Robert Pinelli, MD

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Age-related macular degeneration (AMD) is an eye disease that leads to vision loss and can cause blindness. 

The dry form affects 80% of individuals with AMD; it tends to progress more slowly than the wet type and results in a subsequent loss of visual acuity.

At present, there is no approved treatment or cure for the dry form. In dry AMD, drusen form beneath the macula, causing a progressive loss of central vision over time.

ASRS 2020: Augmented-reality headset provides vision for AMD patients

However, several studies with strong and moderate evidence in the past 5 years have shown encouraging results in treating eye diseases, such as AMD,

retinopathy of prematurity, and diabetic macular edema, with a technique known as photobiomodulation (PBM).

PBM has also been used in the last 20 years for musculoskeletal pain, injury, dysfunction, and wound healing; to improve acute muscle performance and reduce muscle damage after exercise;

 and for neuropathic pain, lymphedema, and oral mucositis

PBM, or low-level light therapy, is the application of monochromatic light to a part of the body with the aim of repairing tissues and reducing inflammation, edema, and pain.

The process is not a heat therapy, but is more akin to photosynthesis in plants. Light, in the far red and near-infrared spectral range, can stimulate the cells, which leads to a cascade of photochemical reactions. 

The low-powered light is absorbed locally by the cytochrome c oxidase; mitochondrial energy is then produced by releasing oxygen, which results in increased adenosine triphosphate concentration and reduced oxidative stress. 

This photochemical reaction then activates enzymes and second messengers, leading to a cellular and, indirectly, systemic response by tissues that have not absorbed photons.

PBM can be used in acute and chronic eye diseases such as dry AMD, as mitochondrial dysfunction and oxidative stress play a key role in many macular diseases.

The technique does not worsen the disease, has no side effects, and is completely noninvasive.

 The protocol we use provides a combination of 9 PBM therapies.

Vision-related qualities of life: Impacts of advanced AMD

PBM is performed through a medical device which applies light-emitting diodes (LEDs) to stimulate cellular function and improve energy production. 

Each cycle of therapy delivers wavelengths between 590 nm and 850 nm for 4 minutes per eye. The PBM cycles are completed in approximately 1 month.

Clinical outcomes are determined using an optical coherence tomography (OCT) test; an Amsler grid, to detect wavy, broken, or distorted lines; a Pelli-Robson chart, for assessment of contrast sensitivity; a Snellen chart, for far visual acuity (VA); and a Jaeger chart, for near VA. The outcomes are measured at the end of the PBM procedure, after 3 months and after 6 months.

The clinical results of a case after PBM are shown in 

. Nine PBM cycles were administered to a patient over 1 month. 

After 1 month and 6 months, the OCT scan showed reduced drusen. The patient obtained subjectively improved vision, less eye strain, more color contrast, higher definition, and better far and near uncorrected VA. Contrast sensitivity improved from 1.8 to 2.0. Outcomes remained stable at the 6-month follow-up.

ASRS 2020: What Aviceda's lead candidate AVD-104 may mean for dry AMD

This case demonstrates a successful noninvasive treatment with improved quality of vision in dry AMD. Irradiation could, therefore, offer a new, noninvasive, adverse effect–free means of stimulating retinal stem cells to regenerate.

PBM is a treatment whereby quality of vision is improved and not worsened in some patients suffering from dry AMD, leading to better VA and contrast sensitivity and a less damaged macular profile. 

Overall, these results are encouraging and indicate how protocols could be consolidated in the future.

Promoting cellular regeneration by using light waves represents a challenge in ophthalmology. 

To date, there are no approved theories for many retinal diseases. Intriguingly, this protocol seems to offer an extremely promising approach to prevent VA from worsening and to promote tissue repair in the dry form of AMD. Moreover, the approach has the enormous advantage of being entirely noninvasive.

Characterizing local retinal layer changes in AMD

According to this hypothesis, at certain wavelengths, irradiation could regenerate retinal cells.

Thus, modulated light can offer a novel, valid therapeutic approach for dry AMD, which may facilitate the repair of damaged tissues in the retina and promote the survival and function of epithelial cells within the retinal pigmented epithelium.

Miorica Bertelli, OD, and Elena Scaffidi, MS, contributed to this report.

Roberto Pinelli, MD, is founder of the Switzerland Eye Research Institute in Lugano.

Markowitz SN, Devenyi RG, Munk MR, et al. A double-masked, randomized, sham-controlled, single-center study with photobiomodulation for the treatment of dry age-related macular degeneration. 

. Published online August 9, 2019. doi:10.1097/IAE.0000000000002632

2. Forte R, Cennamo G, Finelli ML, Bonavolontà P, de Crecchio G, Greco GM. Combination of flavonoids with Centella asiatica and Melilotus for diabetic cystoid macular edema without macular thickening. 

 2011;27(2):109-113. doi:10.1089/jop.2010.0159

3. Khoo HE, Ng HS, Yap WS, Goh HJH, Yim HS. Nutrients for prevention of macular degeneration and eye-related diseases. 

4. Pawlowska E, Szczepanska J, Koskela A, Kaarniranta K, Blasiak J. Dietary polyphenols in age-related macular degeneration: protection against oxidative stress and beyond. 

 2019;2019:9682318. doi:10.1155/2019/9682318

5. Riva A, Togni S, Franceschi F, et al. The effect of a natural, standardized bilberry extract (Mirtoselect) in dry eye: a randomized, double blinded, placebo-controlled trial. 

6. Tao Y, Chen T, Yang GQ, Peng GH, Yan ZJ, Huang YF. Anthocyanin can arrest the cone photoreceptor degeneration and act as a novel treatment for retinitis pigmentosa. 

. 2016;9(1):153-158. doi:10.18240/ijo.2016.01.25

7. Hamblin MR. Photobiomodulation or low-level laser therapy. 

. 2016;9(11-12):1122-1124. doi:10.1002/jbio.201670113

8. Merry G, Devenyi R, Dotson R, Markowitz SN, Reyes SV. Treatment of dry age-related macular degeneration with photobiomodulation. Paper presented at: Association for Research and Vision in Ophthalmology 2012; May 7, 2012; Fort Lauderdale, FL.

9. Natoli R, Valter K, Barbosa M, et al. 670nm photobiomodulation as a novel protection against retinopathy of prematurity: evidence from oxygen induced retinopathy models. 

. 2013;8(8):e72135. doi:10.1371/journal.pone.0072135

10. Tang J, Herda AA, Kern TS. Photobiomodulation in the treatment of patients with non-center-involving diabetic macular oedema. 

. 2014;98(8):1013-1015. doi:10.1136/bjophthalmol-2013-304477

11. Ferraresi C, Kaippert B, Avci P, et al. Low-level laser (light) therapy increases mitochondrial membrane potential and ATP synthesis in C2C12 myotubes with a peak response at 3-6 H. 

 2015;91(2):411-416. doi:10.1111/php.12397

12. Koev K, Avramov L, Borissova E. Clinical results from low-level laser therapy in patients with autosomal dominant cone-rod dystrophy. 

https://iopscience.iop.org/article/10.1088/1742-6596/992/1/012060

13. Holanda VM, Chavantes MC, Wu X, Anders JJ. The mechanistic basis for photobiomodulation therapy of neuropathic pain by near infrared laser light. 

. 2017;49(5):516-524. doi:10.1002/lsm.22628

14. Baxter GD, Liu L, Petrich S, et al. Low level laser therapy (photobiomodulation therapy) for breast cancer-related lymphedema: a systematic review. 

 2017; 17(1):833. doi:10.1186/s12885-017-3852-x

15. Zadik Y, Arany PR, Fregnani ER, et al; Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines. 

 2019;27(10):3969-3983. doi:10.1007/s00520-019-04890-2

16. Natoli R, Zhu Y, Valter K, Bisti S, Eells J, Stone J. Gene and noncoding RNA regulation underlying photoreceptor protection: microarray study of dietary antioxidant saffron and photobiomodulation in rat retina. 

17. Gkotsi D, Begum R, Salt T, et al. Recharging mitochondrial batteries in old eyes. Near infra-red increases ATP. 

. 2014;122:50-53. doi:10.1016/j.exer.2014.02.023

18. Huang YY, Chen ACH, Carroll JD, Hamblin MR. Biphasic dose response in low level light therapy. 

2009;7(4):358-383. doi:10.2203/dose-response.09-027.Hamblin

19. Saini JS, Temple S, Stern JH. Human retinal pigment epithelium stem cell (RPESC). 

2016;854:557-562. doi:10.1007/978-3-319-17121-0_74

Articles

Study results demonstrate effectiveness in treating dry age-related macular degeneration

Photobiomodulation shows the power of light

Novel procedures continue to provide refractive patients with surgical options that are safe, virtually painfree, and with reduced risk of postoperative complications.
	
	 

The Switzerland Eye Research Institute, for one, is oriented toward less-invasive 

 techniques that reshape the corneal surface without penetrating the eye. Femtolasik and Femtolasik Xtra are established procedures worldwide,

 and involve customized reshaping of the 

 to eliminate myopia, hyperopia, astigmatism, and presbyopia. 
	
	

Exploring ins, outs of better imaging for LASIK, refractive surgery 

Over the past six years, we have been approaching corneal surgery in Lugano using a novel procedure that unites Femtolasik and transepithelial crosslinking. 

This combined technique is known as Femtolasik Lux, and aims to increase the stability of the visual outcome in patients, thereby maintaining a healthy and robust 

Femtolasik Lux is a non-invasive, “no-touch” procedure, which-at no point touching the eye with any instrument-uses three different light sources to resolve any visual defect in a few minutes without pain.

This procedure leads to a final sharp refractive result, provides a stronger 

 tissue that is less vulnerable to curvature change, and reduces refractive error regression and incidence of corneal ectasia.

Safety, effectiveness, and excellent long-term results have been demonstrably achieved.

There is a protocol for this technique called the Lugano Protocol. ParaCel eye drops are used to soak the corneal epithelium for a time that cn range from 30 to 50 seconds after the repositioning of the flap. 
	
	

CXL-LASIK pairing can enhance refractive outcomes

Soaking is thus customized and a very minimal quantity of riboflavin is delivered to the

 in a short time, which is possible due to its osmotic properties.

Exposure to UV-A is performed with Avedro technology at 30 mW/cm

. This quantity of ParaCel and timing of exposure are enough to permit ParaCel to penetrate the flap and spread into the stroma.

Unlike other data reported in the current literature, we osmotically soak the 

over the flap leaving the interface free from any possible irregularity due to riboflavin on the 

Facing challenge of corneal infection management in operated eyes

The purpose is to take advantage of CXL treatment, usually performed to strengthen corneal tissue, in order to stiffen a prospective weakened 

and prevent corneal ectasia, which is every refractive surgeon’s nightmare. 

Though the chances of ecstasia occurring have become very much reduced over the past decade, it nonetheless remains a remote possibility to be avoided. I am pleased to report that after our six years with this procedure, we have not experienced one case of ectasia.

As far as side effects are concerned, I believe that there are no adverse events to report and no flap wrinkles. 

It seems that the riboflavin penetration did not induce any refractive change. On the contrary, a greater stability and a better and softer crosslinking of the 

were observed, and less regression, particularly regarding myopic astigmatism.
	
	

Traversing the CXL pathway: Where do we go from here?

With ParaCel being osmotic, its penetration through the cap to the corneal stroma probably restores biomechanical strength to the 

.
	
	This aspect enables the flap to become better reintegrated into the 

, becoming one with the other corneal layers, and thereby more stable and less susceptible to dislodging, unlike the situation in the past. I believe that this is why we don’t see any ectasia.

In addition to the assessment of postoperative visual data, the self-perceived satisfaction with the procedure was evaluated by our Psychology of Vision Unit: objective/subjective outcomes were found to be equally positive.

Researchers said their experience with Femtolasik Lux with the Lugano Protocol has also been positive, and they fully intend to continue with this technique in order to restore vision and improve the overall quality of life in our patients

Miorica Bertelli, OD, Caterina Berti, OD, and Elena Scaffidi, MS, contributed to this report.

Dr. Pinelli is founder of the Switzerland Eye Research Institute.

1. Aslanides IM, Mukherjee AN. Adjuvant corneal crosslinking to prevent hyperopic LASIK regression.

2. Wu Y, Tian L, Wang LQ, Huang YF. Efficacy and Safety of LASIK Combined with Accelerated Corneal Collagen Cross-Linking for Myopia: Six-Month Study. Biomed Res Int. 2016;2016: Article number: 5083069.

3. Rajpal RK, Wisecarver CB, Williams D, Rajpal SD, Kerzner R, Nianiaris N, Lytle G, Hoang K. Lasik Xtra Provides Corneal Stability and Improved Outcomes. 

4. Raiskup F, Pinelli R, Spoerl E. Riboflavin osmolar modification for transepithelial corneal cross-linking. 

Robert Pinelli, MD

Articles

Photobiomodulation shows the power of light

Procedures set a new horizon in refractive surgery