Peri-papillary Ischemia as a Potential Screening Biomarker for Early Detection of Tick-Borne Infection

Objective

The objective of this study was to determine whether an observed peri-papillary ischemia is a potential biomarker of tick-borne infection (TI).

Methods

An experimental design analyzing the optic nerve to demonstrate peri-papillary ischemia and vessel density changes through ocular coherence tomography with angiography (OCT-A) in subjects with TI. Glaucoma was ruled out and the study engaged subjects in the age range between 8-40 years. All subjects in the experimental group experienced visual symptoms. Subjects in the control group were asymptomatic and not previously diagnosed with TI. The OCT-A scanned vessel density of peri-capillary plexus surrounding the optic nerves, the images were rated by percentage of vessel density. A two-tail t-test analysis was used to analyze the results.

Results

The t-test for each measure comparing the difference-of-differences to a zero change at baseline returned statistically significant results demonstrating reduced vessel density for the subjects in the experimental group (p < .0001; 95% CI [32.37409-43.50091]).

Conclusion

The appearance of peri-papillary ischemia in persons below the age of 50 represents a potential screening biomarker of TI. Primary care physicians, ophthalmologists and optometrists who have patients presenting sudden onset of visual symptoms in addition to the appearance of peri-papillary ischemia should be tested to rule out a tick-borne infection.

• tick-borne infections
• vision
• peri-papillary ischemia
• visual dysfunction
• OCT-angiography

The early diagnosis and detection of tick-borne infection (TI), including Lyme disease, remains a challenge.[1] Since tick-borne disease is “The Great Mimicker,” symptoms often appearing similar to other systemic and neurological conditions causing the correct diagnosis to be missed or delayed.[1] Lack of diagnosis and treatment in the acute phase may result in a chronic and even neurological advancement in the undiagnosed disease.

The literature is sparse concerning the consequences and effect of TI to vision, retinal changes and the vascular network within the eyes. The borrelia species of spirochete has been found in ocular tissue delivered through the vascular network.[2] The superficial capillary network of the inner layers of retina is the radial peripapillary capillary plexus.[3] This network is responsible for supplying the densely packed nerve fiber layer.

Ischemia surrounding the optic nerve head (peri-papillary ischemia) is not a common finding in younger and middle-aged patients and is more prevalent with persons over 60 years of age.[4] A common cause of peri-papillary ischemia is glaucoma. Park, et. al. reports that pseudoexfoliation glaucoma (PXG) produces vessel density (VD) reduction in the peri-papillary area causing ischemia compared to subjects with primary open angle glaucoma (POAG).[4] De Carlo et. al illustrates the potential use of OCT-A in pinpointing areas of capillary non-perfusion, ischemia and edema.[5, 7]

The central retinal artery diameter is approximately 160 um. The peri-papillary capillaries are about 15 um in diameter.[6] A spirochete is approximately 1 um in diameter and can easily invade the capillary plexus of the inner retina.[7, 8] Spirochetes can lead to formation of a biofilm as large as 50 um.[9] The capillaries of the radial peri-papillary plexus being approximately 15 um in diameter are too narrow to permit passage of the spirochete produced biofilm.[10, 11] This can potentially lead to blockage and ischemia. The authors have observed that a peri-papillary ischemia surrounding the optic nerve is common when observing the fundus of a patient with TI.

It is hypothesized that ischemia is due to the accumulation of biofilm(s) in the peri-papillary capillary plexus and that retinal peri-papillary ischemia is a potential biomarker of tick-borne infection. This potential will provide evidenced-based practice as quality improvement (QI) and provide measured outcome to adjust care based on resulting outcomes.

An experimental design was used. All subjects in the experimental group presented symptoms such as visual fatigue, headaches, light sensitivity, brain fog, etc. and were diagnosed with TI. Subjects in the control group were asymptomatic with no history of TI.

There were 20 subjects in each cohort group including 14 female in the control group and 11 female in the experimental group. The average estimated time since onset of infection was 22 months for subjects in the experimental group. The age range for the experimental group was from 9-32, with an average age of 22. For the control group, the age range was 12-35 years of age, with an average age of 30. Borrelia burgdorferi was found to be the most common TI confirmed by CDC guidelines using the Western Blot Test. The experimental group was compared to a control cohort group (n = 20) with no history of TI or related symptoms. Subjects were chosen between the ages of 8-40 years old. Subjects were age matched.

The fundi were evaluated using retinal photography (Nidek Auto Focus AFC-330) and ocular tomography angiography (OCT-A) of the optic nerve head using an Optovue RTVue XR OCT-AngioVue was used to assess VD. Fundus photos and OCT-A imaging of TI positive subjects were compared with control subjects to determine changes in the appearance of the retina along with comparison of retinal capillary bed in the radial peri-papillary layer. A color-coded rating scale (0% – red for no loss to 100% – blue maximum loss respectively) was used to evaluate VD for both cohort groups.[Figure 1] Intra-ocular pressure (IOP), measured by Goldmann tonometry, and symmetry of the optic nerve cup-to disc ratio for all subjects to rule out glaucoma.

Figure 1 Shown are fundus photographs for subject in the experimental group (left) and control group (right). The left top and bottom images of the right and left eye are presented with and without filter. On the right are images of the right and left eye of a control group subject. The color-coded rating scale for assessing vessel density with red scaling (0%) for no drop-out and blue scaling (100%) for maximum vessel drop-out (middle). In the lower figures are OCT-A scans of a subject in the experimental group demonstrating Va in the peri-papillary area of the right (left image) and left eye (right image). In comparison, the bottom 2 images are of a subject in the control group, showing normal vessel density in the peri-papillary area of the right and left eye.

The Cahill Study of Ethical Submission was used as a guideline to determine that this study qualifies as a QI study since patients were not deviated from standard care nor were invasive tests used.[12]

The VD measured on the OCT-A was used to create a ratio of maximum reduced VD (VDR) to the average normal VD (VDN) for each eye in both cohort groups. This enabled measurement of peri-papillary area (millimeters2) to provide a percentage that corresponded to VDR. VDR was compared to the remaining area of VDN in each quadrant of the peri-papillary area surrounding the optic nerve and the quadrants of VDR and VDN were summated for each eye (SVDR and SVDN respectively).
An algorithm was developed to quantify VDR normal density of vessels represented as a value of 10 and the reduction in density represented accordingly. An example would be if a quadrant showed 30% reduction in VD, the quantification would be represented as 7.

The algorithm is:

VD_R: Reduced vessel density

SVD_R: Summation of 4 quadrants reduced vessel density

SVD_N: Summation of 4 quadrants normal vessel density

Analysis utilized a two-tail t-test to compare unadjusted differences in main outcomes measures between each cohort at the 95% confidence level.

In Figure 1, the top photographs demonstrate an area of peri-papillary ischemia for a subject in the experimental group compared to the bottom photographs without peri-papillary ischemia for a subject in the control group. The OCT-A demonstrates that subjects in the experimental group had VDR surrounding the ONH. In comparison, only one subject in the control group showed VDR. Subjects in both groups showed no other abnormal characteristics to indicate compromise of health to the optic nerve or surrounding area. Using average calculated values of VD, it was determined that the experimental group generally showed an increased percentage of VD compared to the control group. Careful assessment of both eyes was conducted by the researchers and the average of two eyes was then used to determine overall VDR for each subject. Table 1 shows the average VDR for the subjects in the experimental group was 49.594% and the average VDR or subjects in the control group was 11.656%. The standard deviation for the experimental group is 10.361 and for the control group 6.168.

Table 1Comparison of OCTA vessel density (VD) [in percentage] for the experimental and control groups. Results of two-tailed test for 2 dependent means.

A two-tailed t-test for dependent means was used to compare the percentage of VDR for the subjects in the experimental and control groups.[Table 1] The mean for the experimental and control group are 49.594 and 11.656 respectively. The t -value is 14.538. The standard deviation for the experimental and control groups are 10.361 and 6.168 respectively. The analysis is statistically significant at p < 0.001 with a confidence interval of 95% [32.374-43.501] for VDR and is greater for subjects in the experimental group.

The results of the study demonstrate that there is statistical significance of reduction in VD within the peri-papillary vessel plexus for those subjects in the experimental group. This study did not search for or prove the existence of spirochetes or biofilms in the eye. It could be speculated, however, that spirochetes and/or biofilm may be present but it was not the purpose of this study to prove the existence of them. The authors recommend that this should be a component of future studies.

We propose that the VD is caused by biofilms (50 um) produced by spirochetes affecting blood flow in the narrow peri-papillary plexus of vessels (15 um in diameter) surrounding the optic nerve.

The proposed algorithm (VDR = SVDR / SVDN), demonstrates vessel density is matched with the peri-papillary ischemia shown in fundus photos.

The conclusion from this research is that peri-papillary ischemia surrounding the optic nerve is caused by VDR as measured by OCT-A. Therefore, the statistically significant finding of VDR serves as a potential screening biomarker of tick-borne infection. Peri-papillary ischemia caused by VD should be used as a screening technique by health care professionals and especially optometrists and ophthalmologists for patients who have sudden onset of symptoms. This will fortify decision making to rule out tick-borne infection for early diagnosis and to establish the retina as a source for further study related to tick-borne infection.

The authors have no conflicts of interest to declare, financial or other.

This research was funded by the Lyme Disease Association (LDA).

The study was exempted from institutional review board approval as a non-invasive analysis of diagnostic quality improvement

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[3] Ghassemi F, Fadakar K, Bazvand F, et al. The Quantitative Measurement of Vascular Density and Flow Areas of Macula Using Optical Coherence Tomography Angiography in Normal Volunteers. OSLI Retina 2017; 48(6), 478-86. Available https://journals.healio.com/doi/full/10.3928/23258160-20170601-06. Accessed January 2021.

[4] Park, Ji-Hye; Yoo, Chungkwon ; Girard, Michael J.A.; Mari, Jean-Martial ; Kim Yong Yeon. Peripapillary vessel density in glaucomatous eyes: comparison between pseudoexfoliation glaucoma and primary open-angle glaucoma. : Journal of Glaucoma, Volume 27, Number 11, November 2018, pp. 1009-1016(8).

[5] de Carlo, T.E., Romano, A., Waheed, N.K. et al. A review of optical coherence tomography angiography (OCTA). Int J Retin Vitr 1, 5 (2015). https://doi.org/10.1186/s40942-015-0005-8.

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[8] Campbell JP, Zhang M, Hwang TS, et al. Detailed vascular anatomy of the human retina by projection-resolved optical coherence tomography angiography. Scientific reports 2017;7(1):1-11. Available at: https://www.nature.com/articles/srep42201. Accessed January 2021.

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[11] Mase, T., Ishibazawa, A., Nagaoka, T., Yokota, H., & Yoshida, A. Radial peripapillary capillary network visualized using wide-field montage optical coherence tomography angiography. Investigative ophthalmology & visual science, 2016; 57(9).

[12] Patterson-Fortin J, Kohli A, Suarez MJ, Miller PE. Ocular Lyme borreliosis as a rare presentation of unilateral vision loss. BMJ Case Rep. 2016;2016:bcr2016215307. Published 2016 Apr 25. doi:10.1136/bcr-2016-215307.

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