Structural and Metabolic Imaging after Short-term use of the Balance Goggles System in Glaucoma Patients: A Pilot Study

Abstract

Objective:

To determine whether the intraocular pressure (IOP)-lowering effects of the Balance Goggles System (BGS) are accompanied by changes in retinal thickness measured by ocular coherence tomography, retinal vascular density measured by OCT-angiography, or novel peripapillary metabolic profiling using flavoprotein fluorescence (FPF) measured by a fundus camera.

Design:

Prospective comparative case-series.

Subjects:

8 eyes from 8 patients with open-angle glaucoma ranging from mild to severe.

Methods:

In this prospective, single-center, open-label, non-randomized, single-arm study patients received a baseline evaluation including retinal imaging, then one hour of negative pressure application through the BGS, followed by repeat retinal imaging. Participants then used the BGS at home for 1 month and underwent a repeat evaluation at the conclusion of the trial.

Main Outcome Measures:

Changes in nerve fiber layer thickness, OCTA vascular parameters and FPF scores.

Results:

Mean baseline IOP was 18.0±3.1 mmHg and there was no significant change in IOP at follow-up. At 1 month compared to baseline, there was a statistically significant improvement in FPF optic nerve head rim scores (12.7±11.6 to 10.5±7.5; p=0.04). Additionally, there was there was a trend towards an increase in RNFL thickness after 1 month (69.5±14.2 to 72.0±13.7; p=0.1), but there were no statistically significant differences observable with any of the OCTA vascular parameters either at 1 hour or after 1 month.

Conclusions:

There were no significant changes observable using conventional OCT imaging following short-term use of the BGS, although metabolic imaging using FPF may be a useful potential biomarker to complement existing investigations. Additional studies are warranted to further investigate these changes.

PRECIS

Short-term use of the Balance Goggles System in glaucoma patients was not associated with observable changes in conventional OCT imaging but metabolic imaging using peripapillary flavoprotein fluorescence may represent a useful adjuctive investigation.

INTRODUCTION

Intraocular pressure (IOP) reduction remains the only modifiable risk factor in glaucoma with various medical, laser and surgical treatment strategies available.^{1, 2} However, a significant proportion of patients have difficulty tolerating conventional therapies or continue to exhibit disease progression despite seemingly reasonable IOP control, and thus new approaches to IOP-lowering therapy are required.³ The Balance Goggles System (BGS, Equinox Ophthalmic Inc., CA) is a wearable device which exerts continuous negative pressure over the eye via a programmable pump, resulting in a corresponding decrease in IOP. The mechanism of IOP reduction is based upon the negative pressure microenvironment created by the device, which results in a corresponding atmospheric pressure reduction with resultant immediate IOP lowering.⁴ The negative pressure is thought to influence both the aqueous humor dynamics and episceral venous flow, with an increase in globe volume and a reduction in episceral venous pressure. While a decrease in external (air) pressure increases the trans-corneal pressure difference measured by some tonometry methods, this pressure difference in unlikely to be transmitted in the retrolaminar space most relevant in glaucomatous pathology, and experimental studies have shown an IOP reduction when measured using gauge pressure (i.e absolute pressure in the eye with respect to surrounding pressure).⁴ Subsequent models, now renamed the multi-pressure dial, have been shown to be safe when worn continuously overnight, with demonstrable IOP lowering using traditional corneal measurements compared to atmospheric pressure in both glaucoma patients and healthy subjects.^{5, 6}

Since its development, OCT-angiography (OCTA) has emerged as a promising non-invasive imaging modality capable of providing both quantitative and qualitative assessment of optic nerve head vasculature.^{7, 8} Patients with glaucoma have been found to have reduced superficial vessel density in the peripapillary region and associated reduction in perfusion which has found to correlate with visual field loss.^{7, 9} More recently, functional imaging of retinal mitochondria using flavoprotein fluorescence (FPF) has attracted increasing interest as a potential novel biomarker for various retinal diseases.^10-13 Under conditions of oxidative stress, flavoproteins are excited by blue light and emit green autofluorescence which can be captured using fundus photography, where higher FPF intensity is associated with mitochondrial dysfunction.¹⁰ Unlike existing imaging modalities only able to assess structure, FPF is a promising non-invasive measure of metabolic function, with recent studies demonstrating higher FPF measurements at the optic disc rim in POAG patients compared to controls.¹⁴

We sought to determine whether the IOP-lowering effects of the BGS are accompanied by structural and metabolic retinal changes using both conventional OCT and OCTA imaging, as well as novel peripapillary flavoprotein fluorescence (FPF) quantification.

METHODS

This was a prospective, single-center, open-label, non-randomized, single-arm study at an academic center. Informed consent was obtained for each subject prior to the study. This study was approved by the Stanford Institutional Review board (IRB) and was registered as a clinical trial (clinicaltrials.gov NCT04035239).

Eligible patients included those aged over 21 years with a clinical diagnosis consistent with open-angle glaucoma or ocular hypertension with intraocular pressure >21 mmHg at initial diagnosis. Subjects were required to have orbital anatomy permitting proper seal of the BGS over both eyes and to tolerate measurements with the goggles in place. Exclusion criteria included any ocular disorder likely to interfere with study results or compromise subject safety, a history of a prior retinal detachment, unresolved cystoid macular edema, any other fundus findings that may prevent visualization of the retina in either eye, history of prior penetrating glaucoma surgery in either eye or history of any intraocular surgery in the 12 weeks prior to screening visit, eyelid edema/skin laxity or conjunctival chemosis, history of allergy to silicone, pregnancy or breastfeeding.

Baseline evaluation of all patients included IOP measurement, BCVA, slit-lamp examination with optic nerve assessment, optical coherence tomography (OCT, Cirrus Zeiss) of the retinal nerve fiber layer (RNFL) and OCT-angiography (OCTA, Cirrus Zeiss) of the optic disc, along with peripapillary flavoprotein fluorescence (FPF) measured by a fundus camera (OcuMet Beacon, OcuSciences, Inc MI). Before application of negative pressure, all subjects were fitted with the BGS to ensure adequate seal. The pressure-modulating programmable pump was used to set the target negative pressure. The BGS were set to a target IOP of 50% of the in-clinic baseline measure for each eye based upon previous studies establishing IOP lowering of approximately 50-60% of the negative pressure within the goggles.⁴ Repeat measurements were taken after study subjects wore the BGS continuously for an hour in the clinic, and again after a period of 1 month of in-home use of at least 1 hour each night. Home compliance was measured using integrated software within the BGS system. Main outcome measures studied were changes in average RNFL thickness, OCTA vascular density parameters (assessed at superficial depth of the optic disc and peripapillary vasculature using scores from Zeiss OCTA software, Cirrus HD-5000 version 9.5.2.19038) and peripapillary FPF scores.

The Ocumet Beacon fundus camera (OcuSciences, Inc MI) was used to obtain infrared and peripapillary FPF measurements with built-in software algorithms able to identify optic disc margins. This third-generation camera captures a 60 degree infrared image and 19 degree FPF image and incorporates a confocal infrared scanner and metabolic detector designed to optimally detect FPF peak wavelengths.¹⁰ FPF images and special algorithms were used to calculate quantitative measures for both the overall optic disc region and of the optic nerve head rim specifically, by segmenting an annulus around the rim and adjusting for lens status (phakic or pseudophakic). Higher FPF scores are indicative of increased retinal metabolic stress, although current scores are referenced against a small normative population. Each image was also manually assessed for image quality and accuracy of the retinal and optic disc structures present in the region of analysis by an experienced technician.

One eye per patient was included for analyses, selecting the eye with less severe glaucoma unless there was a significant difference in scan quality as we hypothesized that more mildly affected eyes may have more metabolic “reserve”; in two such cases the more severely affected eye had more complete imaging and was included for analyses. Continuous variables were presented as mean ± standard deviation as appropriate to distribution. Paired t-tests were used to compare IOP, OCT RNFL, OCTA vascular parameters and peripapillary FPF quantitative parameters between baseline and 1 hour, and between baseline and 1 month. Linear regression analysis was undertaken to characterize the relationship between average BGS usage with peripapillary FPF and OCT/OCTA parameters. Statistical analysis was performed using Stata 16.0 (Stata Corporation, Texas, USA) and p<0.05 was considered statistically significant.

RESULTS

The study analyzed 8 eyes from 8 patients with open-angle glaucoma. Baseline demographics and goggle use are summarized in Table 1. Glaucoma was classified as mild in 4 eyes, moderate in 3 eyes and severe in 1 eye based upon mean deviation visual field indices. Mean number of medications was 2 (range 0-4). No patient had a history of glaucoma surgery and one patient had previous SLT. Mean age was 52.8 years (range 25-73 years) and 62.5% were male. Mean baseline IOP was 18.0±3.1 mmHg and there was no significant difference between baseline and follow-up IOP measurements measured without BGS use at the 1-month visit (mean IOP at 1 month 19.6±5.2 mmHg; p=0.2).

Table 1:

Baseline Characteristics and Goggle Usage

Characteristic	N (%)
Mean Age (SD)	52.8 (19)
Male (%)	5 (62.5)
Race
Caucasian	4 (50)
Asian	3 (37.5)
Black	1 (12.5)
Ophthalmic Parameters
Mean CCT (SD)	543 (35)
Pseudophakic N(%)	1 (12.5)
VA N(%)
>20/40	5 (62.5)
20/40-20/60	3 (37.5)
Visual Field
Mean MD dB(SD)	−4.41 (4)
Mean VFI %(SD)	88 (11)
BGS Usage/Day N(%)
<2 hours	3 (37.5)
2-4 hours	3 (37.5)
4-6 hours	1 (12.5)
>6hours	1 (12.5)
BGS Issues N(%)
Discomfort	3 (37.5)
Lid swelling	1 (12.5)
Headache	1 (12.5)

All patients underwent a 1-hour observed treatment period with BGS use during the baseline visit. Thereafter in-home usage averaged 3 hours per night (range 0.5 to 8 hours/night) for an average of 14.6 nights (range 1 to 28 nights). Table 2 describes the changes in various measured OCT RNFL, OCTA and FPF parameters between baseline, 1 hour, and 1 month of BGS use. At 1 month compared to baseline, there was a statistically significant improvement in a novel FPF optic nerve head rim score (p=0.04). Additionally, there was an increase in mean OCT RNFL thickness and OCTA peripapillary vasculature, a decrease in mean OCTA superficial vasculature parameters, and a reduction in FPF computed optic disc scores, although these did not reach statistical significance due to wide confidence intervals. Figure 1 demonstrates improvement in peripapillary metabolic imaging parameters with reduction of FPF scores in one patient who consistently used the BGS on average 8 hours each night for one month. There were no serious adverse effects reported, while minor side effects from BGS use included goggle discomfort, headache, and eyelid swelling.

Table 2:

OCT, Retinal Vascular and Metabolic Parameter Changes with Balance Goggles System Use

Parameter (mean±SD)	Baseline	1-Hour (p-value)	1-Month (p-value)
OCT RNFL thickness	69.5±14.2	70.6±16.1 (0.4)	72.0±13.7 (0.1)
OCTA superficial vasculature	43.8±4.3	43.3±3.8 (0.6)	42.3±3.9 (0.2)
OCTA disc vasculature	43.7±5.3	43.4±5.1 (0.7)	43.5±4.6 (0.9)
OCTA peripapillary vasculature	50.8±7.4	50.0±7.1 (0.2)	51.2±9.4 (0.8)
Average FPF Computed Disc	19.1±3.7	19.5±3.3 (0.4)	15.4±5.8 (0.2)
Average FPF Computed Optic Nerve Head Rim	12.7±11.6	13.1±9.3 (0.9)	10.5±7.5 (0.04)

OCT: optical coherence tomography, OCT-A: OCT-angiography, RNFL: retinal nerve fiber layer, FPF: flavoprotein fluorescence

Figure 1: Peripapillary Metabolic Imaging Before and After Balance Goggle System Wear.

(a) Optic disc infra-red (IR) images; (b) Optic disc fundus flavoprotein (FPF) images; (c) plotted FPF intensity profiles measured circumferentially around white ring; (d) sector-wise means from profile plot. Top row captured at start of trial; bottom row captured at end of trial (except intensity profiles, in which start [gray] is overlaid on end [black]). Green boxes on images indicate region-of-interest. White ring on images are perimeter of algorithmically segmented optic nerve head. Green band on intensity profile is range typical for known healthy optic nerves. Red pie sectors represent elevated, green is normal, and blue are diminished means relative to typical healthy. Measurements are in black and typical control patient values in green.

In this small series, linear regression analyses did not demonstrate a significant correlation between duration of BGS use and FPF scores or OCT/OCTA parameters (p>0.05 for all).

DISCUSSION

In this pilot study, there were no signfiicant differences following short-term BGS wear using conventional OCT, although there was an observable improvement in one of the two metabolic peripapillary FPF parameters after 1 month of BGS use. Our findings suggest that metabolic imaging of FPF may be a useful adjuctive tool in assessing short-term retinal metabolic changes, and further larger-scale and long-term studies are warranted to investigate the potential therapeutic effect of negative periocular pressure, as well as potential correlation of novel FPF imaging with disease progression.

Previous studies investigating OCT and OCTA changes following medical or surgical IOP-lowering have been inconclusive. One study found no difference in RNFL thickness using Stratus OCT (Carl Zeiss Meditec, Dublin, CA) after medical or surgical IOP-lowering in 21 patients after 2-3 months,¹⁵ while another demonstrated significant increase in mean RNFL thickness following glaucoma filtration surgery in 38 eyes at 6-12 months after surgery which correlated with IOP decrease but not any visual field indices.¹⁶ More recently Liu et al found no difference in RNFL thickness but an improvement in OCTA capillary perfusion at 6 months following surgical IOP-lowering in 17 patients.¹⁷ We found there was a trend towards an increase in RNFL thickness after 1 month, but did not detect in this study any statistically significant differences observable with any of the OCTA vascular parameters either at 1 hour or after 1 month.

The addition of peripapillary metabolic imaging using FPF provided further useful insights into the effect of BGS on retinal metabolic function and may be a useful adjunct in glaucoma disease monitoring. With mitochondrial dysfunction now understood to play a critical role in glaucomatous optic neuropathy, FPF has emerged as a potential novel biomarker among noninvasive options being developed.^{10, 18} Previous studies have demonstrated the utility of FPF in detecting retinal metabolic stress in diabetic retinopathy,¹² with correlations found between FPF and visual acuity responses in patients undergoing treatment for diabetic macula edema independent of OCT findings.¹⁹ Patients with age-related macular degeneration, central serous chorioretinopathy retinal dystrophies, ocular hypertension and primary open angle glaucoma have also been found to have higher retinal FPF scores indicative of mitochondrial dysfunction in various observational studies.^{11, 13, 20, 21} More recently, FPF measurements have been obtained from the optic disc rim and found to be increased in POAG patients compared to controls,¹⁴ although advances in software computational algorithms for FPF mean that our scores were not directly comparable to prior studies. We found that there was a statistically signficiant reduction in mean computed FPF of the optic nerve head rim at the 1-month follow-up, while mean computed optic disc scores were not significantly different. This difference may be attributable to the fact that the optic nerve head peripapillary rim scores are more specific to the surrounding retinal nerve fiber layer than the overall optic disc score which includes optic cup imaging that does not include retinal ganglion cell axons, and thus may be a more sensitive indicator of metabolic stress in glaucoma. These findings taken together with the OCTA results suggest that assessment of mitochondrial function using FPF may represent a potential indicator of disease and dysfunction in glaucoma. Kudrna and colleagues demonstrated changes in electroretinography measurements following 2-hours of negative periocular pressure also set at 50% of baseline IOP in a small randomized trial of nine eyes (fellow eye control), with the results approaching statistical significance, suggesting there was similarly demonstrable short-term improvement in retinal ganglion cell function.²² However, additional larger scale studies are warranted to further investigate whether acute or chronic IOP lowering leads to detectable changes in FPF imaging, and in longitudinal studies, whether scores or detectable changes are predictive of glaucoma progression assessed by functional measures such as visual field perimetry.

Several previous studies on the use of periocular negative pressure application using the BGS or similar device have demonstrated favourable safety profile, as well as IOP-lowering effect limited to the duration of wear.^{5, 6, 22, 23} Theoretically, an increase in globe volume from negative periocular pressure may elevate the IOP when measured using trans-corneal methods which could be of concern for with the application of negative pressure with the BGS, an increase the transcorneal pressure difference referenced to the goggle space occurs. However the absolute IOP and the IOP referenced to atmosphere and the rest of the body including the retro-orbital space decreases.²⁴ Caution should be used in patients with advanced glaucoma and brittle IOP control, but reassuringly several studies measuring absolute IOP using traditional methods have not shown an acute increase following application of negative pressure.^{5, 23}

This study has a number of limitations which warrant recognition. First, the small sample size was likely underpowered to detect clinically meangful differences in IOP and imaging parameters. The real-world nature of the study design without randomization or a control group meant that there were numerous confounders, including a range of glaucoma severities, baseline characteristics and significant variation in BGS compliance between patients. A number of our patients had discomfort associated with BGS use which limited compliance with device wear. We did not assess patients’ sleep qualitatively or quantitatively; further studies analyzing impact on sleep would also be of interest given the device is ideally worn overnight. Given the slowly progressive nature of glaucomatous degeneration, the lack of significant differences in conventional OCT/OCTA analyses at our short follow-up of 1 month was expected, especially since the imaging was not performed during negative pressure application. However, the significant changes in FPF imaging parameters does highlight the potential utility of this novel imaging method to study short-term changes in glaucoma, although it is unknown how well this correlates with or predicts long-term progression; additional larger studies with extended follow-up are required to validate these findings.

In summary, short-term application of negative periocular pressure using the BGS was not associated with observable changes in conventional OCT imaging. However, given the improvement in peripapillary FPF scores noted in our small study, retinal metabolic parameters, particularly peripapillary FPF measurement may represent a potential useful adjunct in evaluating glaucomatous disease and further larger scale studies are required to further investigate these findings.