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Five-year follow-up of low-level laser therapy (LLLT) in patients with age-related macular degeneration (AMD)

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Journal of Physics: Conference Series
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Five-year follow-up of low-level laser therapy
(LLLT) in patients with age-related macular
degeneration (AMD)
To cite this article: K Koev et al 2018 J. Phys.: Conf. Ser. 992 012061
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1234567890 ‘’“”
20th International Summer School on Vacuum, Electron and Ion Technologies IOP Publishing
IOP Conf. Series: Journal of Physics: Conf. Series 992 (2018) 012061 doi :10.1088/1742-6596/992/1/012061
Five-year follow-up of low-level laser therapy (LLLT) in
patients with age-related macular degeneration (AMD)
K Koev1,3, L Avramov 2 and E Borissova2
1Department of Ophthalmology, Medical University-Sofia,
8 Bialo More Str., 1000 Sofia, Bulgaria
2E. Djakov Institute of Electronics, Bulgarian Academy of Sciences,
72 Tzarigradsko Chaussee, 1784 Sofia, Bulgaria
E-mail: k00007@abv.bg
Abstract. The objective of this study was to examine long-term effects of low-level laser
therapy (LLLT) in patients with age-related macular degeneration (AMD). The research was
implemented for a period of five years. For LLLT, a He-Ne Laser with continuous emission at
633 nm (0.1 mW/cm2) was used in patients with AMD of all stages (dry to wet exudative forms
were included). In total, 33 patients (16 men and 17 women 66 eyes) with AMD of various
stages and a mean age of 68.7 ± 4.2 years were included in the study. Progressive, exudative
AMD was diagnosed in 8 eyes. 58 eyes had drusen or were depigmented. Laser radiation was
applied transpupillary to the macula for six times for three minutes once in two days; 22
patients with AMD (44 eyes) were randomly selected to receive mock treatment (control group
10 men and 12 women with a mean age of 69.3 ± 4.8 years). The visual acuity was followed
for a five-year period. The perimetry and Amsler test were used to screen central scotomas.
The fluorescein angiography of AMD and the control groups was examined. The visual acuity
remained unchanged in all patients in the control group. There was a statistically significant
increase in the visual acuity (p<0.001, end of study versus baseline) for AMD patients for the
period of five years after the treatment. The edema and hemorrhage in the patients with
progressive, exudative AMD significantly decreased. No side effects were observed during the
therapy. The prevalence of metamorphopsia, scotoma in AMD group was reduced.
In conclusion, this study shows that LLLT may be a novel long-lasting therapeutic option for
both forms of AMD. It is a highly-effective treatment that results in a long-term improvement
of the visual acuity.
1. Introduction
Age-related macular degeneration (AMD) affects 3050% of the individuals aged 60 years or older [1,
2]. AMD is diagnosed as either dry (non-neovascular) or wet (neovascular) [3]. Neovascular refers to
growth of new blood vessels in an area, such as the macula, where they are not supposed to be any [4].
Macular degeneration mainly affects the central vision, causing "blind spots" directly ahead [5]. The
dry form is more common than the wet form, with about 85 to 90 percent of all AMD patients
diagnosed with dry AMD [6]. The wet form of the disease usually leads to a more serious vision loss.
AMD results from defects in the choriocapillaris, Bruch’s membrane, and the retinal pigmented
3 To whom any correspondence should be addressed.
2
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20th International Summer School on Vacuum, Electron and Ion Technologies IOP Publishing
IOP Conf. Series: Journal of Physics: Conf. Series 992 (2018) 012061 doi :10.1088/1742-6596/992/1/012061
epithelium (RPE) underneath the macula [7]. The epitheliopathy diminishes the lysosomal activity and
phagocytosis of the outer photoreceptors and disrupts the transportation of cell debris through the RPE
to the choriocapillaris [2]. Certain types of therapy, including electrical stimulation and laser therapy,
have been developed during the recent years to decrease the regenerative process and return the
function [8, 9, 10]. Other studies [11, 12, 13] using He-Ne low-energy laser have indicated that it is
mainly the laser energy at 633 nm wavelength that affects the healing dynamics, producing changes in
the early phase of the repair process, i.e., the inflammatory phase. The incident beam of a helium-neon
laser (red light at 632.8 nm) can partially reach into 15 mm in the tissue, causing local vascular
dilation and accelerated blood flow. The laser thus plays a role in reducing inflammation, it has an
anti-swelling effect and promotes functional recovery. In addition, low-energy helium-neon lasers
strengthen the phagocytosis by macrophages and promote the absorption of inflammation factors [12].
Local helium-neon laser therapy contributes to the prevention of the inflammatory reaction and
promotes local tissue proliferation and wound healing [13].
Low-level laser therapy (LLLT) is a special type of laser therapy, whereby the irradiation used is
red or near infrared with a wavelength of 600 nm 1100 nm and an output power of 1 mW 500 mW
in a continuous-wave mode, or of low-energy density (0.0450 J/cm2) in a pulsed mode [14-17].
LLLT represents a novel therapeutic method that, in contrast with surgical laser applications, does not
damage tissues [18, 19].
A major cause of blindness in the Western world is degeneration of photoreceptors as a result of
point mutations in genes coding for either phototransduction-related proteins or other proteins
important for retinal function. Despite the diversity of mutated genes and proteins involved in this
heterogeneous group of progressive retinal dystrophies with homologous phenotypes, the final event
leading to blindness is apoptosis of photoreceptors [29]. .
Interleukin 1β (IL-1β), tumor necrotic factor-α (TNF-α), and interferon-γ (IFN-γ) play an important
role in inflammation, while platelet-derived growth factor (PDGF), transforming growth factor-β
(TGF-β) and blood-derived fibroblast growth factor (bFGF) are the most important growth factors of
periodontal tissues. Several authors have investigated the effect of low-level HeNe laser irradiation
on the gene expression of these mediators, e.g., in rats’ gingiva and mucosal tissues [30].
Twenty male Wistar rats were randomly assigned into four groups (A24, A48, B24, B48) in which A24
and A48 were cases and B24, B48 were controls. An incision was made on gingiva and mucosa of the
labial surface of the rat’s mandibular incisors. Group A24 was irradiated twice with 24 hours interval,
while the inflamed tissues of group A48 was irradiated three times with continuous HeNe laser
(632.8 nm) at a dose of 7.5 J/cm2 for 300 s. A cumulative dose of energy of 5.1 J impinged on the
68 mm2 irradiation zone. The authors found that the gene expression of IL-1β and IFN-γ was
significantly inhibited in the test groups (P < 0.05), while the gene expression of PDGF and TGF-β
were significantly increased (P < 0.05). The case and control groups did not have a significant
difference in the gene expression of TNF-α and bFGF (P > 0.05). These findings suggest that low-
level He-Ne laser irradiation decreases the amount of inflammation and accelerates the wound healing
process by changing the expression of genes responsible for the production of inflammatory cytokines
[30].
The combined treatment with He-Ne laser, Aftaquix and Cornergel was shown to be an efficient
method for eye therapy of cornea trauma [31]. Thus, the triple combination has a strong additive
effect, assuring total healing of the affected eyes with pronounced shortening of the mean duration of
the disease [31].
LLLT may increase cellular metabolism in choroidea, RPE, and in photoreceptors, where the
energy is absorbed by pigments [8].
Regular metabolic processes may be enhanced, and repair processes may be triggered or
accelerated. Recently, an increase in the expression of heat shock proteins was found in the retinal and
choroidal layers after sub-thermal transpupillary application of laser energy [24]. In in vitro
experiments, application of laser light was shown to increase cellular metabolic activity, the
generation of adenosine triphosphate, and phagocytosis [16].
3
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20th International Summer School on Vacuum, Electron and Ion Technologies IOP Publishing
IOP Conf. Series: Journal of Physics: Conf. Series 992 (2018) 012061 doi :10.1088/1742-6596/992/1/012061
The objective of this study was to examine the long-term effects of low-level laser therapy (LLLT)
in patients with age-related macular degeneration (AMD).
2. Methods and materials
This study of a case series was conducted in accordance with the Helsinki declaration. Informed
consent was obtained from all patients before entry into the study.
The research was implemented for a period of five years. For LLLT, a He-Ne Laser with
continuous emission at 633 nm (01 mW/cm2) (Mediray 04, Optella Ltd., Sofia, Bulgaria) was used in
patients with AMD of all stages (dry to wet exudative forms were included). In total, 33 patients (16
men and 17 women - 66 eyes) with AMD of various stages and a mean age of 68.7 ± 4.2 years were
included in the study. Progressive, exudative AMD was diagnosed in 8 eyes. 58 eyes had drusen or
were depigmented. Laser radiation was applied transpupillary to the macula for six times for three
minutes once every other day; 22 patients with AMD (44 eyes) were randomly selected to receive
mock treatment (control group of 10 men and 12 women with a mean age of 69.3 ± 4.8 years). The
visual acuity was followed for a five-year period. Perimetry and the Amsler test were used to screen
central scotomas. Fluorescein angiography of AMD and control groups was examined.
3. Results
Visual acuity remained unchanged in all patients in the control group. There was a statistically
significant increase in visual acuity (p<0.001, end of study versus baseline) for AMD patients for the
period of five years after the treatment. After LLLT, the visual acuity improved in a larger proportion
of patients.
Visual acuity improved optotypes in 62/66 eyes (93.9%; p <0.001)
Eyes:
by one row of optotypes in 18/66 (27,3%),
by two rows in 32 /66 (48,5.0%),
by three rows in 10/66 (15,2 %),
by four rows in 2/66 (2,9 %).
Visual acuity remained unchanged in 4/66 eyes (6.1%).
In patients treated by LLLT the improvement in visual acuity was in most cases accompanied by a
decrease in metamorphopsis, scotomas.
In patients with wet AMD, edema and bleeding were reduced.
4. Discussion
The results of this retrospective analysis of a case series are encouraging, as they unambiguously
demonstrated the beneficial effect of the LLLT, namely, improvement in the visual acuity in most
patients with AMD (93,9%). An increase of one to two rows of optotypes was observed in 40/66 eyes
with AMD. It has been found earlier that low-power laser light in the range of 1 1000 mW at
wavelengths from 632 nm to 1064 nm, stimulates a biological response [20, 21, 23]. These lasers emit
no heat, sound, or vibration. In particular, LLLT acts by inducing a photochemical reaction in the cell,
a process referred to as biostimulation or photobiomodulation [24]. Our eye examinations revealed
that LLLT diminished pigment accumulations and cystic drusen. Photo-biology works on the principle
that, when light hits certain molecules called chromophores, the photon energy causes electrons to be
excited and jump from low-energy orbits to higher-energy orbits. Absorption of photon energy by
neuronal mitochondria leads to numerous downstream neuroprotective effects [25]. Red and near
infrared (NIR) light is associated with significantly less safety concerns than light of shorter
wavelengths; they are therefore, the optimal choice for irradiating the retina [26]. Similar results were
obtained in diabetic rats by Maiya et al. [27], showing that laser-treated animals healed faster and
better than controls. LLLT accelerates wound healing in ischemic rat and murine diabetic wound
healing models, attenuates the retinotoxic effects of methanol-derived formic acid in rat models, and
attenuates the developmental toxicity of dioxin in chicken embryos. Potent neuroprotective effects
4
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20th International Summer School on Vacuum, Electron and Ion Technologies IOP Publishing
IOP Conf. Series: Journal of Physics: Conf. Series 992 (2018) 012061 doi :10.1088/1742-6596/992/1/012061
have been demonstrated in various models of retinal damage by red - 633/NIR light, with limited data
from human studies showing its ability to improve visual function. Improved neuronal mitochondrial
function, increased blood flow to neural tissue, upregulation of cell survival mediators and restoration
of normal microglial function have all been proposed as potential underlying mechanisms of the effect
of red/NIR light [16, 17].
Low-intensity light therapy uses light in the far-red region of the spectrum (633 nm) and modulates
numerous cellular functions [28]. Positive effects of LLLT include acceleration of wound healing,
improved recovery from ischemic injury of the heart, and attenuated degeneration of injured optic
nerves by improving mitochondrial energy metabolism and production. Various in vitro and in vivo
models of mitochondrial dysfunction were treated by a variety of wavelengths in LLLT. These studies
were performed to determine the effect of LLLT on physiologic and pathologic processes. LLLT
stimulates the photoacceptor cytochrome c oxidase, resulting in increased energy metabolism and
production. The experimental results demonstrate that LLLT stimulates mitochondrial oxidative
metabolism in vitro and accelerates cell and tissue repair in vivo.
5. Conclusions
Our study demonstrated that the LLLT has potential to become a long-term therapeutic option for both
forms of AMD, as it is effective in improving the patients’ visual acuity.
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The objective of this study of a case series was to examine the effects of low-level laser therapy (LLLT) in patients with age-related macular degeneration (AMD). AMD affects a large proportion of the elderly population; current therapeutic options for AMD are limited, however. In total, 203 patients (90 men and 113 women; mean age 63.4 +/- 5.3 y) with beginning ("dry") or advanced ("wet") forms of AMD (n = 348 eyes) were included in the study. One hundred ninety-three patients (mean age 64.6 +/- 4.3 y; n = 328 eyes) with cataracts (n = 182 eyes) or without cataracts (n = 146 eyes) were treated using LLLT four times (twice per week). A semiconductor laser diode (780 nm, 7.5 mW, 292 Hz, continuous emission) was used for transconjunctival irradiation of the macula for 40 sec (0.3 J/cm2) resulting in a total dose of 1.2 J/cm2. Ten patients (n = 20 eyes) with AMD received mock treatment and served as controls. Visual acuity was measured at each visit. Data were analyzed retrospectively using a t-test. LLLT significantly improved visual acuity (p < 0.00001 versus baseline) in 162/182 (95%) of eyes with cataracts and 142/146 (97%) of eyes without cataracts. The prevalence of metamorphopsia, scotoma, and dyschromatopsia was reduced. In patients with wet AMD, edema and bleeding improved. The improved vision was maintained for 3-36 mo after treatment. Visual acuity in the control group remained unchanged. No adverse effects were observed in those undergoing therapy. In patients with AMD, LLLT significantly improved visual acuity without adverse side effects and may thus help to prevent loss of vision.
  • R Velez-Montoya
  • S C Oliver
  • J L Olson
  • S L Fine
  • H Quiroz-Mercado
  • N Mandava
Velez-Montoya R, Oliver S C, Olson J L, Fine S L, Quiroz-Mercado H and Mandava N 2014 Retina 34/3 423-41
  • J Ambati
  • B K Ambati
  • S H Yoo
  • Ianchulev S Adamis
Ambati J, Ambati B K, Yoo S H, Ianchulev S and Adamis A P 2003 Surv. Ophthalmol. 48/3 257-93