or greater than 100 mm Hg. The suspect segment, along with five seconds of data both before and after the suspect segment, were eliminated from the analysis and results presented in this study. This was done to ensure data quality and minimize the possibility of reporting erroneous IOP data. Only 24-hour blocks wherein 80% of the data in all the 2-hour time windows remained after filtering were used for the analyses. Only one 24-hour period (compared with a total of 41 reported herein) did not meet the criteria. 

Data Analysis

After the IOP data were adjusted according to the IOP transducer calibration tests and digitally filtered, they were analyzed by using a time-window–averaging technique. For each 24-hour block, the data were separated into time windows of 10 minutes and 2 hours, and the average IOP for each time window were plotted against time. The averaged data points were assigned a continuous color from green to red, with green, yellow, and red indicating that 0%, 50%, and 100% of the data were eliminated for noise and/or dropout within that particular time window, respectively. This scheme immediately shows the quality of the data for each time-window average in each 24-hour block on inspection. 

The two-hour time-window averaged data were then statistically analyzed for the presence of a repeatable nycthemeral rhythm. First, each 24-hour block of IOP data were plotted in 2-hour time windows, using a box-and-whisker plots to represent the distribution of the calibrated and filtered IOP measurements (500 per second) within that 24-hour period. These are presented in the Results section for 19 and 18 days for two animals, respectively, and 4 days for a third animal in which the IOP transducer portion of the implant failed for unknown reasons 5 weeks after implantation. Hence 4 days of reliable data were all that were acquired for that animal. The data for each 2-hour period (e.g., 9–11 AM, 11 AM–1 PM, and so on) were then averaged across all the 24-hour blocks for each animal and represented by box-and-whisker plots showing the distribution of continuous IOP within each 2-hour period across 19, 18, and 4 days for the three animals. 

Results

Surgical Outcomes

We implanted the final prototype of the IOP transducer-equipped implanted pressure monitor (T30F; Konigsberg Instruments) in the right eyes of three rhesus macaques. All surgical wounds healed well, with minor areas of dehiscence in the lateral orbital wall skin wounds in two animals that resolved with placement of supplemental interrupted sutures where necessary. Orbital congestion resolved and chewing of hard food resumed within the first week of surgery in all three animals. No gaze restrictions were noted by direct observation or on forced duction, as performed during each IOP calibration session. 

Postoperative anterior segment inflammation was moderate (grade 2+ cell and flare, but no fibrin) and resolved completely in two of the three animals within the first two postoperative weeks. The third animal (monkey 18012) exhibited continuous low-grade anterior chamber inflammation (trace anterior segment cell and flare without evidence of vitreous involvement, cataract, or fibrin formation) in the implanted eye for the first 3 months of the 7-month period of postoperative observation. Within 3 weeks after surgery, tonometric measures of IOP in all implanted eyes (Tonopen; Reichert Technologies, Depew, NY) were not markedly different from those in the contralateral nonimplanted eye. 

Total Implant System Performance

Data were collected in two of the three animals for approximately 7 months until battery failure. The IOP transducer failed from unknown causes in the third animal 5 weeks after implantation. We tested IOP transducer accuracy from 5 to 45 mm Hg in the three implanted monkeys by cannulating the anterior chamber with a 27-gauge needle connected to an adjustable saline reservoir equipped with a digital in-line pressure gauge. We recorded continuous telemetric IOP and ECG data during IOP calibration tests while the animals were under isoflurane anesthesia, with steady heart rates between 110 and 130 beats/min, O₂ saturation above 95%, and blood pressures of ∼110/65 mm Hg. The IOP transducers in all three animals were accurate to within 1 mm Hg, from 5 to 45 mm Hg, with a base noise level of ≤0.4 mm Hg. The transducers measured transient IOP elevations up to 20 mm Hg above baseline in response to corneal tonometer contact, and were extremely sensitive to any manipulation of the eye or eyelids. High-frequency IOP fluctuations were captured with the system (Fig. 3), which our preliminary data indicate were due to saccades and blinks. The ocular pulse amplitude (OPA) was readily discernable in the IOP signal when OPA was greater than approximately 0.6 mm Hg (Fig. 4). 

Figure 3.

 

Screen capture of approximately 6 seconds of the continuous IOP telemetry signal in an awake, unrestrained nonhuman primate, showing the dynamic nature of IOP and demonstrating the ability of the system to capture high-frequency IOP fluctuations. A preliminary analysis of these fluctuations suggested that they resulted from blinks and saccades (Seigfreid WP, et al. IOVS 2011;52:ARVO E-Abstract 656), but that has yet to be confirmed.

Figure 4.

 

Screen captures of typical telemetric ECG and IOP signals for IOPs of 3.5 up to 54 mm Hg in monkey 18012, showing ocular pulse amplitude (OPA) increasing with IOP. The IOP is scaled identically for each tracing, and all these data were captured within approximately 10 minutes in an anesthetized animal during an IOP transducer calibration test. Note the transducer noise of ∼0.4 mm Hg in the top IOP trace at 3.5 mm Hg baseline IOP.

We evaluated the effects of head position, manipulation of the SC lead wires, hard tapping on the transducer electronics package, hard tapping on the orbital ridge, and hard tapping on the tissue above the transducer itself. None of these perturbations induced any change whatsoever in the IOP signal of the anesthetized animals. Forced ductions performed by gently grasping the conjunctiva with forceps induced IOP elevations from 8 to 15 mm Hg above baseline in anesthetized animals. Finally, the system records transient IOP elevations as short as 20 ms (Fig. 3), which is sufficient to capture IOP fluctuations from blink, saccade, ocular pulse, and other sources (see Supplementary Movie S1). 

IOP Transducer Signal Noise and Drift

A very important feature of the pressure transducer (T30F; Konigsberg Instruments) design is that its signal noise is less than 0.4 mm Hg, and signal drift is rated at less than 3 mm Hg/mo monotonic. As such, signal drift errors can be subtracted automatically in the software (CA Recorder; DISS) as long as pressure calibration checks are routinely performed (performed approximately every 2 weeks in this study). Post hoc adjustment for IOP drift between IOP transducer calibration tests was accomplished using digital signal compensation, as described above. All three transducers exhibited an initial postimplantation period of high drift (up to 17 mm Hg per month) for periods of up to 6 weeks, after which two of the three implants settled into a monotonic drift pattern of 6 mm Hg per month or less. The IOP transducer in monkey 24251, whose implant failed 5 weeks after implantation, never settled into the lower drift phase. IOP signal noise was <0.4 mm Hg in all three implants for all data collected (Fig. 4, top IOP trace). 

IOP Dynamics

IOP was plotted in 10-minute and 2-hour time windows for 19, 18, and 4 24-hour blocks for monkeys 18012, 21356, and 24251, respectively. Figure 5 shows a representative plot of the 10-minute time-window average plot of IOP for a single 24-hour period from animal 18012. Figures 6, 7, and 8, show the 2-hour time-window average box-and-whisker plots for all 24-hour blocks collected for each animal, respectively. Calibrations were performed routinely, and so these data should be accurate to within 1 mm Hg of true IOP. The dates of the 24-hour recording periods are shown above each 24-hour plot; note that many of the plots are for Monday, Wednesday, and Friday of the same week. When data are compared within animals across 24-hour periods in Figures 6 to 8, there does not seem to be any particular nycthemeral rhythm or repeatable pattern for any of these animals. 

Figure 5.

 

(A) Representative plot of the 10-minute time-window average of 24 hours of continuous IOP showing low-frequency IOP fluctuation from monkey 18012. The color of the plot points and lines indicates how much data were removed from each 10-minute window after post hoc filtering signal dropout and noise. Green indicates that 100% of the continuous IOP data were used in the 10-minute average IOP plotted in each point, and yellow indicates that 50% were eliminated due to signal dropout or noise. (B) Histogram of IOP for the 24-hour period presented in (A). Note the width of the IOP distribution within this single 24-hour period relative to the median value of 11 mm Hg.

Figure 6.

 

The 2-hour time-window distributions of IOP for 19 24-hour periods in animal 18012. The dates of data capture are shown above each plot. In the box-and-whisker plots, the central bar indicates the mean IOP in each 2-hour segment, the ends of the box show the central 50% of the measurements, and the whiskers indicate the 95% limits of the measurements in that time window; (○) outliers.

Figure 7.

 

The 2-hour time-window distributions of IOP for 18 24-hour periods in animal 21356. The dates of data capture are shown above each plot. In the box-and-whisker plots, the central bar indicates the mean IOP in each 2-hour segment, the ends of the box show the central 50% of the measurements, and the whiskers indicate the 95% limits of the measurements in that time window; (○) outliers.

Figure 8.

 

The 2-hour time-window distributions of IOP for 4 24-hour periods in animal 24251. The dates of data capture are shown above each plot. In the box-and-whisker plots, the central bar indicates the mean IOP in each 2-hour segment, the ends of the box show the central 50% of the measurements, and the whiskers indicate the 95% limits of the measurements in that time window; (○) outliers. Only four 24-hour periods of continuous IOP for animal 24251 are shown, because the IOP transducer failed prematurely. The data reported for this animal fall within the high-drift phase of the IOP transducer. Although we are confident that the IOP patterns shown are representative of the relative 24-hour IOP distributions, the absolute IOP values should be viewed with caution (see the Limitations section of the Discussion).

Nycthemeral Rhythm of IOP

All the data for the 2-hour time window plots were combined into single box-and-whisker plots for animals 18012, 21356, and 24251, as shown in Figures 9, 10, and 11, respectively. When all the data are combined, there is a weak trend of nocturnal elevation in the IOP distributions (in the boxes and whiskers, but not necessarily the mean) in all three animals. 

Figure 9.

 

The distribution of IOP in 2-hour time windows for 18 24-hour periods in animal 18012. In the box-and-whisker plots, the central bar indicates the mean IOP in each 2-hour segment, the ends of the box show the central 50% of the measurements, and the whiskers indicate the 95% limits of the measurements in that time window; (○) outliers.

Figure 10.

 

The distribution of IOP in 2-hour time windows for 18 24-hour periods in animal 21356. In the box-and-whisker plots, the central bar indicates the mean IOP in each 2-hour segment, the ends of the box show the central 50% of the measurements, and the whiskers indicate the 95% limits of the measurements in that time window; (○) outliers.

Figure 11.

 

The distribution of IOP in 2-hour time windows for four 24-hour periods in animal 24251. In the box-and-whisker plots, the central bar indicates the mean IOP in each 2-hour segment, the ends of the box show the central 50% of the measurements, and the whiskers indicate the 95% limits of the measurements in that time window; (○) outliers. Note that these data are derived from only four 24-hour periods of continuous IOP in this animal, because the IOP transducer failed prematurely. The data reported for this animal fall within the high-drift phase of the IOP transducer. Whereas we are confident that the relative patterns of IOP distribution shown are representative, the absolute IOP values should be viewed with caution (see Limitations section of the Discussion).

Discussion

In this study, we have described a new, fully implantable IOP telemetry system for nonhuman primates that allows continuous monitoring of IOP, ECG, and body temperature at a rate of 500 measurements per second for up to 7 months. Note that the T30F pressure monitor implants that we used for this study are designed for short-term use of 6 to 9 months, but the equivalent T27G-series implant system (both by (Konigsberg Instruments) equipped with a separate battery can achieve 2.5 years of continuous monitoring. The transducer sits in the orbital wall adjacent to the eye, and so artifacts due to head movement are minimized—that is, the transducer moves with the head as the head moves, and there is no hydrostatic pressure head due to difference in height. IOP measurements are taken through a tube inserted into the anterior chamber, which eliminates the retinal damage associated with probes placed in the vitreous chamber. After implantation in three nonhuman primates, the IOP telemetry system exhibited high accuracy (<1 mm Hg of error over the physiologic range), low noise (±0.2 mm Hg), and the ability to capture IOP fluctuations on the order of 10s of milliseconds. Two of the three IOP transducers settled into a monotonic drift phase of ≤6 mm Hg per month after an initial 1- to 2-month period of high drift. The third IOP transducer failed 5 weeks after implantation and never entered the low-drift phase. 

The continuous IOP signal was digitally filtered for noise and dropout, and reported by using time-window averaging for 19, 18, and 4 24-hour periods in three animals. IOP transducer calibrations were performed routinely, and these data should therefore be accurate to within 1 mm Hg of true IOP (see the Limitations section for a discussion of drift in animal 24251). Continuous IOP was extremely dynamic and demonstrated frequent, short-duration IOP fluctuations up to 12 mm Hg (Fig. 3), although the source of these fluctuations has yet to be validated. This observation is consistent with the relative IOP fluctuation observed in humans fitted with a contact lens–based IOP telemetry system ³⁷ that uses corneal stretch as a surrogate measure for IOP. Ten-minute time-window averaging for 24-hour periods showed that IOP fluctuated up to ±7 mm Hg from baseline during a 24-hour period, and those changes occurred frequently and quickly (Fig. 5). Again, this is consistent with human results shown by Mansouri and Shaarawy. ³⁷  

Two-hour time-window averaging of continuous IOP in multiple 24-hour periods for three nonhuman primates revealed two important observations. First, there did not seem to be any repeatable day-to-day pattern of IOP fluctuation in these animals (Figs. 6 7–8), which agrees with recent reports in patients. ^31,32 The dates of the 24-hour recording periods are noted above each 2-hour time window plot shown, and many of the plots are for Monday, Wednesday, and Friday of the same week. In a significant number of the 24-hour periods shown in Figures 6 to 8, the whiskers (95% limits) indicate that that IOP was more than 3 mm Hg higher or lower than the mean value for at least 12 minutes during the 2-hour block. In some cases, these fluctuations were up to ±5 mm Hg from the mean. 

Second, 2-hour time window data averaged across multiple 24-hour periods in three animals show a nycthemeral trend of IOP elevation in the early morning hours (Figs. 9 10–11), although this trend is neither statistically significant nor as strong as that reported for humans. ^32,43,44 The lack of a more prominent nycthemeral rhythm in these animals could be caused by their upright position during sleep. It is also possible that the monkeys are more active at night than humans and therefore have a lesser nocturnal rise in IOP that that of humans, who sleep deeply throughout the night. Humans sleep supine, which has been shown to increase IOP, ^{44 –46} although one study indicates that the nocturnal IOP elevation in patients is still present in the sitting position. ⁴⁷ Nocturnal postural differences, nocturnal activity, and/or measurement artifacts induced by waking patients for IOP measurement could account for some of the difference in the magnitude of nocturnal IOP elevation reported in humans compared with the primate data reported herein. 

Limitations

This study was limited by several important factors. First, we acquired only four 24-hour periods of continuous IOP in animal 24251 because the IOP transducer failed prematurely; our discussions with Konigsberg Instruments and with other users of the company's pressure telemetry systems indicate that a 10% to 15% failure rate is to be expected. The data reported for this animal fall within the high-drift phase of the IOP transducer, and so we are much less confident that the absolute IOP values reported in Figures 8 and 11 are accurate. Although the absolute IOPs reported for this animal should be viewed with caution, the IOP distributions and nycthemeral rhythms within each 24-hour period should be relatively unaffected by the noted transducer drift. Second, we have not fully validated the source of the high-frequency IOP fluctuations seen in Figure 3, although preliminary evidence suggests that they are due to blinks and saccades (Seigfreid WP, et al. IOVS 2011;52:ARVO E-Abstract 656). Therefore, the results are focused on average IOP data for 2-hour time windows, in which these fluctuations are averaged out. In the future, we will use video monitoring of blinks and saccades that are time-synced to the IOP signal, along with optokinetic nystagmus (OKN) testing, to confirm the source of these fluctuations. It will also be necessary to perform in vitro experiments that mimic saccades to confirm that inertial effects of tube movement do not induce the IOP fluctuations that we recorded. Third, with the exception of the light–dark cycle, we did not monitor environmental conditions or food and water intake to isolate those variables from the IOP variations noted in Figures 6 to 11. In the future, careful monitoring of sound, caretakers entering the room, cage changes, food and water intake, and all other environmental factors and events must be logged, to ensure that we are measuring true resting IOP in the implanted animals. Finally, we report IOP data for three nonhuman primates, and thus our ability to apply the conclusions reached to the primate population at large or to human subjects is limited. 

As with all transducers in the implant system, the body temperature signal drifts with time and must be calibrated regularly, which we did not perform to simplify the protocol. Hence, we do not report body temperature data in this article. In addition, the circadian rhythms of body temperature known to occur in higher primates likely induce temperature-related fluctuations in the IOP signal. Konigsberg Instruments rates the battery and transmitter for the T30F implants used in this study at less than 0.01 mm Hg/°C of temperature-induced fluctuation. The IOP transducer itself is rated for less than a 0.5-mm Hg/°C change in IOP, although this temperature-induced fluctuation could be significant in light of the 1.8°C circadian variation in body temperature in female rhesus macaques. ⁴⁸ Unfortunately, there is no way to predict the direction of the temperature-induced fluctuation in the IOP signal, and it is likely to be different between implants. Hence, the uncertainty of the temperature-induced fluctuation in the IOP signal must be factored into the weak nycthemeral pattern of IOP shown in Figures 9 to 11. 

We did not characterize the magnitude and extent of high-frequency IOP fluctuations in this report or focus our results on data for time windows shorter than 2 hours. The telemetry data are much more sensitive to high-frequency fluctuations and environmental variables in shorter time windows (Figs. 3, 5), and some portion of the high-frequency data may be artifactual (e.g., inertial pressure effects of eye movement on the aqueous in the tube and environmental factors, as discussed above). In addition, most human IOP data are collected using snapshot devices that preclude IOP spikes from blinks and saccades. Hence, to compare our IOP telemetry data in primates to that from human studies, it is necessary to remove the high-frequency IOP spikes from the telemetry data and take shorter time-window averages of the resulting baseline IOP. The IOP signal validation and filtering necessary to accomplish this are not trivial, however, and so those data will be the subject of a future report. 

Summary

We have successfully measured IOP continuously using a newly developed, fully implantable IOP telemetry system. IOP fluctuates as much as 10 mm Hg day to day and hour to hour in unrestrained nonhuman primates, which indicates that snapshot IOP measurements may be inadequate to capture the true dynamic character of IOP. The distributions, magnitudes, and patterns of IOP are not reproducible from day to day within animals when IOP is averaged in 2-hour time windows. When IOP data are averaged across multiple 24-hour periods within animals, a weak nycthemeral rhythm is present in the nonhuman primate, in which IOP tends to be highest at night. IOP fluctuations of this frequency and magnitude may be an important yet unknown contributor to IOP-related glaucomatous damage. 

Supplementary Materials

Movie sv01, MOV - Movie sv01, MOV 

Footnotes

 Presented in part at the annual meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, May 2011.

Footnotes

 Supported by National Institutes of Health Grant R21-EY016149 (JCD) and the Legacy Good Samaritan Foundation, Portland, Oregon

Footnotes

 Disclosure: J.C. Downs, None; C.F. Burgoyne, None; W.P. Seigfreid, None; J.F. Reynaud, None; N.G. Strouthidis, None; V. Sallee, None

The authors thank Shaban Demirel for invaluable assistance in the statistical analysis of these data and Yi Liang for assistance in the surgical implantation of the telemetry devices.