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PentaVision

Retinal Physician

Article

Nonsurgical Management of Vision Degrading Myodesopsia

Part 3 of a 3-part series on a vitreous pathology that can profoundly impact patients' lives.

By: Wei Gui, MD, Ronald H. Silverman, PhD, J. Sebag, MD
Retinal Physician August 1, 2022 Vol 19, Issue Special Edition 2022 Page(s): E1-E5

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Vision degrading myodesopsia (VDM) refers to clinically significant vitreous floaters that merit therapeutic consideration. Article 1 of this 3-part series described etiology and diagnostics, while article 2 addressed surgical management. In this article, nonsurgical options will be reviewed.

ND:YAG LASER VITREOLYSIS

Nd:YAG lasers have increasingly been used for vitreous opacities. Unfortunately, no scientific studies have explored the molecular effects of YAG laser on vitreous. Clinically, only opacities relatively far from the fundus (2 mm to 4 mm) and crystalline lens (5 mm) have been treated, to avoid collateral damage.1,2 It is unclear how these distances are measured and with what degree of accuracy. Lastly, it can be quite challenging to know which specific vitreous opacities are most disturbing to the patient, and to visualize/target these for treatment.

The clinical efficacy of YAG laser vitreolysis has been difficult to determine due to the lack of studies employing objective, quantitative outcome measures.2 Multiple (1 to 6) sessions have been used, with variable success.2,3 Heterogeneity in treatment protocols and different criteria for case selection in various reports make it difficult, if not impossible, to draw conclusions about the efficacy of Nd:YAG laser vitreolysis. Indeed, a recent Cochrane review3 determined that randomized clinical trials are needed with sham controls and comparisons to pars plana vitrectomy.

One randomized prospective study used YAG laser to treat visible Weiss rings (Figure 1) in 52 subjects, comparing results to sham treatment.1 The study design was flawed, however, because it was not truly masked, the sham techniques were not properly validated, and there were biases.4 While the YAG laser group reported more frequent symptomatic improvement (54%) than controls (9%; P<.001), this only occurred in about half of the subjects.5 Furthermore, although VFQ-25 had statistical improvements, the findings had little clinical significance, because the magnitude for dependency, role difficulties, near vision, color vision, peripheral vision, and distance vision ranged from only 2.8% to 11.5%. In fact, general vision actually worsened by 3.5%.5

Figure 1. Following posterior vitreous detachment, a Weiss ring (former site of vitreopapillary adhesion) can sometimes be seen via fundus photography (A) and ultrasonography (B). The detached posterior vitreous cortex can also be imaged by ultrasound (C). Reprinted with permission from Sebag J, ed. Vitreous in Health and Disease. Springer; 2014:193-222.
Figure 1. Following posterior vitreous detachment, a Weiss ring (former site of vitreopapillary adhesion) can sometimes be seen via fundus photography (A) and ultrasonography (B). The detached posterior vitreous cortex can also be imaged by ultrasound (C). Reprinted with permission from Sebag J, ed. Vitreous in Health and Disease. Springer; 2014:193-222.

A recent study using objective indices of vitreous structure and visual function to compare patients who had previously undergone YAG laser to controls found that compared to 60 untreated subjects with vitreous floaters, 37 patients previously treated with YAG had 17% less vitreous echodensity (P=.003), but no differences in VFQ-39, best corrected visual acuity, or contrast sensitivity function (CSF).6 The investigators postulated that because YAG lasers have a photo-disruptor effect but cannot photoablate,5 they produce smaller vitreous opacities but a larger number of them, and the net effect on vision was the same; in other words, there was degradation in CSF and unhappiness with vision and quality of life. Interestingly, a small subgroup of individuals who were happy with the results of YAG laser had less vitreous density and better CSF than the unhappy patients. Thus, although evaluations were not performed prior to laser, it is a possible that Nd:YAG is appropriate for some patients, but it is still unclear which patients. Thus, a prospective randomized study of Nd:YAG laser treatment of vitreous is warranted, using uniform laser treatment parameters/techniques and objective quantitative outcome measures, as previously recommended.1-6

COMBINED NANOPARTICLE/LASER VITREOLYSIS

A challenge in any laser therapy of VDM is localizing and targeting the offending vitreous opacities. An alternative to an imaging solution is the use of nanoparticles with an affinity to vitreous opacities. Gold nanoparticles coated with hyaluronan (HA) were found to adhere in vitro to synthetic collagen membranes as well as human vitreous opacities excised at surgery.7 Positively charged carbon quantum dots were also tested with similar findings.8 The plasmon properties of these nanoparticles tremendously enhanced laser light absorption so that low energy (1000-fold lower than YAG) laser nanosecond pulsed-laser (561 nm) illumination resulted in the formation of nanobubbles that generate high-pressure shockwaves (Figure 2). In vitro studies demonstrated efficacy7,8 and subsequently confirmed in vivo in rabbits with no untoward effects (electrophysiology and histopathology).9 Human trials are being planned.

Figure 2. Nanobubble/laser ablation of human vitreous opacities. Dark-field microscopy of human vitreous opacities (surgical specimens from 3 different patients) treated in vitro with 10 nm HA-AuNPs (concentration 1,012 particles/mL). The specimens were exposed to varying numbers of laser pulses (800 &amp;#x3BC;J; ~4.5 J/cm2). Vitreous opacities (yellow rectangles) and the laser beam (circles). Significant ablation of vitreous opacities can be observed with increasing numbers of pulses.7
Figure 2. Nanobubble/laser ablation of human vitreous opacities. Dark-field microscopy of human vitreous opacities (surgical specimens from 3 different patients) treated in vitro with 10 nm HA-AuNPs (concentration 1,012 particles/mL). The specimens were exposed to varying numbers of laser pulses (800 μJ; ~4.5 J/cm2). Vitreous opacities (yellow rectangles) and the laser beam (circles). Significant ablation of vitreous opacities can be observed with increasing numbers of pulses.7

PHARMACOLOGIC VITREOLYSIS

Another nonsurgical approach to treat VDM is pharmacologic vitreolysis.10,11 To date, several agents have been tested in both laboratory and clinical settings, classified as liquefactants (drugs that liquefy gel vitreous) and interfactants (drugs that lyse vitreoretinal adhesion).12 Ocriplasmin is a nonspecific protease that has both liquefactant and interfactant properties, which has received United States and European approval for clinical use.13 However, neither this nor any other agents have been tested to dissolve vitreous opacities that cause VDM. The availability of various collagenases and matrix metalloproteinases14 would seem fertile ground for future research and development efforts toward an injectable drug that would dissolve vitreous opacities and cure VDM.

HIGH-INTENSITY FOCUSED ULTRASOUND

Ultrasound is intricately woven into ophthalmology with B-scan ultrasonography, phacoemulsification, and most recently ultrasound-powered vitrectomy.15 Because ultrasound is a mechanical wave phenomenon whereby heating results when ultrasonic energy is absorbed by tissue, HIFU may be a useful approach to treat VDM. By focusing ultrasound, tissue heating can be restricted to a well-defined zone, the length and width of which depends on ultrasound frequency and the aperture and focal range of the transducer (Figure 3). As early as 1980, HIFU was explored to treat vitreous membranes,16 but is best known for treating glaucoma via thermal ablation of the ciliary body.17

Figure 3. Ultrasound-guided high-intensity (4.7 MHz) ultrasound (HIFU) treatment of simulated vitreous hemorrhage in ex vivo pig eye. Schematic of HIFU assembly (A). Focal region is imaged by B-scan probe. Photograph of assembly (B). B-scan with HIFU beam profile superimposed (C); HIFU focal point is within blood-mass near posterior pole. During HIFU, B-scan image is lost due to interference from HIFU (D). Disrupted hemorrhage after 1-second exposure (E). Further disruption and coagulation after second expo
Figure 3. Ultrasound-guided high-intensity (4.7 MHz) ultrasound (HIFU) treatment of simulated vitreous hemorrhage in ex vivo pig eye. Schematic of HIFU assembly (A). Focal region is imaged by B-scan probe. Photograph of assembly (B). B-scan with HIFU beam profile superimposed (C); HIFU focal point is within blood-mass near posterior pole. During HIFU, B-scan image is lost due to interference from HIFU (D). Disrupted hemorrhage after 1-second exposure (E). Further disruption and coagulation after second expo

The challenge of treating VDM with the thermal effects of HIFU relates to localization of the ultrasound energy. This problem was addressed by using a diagnostic ultrasound probe attached externally to the HIFU assembly, calibrated so that the treatment zone could be imaged during treatment, as shown in Figure 3.16,18,19 Disadvantages of this system are that it requires a water bath for coupling to the eye and that it is based primarily upon a thermal mechanism of action.

Thermal effects, however, are not the sole means by which HIFU can alter tissue. Focused ultrasound produces a radiation force, which is mechanical and unrelated to cancer-causing ionizing radiation.20 High-intensity focused ultrasound can also induce “streaming,” in which a fluid medium (such as vitreous) will flow in response to the ultrasound beam.21 Another potential treatment mechanism is cavitation.22 Histotripsy23 is a form of cavitation in which short, repeated HIFU pulses cause rapid oscillation of microbubbles that can break down soft tissue without significant heating, similar to what has been done using laser-induced nanobubbles.7,9 In addition, lipid-coated perfluorocarbon (PFC) nanodroplets with diameters of a few hundred nanometers have been developed to serve as a diagnostic ultrasound contrast agent and as cavitation nuclei in therapeutic applications,24 including in ophthalmology.25 Figure 4 demonstrates activation of PFC nanodroplets in vitreous. The use of targeting PFC nanodroplets could thus substantially reduce required ultrasound intensity to produce the desired bioeffect, similar to the use of nanoparticles and laser.

Figure 4. Image of ultrasound-activated nanodroplets in posterior vitreous of an ex vivo pig eye. An 18 MHz linear array was used for imaging and activation of nanodroplets in the probe&amp;#x2019;s focal plane. Nanodroplets, measuring approximately 100 nm in diameter, have a perfluoropentane core and lipid shell. The core undergoes a phase transition from liquid to gas when exposed to focused ultrasound at acoustic intensities just above diagnostic levels, minimizing thermal effects.
Figure 4. Image of ultrasound-activated nanodroplets in posterior vitreous of an ex vivo pig eye. An 18 MHz linear array was used for imaging and activation of nanodroplets in the probe’s focal plane. Nanodroplets, measuring approximately 100 nm in diameter, have a perfluoropentane core and lipid shell. The core undergoes a phase transition from liquid to gas when exposed to focused ultrasound at acoustic intensities just above diagnostic levels, minimizing thermal effects.

MYDRIATIC THERAPY

Patients with VDM sometimes describe decreased symptoms and better vision after pupil dilation. Although this phenomenon has not been formally investigated, Alfonso et al26 showed that in patients with diffractive intraocular lenses, increased pupil size was associated with improved CSF. In VDM, increased pupil size may be associated with not only improved CSF but also other aspects of visual function, such as reading accuracy and speed. Thus, there may be a potential role for 0.01% atropine drops, now FDA-approved to treat myopia progression in children.27

OPTICAL THERAPIES

A variety of optical methods have been tried to reduce suffering from the symptoms of VDM. Dark glasses can be limiting and at times worsen vision. Polarized lenses have not been shown to help with glare, nor have yellow lenses.28 However, optical correction of VDM might be possible if the specific optical aberrations can be characterized. Recent studies29 modeled human vitreous opacities that induce the visual phenomenon of floaters using optical software and image processing to study the Fresnel diffraction pattern. Nonsequential software based on Mie scattering theory was applied, determining that the distance between the vitreous opacities and the retina is inversely proportional to the sharpness of the edge of the shadow that will be cast. Characterizing and modulating light scattering30-32 would seem very relevant to nonsurgical management of VDM. RP

Wei Gui, MD, is a retina specialist with the Jules Stein Eye Institute of the Geffen School of Medicine, UCLA, in Los Angeles, California, and the VMR Institute for Vitreous Macula Retina in Huntington Beach, California. Ronald H. Silverman, PhD, is a professor of ophthalmic science in the department of ophthalmology at the College of Physicians & Surgeons of Columbia University in New York, New York. J. Sebag, MD, is a retina specialist with the Jules Stein Eye Institute, Geffen School of Medicine, UCLA, the VMR Institute for Vitreous Macula Retina, and Doheny Eye Institute of UCLA in Pasadena, California. This work was supported in part by the VMR Research Foundation, NIH Grants EB032082, EY028550 and P30 EY019007 and an unrestricted grant to the department of ophthalmology of Columbia University from Research to Prevent Blindness. The authors wish to acknowledge the assistance of Mark Burgess, PhD, in fabrication and imaging of nanodroplets.

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