Using the only imaging modality of its type in the U.S., Moran physician-scientists are working to revolutionize how clinicians diagnose and treat diseases.
By Lydia Sauer, MD; and Paul S. Bernstein, MD, PhD
The imaging of the human eye has long guided clinical care, helping ophthalmologists better understand and diagnose pathologies and diseases of the eye.
The retina was first viewed in living patients by German physician and physicist Hermann von Helmholtz in 1851, who used fundoscopy to see the inside of the eye. Since then, beginning with delicate hand drawings, a variety of modalities have been developed. From fundus photography to advanced imaging technologies, they all give detailed information on the microstructure of the human eye.
Commonly used techniques are optical coherence tomography, which investigates the reflectance of different layers within the eye, and fluorescence-based imaging modalities, which give information about the molecules in the eye. Fluorescent molecules within the eye, known as fluorophores, can absorb and emit light to different extents. Some fluorophores absorb more light; these appear dark on images. Other fluorophores absorb less light; these appear bright on images.
Harvard scientist Francois C. Delori and coworkers spent considerable effort describing the fluorescence of the human retina and established how fluorophores are altered in diseases. The strongest fluorescence is emitted from lipofuscin, the dominant fluorophore within the retina.1 Accumulation of lipofuscin and other strongly fluorescent fluorophores can be seen in diseases such as age-related macular degeneration. Overall, changes in the fluorophores lead to altered light signals, which are emitted from the eye, and subsequently, ophthalmologists can detect these as disease-related changes.
The Possibility of Detecting Eye Diseases Earlier Than Ever Before
A promising but not yet widely established fluorescence-based imaging method is fluorescence lifetime imaging ophthalmoscopy (FLIO), which was invented by German scientist Dietrich Schweitzer and coworkers in 2002.2
In contrast to conventional fluorescence imaging, FLIO investigates a different property of the fluorescence, the fluorescence lifetime. This parameter tells us how long the fluorophores glow, which is independent of the strength of the individual fluorescence. Fluorophores that emit only weak amounts of light can be detected with this novel method.3
As some diseases start with very small changes, conventional fluorescence imaging may not always detect these tiny changes. FLIO, however, can do so, making it helpful in the early detection of diseases. It also helps to understand how eye diseases will progress over time.
A variety of retinal diseases have been investigated with FLIO, and many studies showed the advantages of FLIO technology over other imaging modalities.4, 5 The Moran Eye Center's FLIO, a prototype manufactured by Heidelberg Engineering in Germany, is the only device of its kind in the United States.
These fluorescence lifetime imaging ophthalmoscopy (FLIO) images show a family with MacTel. The youngest sibling (left, male, 22,) shows advanced-stage MacTel, highlighted by the blue center indicating the disease. One sibling, despite normal clinical exam findings, also shows FLIO alterations indicative of MacTel (middle, female, 26), whereas the other sibling has a completely healthy FLIO (right, female, 28). FLIO has been shown to be effective in detecting early stages of MacTel before retinal damage has occurred.
One interesting example of the advantages of FLIO relates to an inherited macular dystrophy called macular telangiectasia type 2 (MacTel). Initially, MacTel was thought to be a rare disease, but recent studies argue for a much higher prevalence than initially assumed.6 Early clinical trials of an implant that is aimed to stop disease progression showed promising results, which means that treatment for this disease might soon be available. It is, therefore, crucial to correctly diagnose this disease at an early stage for the success of the treatment.7 Many findings that lead to the diagnosis of MacTel, such as retinal cysts, para-foveal crystals, and even low macular pigment values, can be absent in early stages of the disease.
There is a need for a reliable imaging modality that can detect changes at early stages. Our research has shown FLIO to be an excellent option.8Not only can FLIO detect retinal changes in MacTel once the disease has manifested, but FLIO has also been shown to detect alterations in individuals before typical retinal damages occur.9As an example, we investigated one family with three siblings, in which the youngest, diagnosed at age 21, had severe MacTel. We found the genetic mutation in this patient.10 His two sisters (aged 26 and 28) showed completely healthy eye exams, although one carried the genetic mutation. Despite the healthy clinical exam, FLIO already shows MacTel-related changes in this woman, which may lead to an earlier treatment that might preserve her vision.
FLIO is a promising new technology that holds the potential to revolutionize how clinicians diagnose and treat diseases. By detecting changes before damages are manifest, FLIO may be a beneficial tool for clinical care in the near future.
About the Authors
Dr. Bernstein specializes in vitreoretinal diseases and surgery, retinal biochemistry, and macular and retinal degeneration. He directs clinical research and serves as associate director of research at the Moran Eye Center.
Dr. Sauer is a research associate in the Bernstein Lab who specializes in FLIO.
Footnotes
1. Delori FC, Dorey CK, Staurenghi G, Arend O, Goger DG, Weiter JJ. In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Investigative Ophthalmology & Visual Science 1995;36:718-729.
2. Schweitzer D, Kolb A, Hammer M, Anders R. [Time-correlated measurement of autofluorescence. A method to detect metabolic changes in the fundus]. Der Ophthalmologe: Zeitschrift der Deutschen Ophthalmologischen Gesellschaft 2002;99:774-779.
3. Lakowicz JR. Principles of Fluorescence Spectroscopy. Springer; 2006.
4. Dysli C, Wolf S, Berezin MY, Sauer L, Hammer M, Zinkernagel MS. Fluorescence lifetime imaging ophthalmoscopy. Progress in Retinal and Eye Research 2017;60:120-143.
5. Sauer L, Andersen KM, Dysli C, Zinkernagel MS, Bernstein PS, Hammer M. Review of clinical approaches in fluorescence lifetime imaging ophthalmoscopy. Journal of Biomedical Optics 2018;23:1-20.
6. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Progress in Retinal and Eye Research 2013;34:49-77.
7. Chew EY, Clemons TE, Peto T, et al. Ciliary neurotrophic factor for macular telangiectasia type 2: results from a phase 1 safety trial. American Journal of Ophthalmology 2015;159:659-666.
8. Sauer L, Gensure RH, Hammer M, Bernstein PS. Fluorescence Lifetime Imaging Ophthalmoscopy: A Novel Way to Assess Macular Telangiectasia Type 2. Ophthalmology Retina 2018;2:587-598.
9. Sauer L, Vitale AS, Andersen KM, Hart B, Bernstein PS. Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) Patterns in Clinically Unaffected Children of Macular Telangiectasia Type 2 (MacTel) Patients. Retina 2019.
10. Gantner ML, Eade K, Wallace M, Handzlik MK, Fallon R, Trombley J, Bonelli R, Giles S, Harkins-Perry S, Heeren TFC, Sauer L, Ideguchi Y, Baldini M, Scheppke L, Dorrell MI, Kitano M, Hart BJ, Cai C, Nagasaki T, Badur MG, Okada M, Woods SM, Egan C, Gillies M, Guymer R, Eichler F, Bahlo M, Fruttiger M, Allikmets R, Bernstein PS, Metallo CM, Friedlander M. Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy. The New England Journal of Medicine 2019 Oct. 10;381(15):1422-1433.