INTRODUCTION

Presbyopia is characterized by a progressive loss of accommodation that causes a decrease in near visual acuity without correction and that affects all individuals from the fourth decade of life. It is expected that the global prevalence of presbyopia will reach 1,400 million in 2020 and 1,800 million in 2050. Without an intervention to increase access to corrective glasses, the global number of individuals that will present a disability associated with uncorrected presbyopia will increase to 563 million by 2020¹.

Even in the developed world it has been shown that patients with corrected presbyopia have a decrease in quality of life similar to that of treated hypertension. It is estimated that approximately up to 10% suffer from such limitation due to the correction of presbyopia, that they could be candidates for another type of correction other than glasses or contact lenses, among others, the surgical².

Although nowadays we have several options for correcting presbyopia surgically, all of them present certain limitations and / or adverse effects, always requiring a balance between advantages and disadvantages³.

It is not strange, therefore, that there is special interest in other types of alternatives other than glasses / contact lenses or surgery.

In this chapter we will review the current state of the medical treatment of presbyopia with eye drops and a recent alternative for its control by electrostimulation.

1. MEDICAL TREATMENT WITH EYE DROPS

In this section we will have to differentiate two types of approaches. In the first place we find the options that aim to induce miosis with or without accommodation stimulation, and in the second, another alternative whose objective is to induce a softening of the lens^4,5.

1.1. Eye drops to induce miosis with or without accommodation

The induction of miosis has a pinhole effect that increases the depth of focus and this is the basis of most treatments that try to treat presbyopia. It is therefore a pseudo accommodation. In some cases, the drug is also capable of inducing contraction of the ciliary muscle, but this effect would only theoretically be effective in pre-presbyopic crystalline lenses that still retain some capacity to deform. Induced miosis must balance the increase in depth of focus, and not produce the side effects of excessive miosis, in terms of reducing the amount of light entering the eye and degradation of the image by diffraction of the light⁴. Several strategies have been proposed, some of them contradictory, for the treatment of presbyopia with eye drops.

1.1.1. Parasympathomimetic antagonists

The most commonly used drug has been pilocarpine. Although it produces miosis, it is also accompanied by an accommodation spasm that can cause myopia and headache. The contraction effect of the ciliary muscle is only successful in patients with incipient presbyopia. Several topical non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with pilocarpine, such as diclofenac, nepafenac and bromfenac. It is argued that the reason for adding an NSAID would be to try to counteract the undesirable effects of pilocarpine by causing a decrease in ciliary spasm and prolongation of miosis. However, it has not been shown that NSAIDs decrease muscle spasm or prolong miosis, moreover, in cataract surgery, what has been shown is that they help maintain mydriasis. In addition, the long-term side effects of treatment with an NSAID on the ocular surface should be considered⁴. In one study, the combination of pilocarpine 1% with diclofenac 0.1% was used in 100 patients aged 45 to 50 years for 5 years, instilling the mix every 6 hours. All the patients could read J1 and preserved far vision of 20/20, the most frequent side effect being the burning sensation after the instillation that caused a patient to abandon the treatment⁶. Another similar combination of two parasympathomimetic drugs and one NSAID called "Presby eye drops", in whose study only 15 patients were included, reported results similar to the previous one⁷. In 2015, the results of another combination of parasympathomimetic and NSAIDs (PresbyDrops, FEPA-SAET group) was presented. The study included 81 patients aged 42 to 74 years. The results showed an increase in vision without correction, both for near and far. A quarter of the patients experienced adverse reactions that included nausea, headache, blurred vision or feeling dry or itchy⁸.

1.1.2. Sympathomimetic agonist and parasympathomimetic agonist

This association has been carried out mainly with the association of pilocarpine or carbacol with brimonidine. Brimonidine is capable of producing miosis, it rather limits the mydriasis that occurs in low light conditions, and reinforces the effect of the parasympathomimetic drug⁹. However, one of the drawbacks of this association is the high frequency of allergy to brimonidine (up to 25.7% of cases)¹⁰. In 2015, Abdelkader published the results of a randomized, double blind, placebo-controlled study of 48 emmetropic and presbyopic patients, treated in one eye with carbacol 2.25% and brimonidine 0.2%, for 3 months. They found an improvement of 4 near vision lines without correction at the time of instillation and a decrease in effect, with an average duration of 8 hours. All patients in the treated group did without glasses for near. Distant vision was not affected, and side effects included burning sensation in 3.3% of cases, headache in 10%, and difficulty in low light vision in 3.3%¹¹.

1.1.3. Muscarinic agonist and muscarinic antagonist

The PRX-100 or Liquid Vision developed by "Presbyopia Therapies" contains aceclidine and tropicamide. With this combination, it is attempted to cause miosis without stimulation of accommodation. In the study that included only 9 patients, the pupil diameter was reduced to 1.6 mm with a duration of 8 hours. Visions of J1 with equal or better visual acuity were obtained and without headache, although there were some cases of hyperemia and stinging sensation¹². Another alternative in the same line is PresbyPlus: two parasympathomimetics and one parasympatholytic. This product was instilled bilaterally twice a day, in a clinical trial in which 90% of patients could see J4 to J1 for one year, without adverse reactions¹³.

1.1.4. Muscarinic agonist with sympathomimetic antagonist

A patent has been published with pilocarpine and dapiprazole and with pilocarpine and thymoxamine. The idea is that miosis occurs due to the synergistic action of both drugs, reducing the spasm of the ciliary muscle (by reducing the dose of the muscarinic agonist). However, there are no clinical results to date¹⁴.

1.1.5. Combination of six active ingredients

Recently a combination of six compounds has been evaluated (patent pending: European Patent Application No. PW34087KMOB) that is instilled bilaterally: pilocarpine 0.247%, phenylephrine 0.78%, polyethylene glycol 0.09%, nepafenac 0.003%, pheniramine 0.034% and naphazoline 0.003%. The reason for the choice of this combination is because it stimulates the contraction of the ciliary muscle while maintaining a physiological variation of the pupil diameter, avoiding the decrease of vision in low light conditions. Pilocarpine stimulates the accommodation, providing both miosis and contraction of the ciliary body and can improve the production of tears by stimulating the secretion of the lacrimal gland. Phenylephrine, nepafenac and pheniramine limit the spasm of the ciliary muscle, vascular congestion and hyperemia induced by pilocarpine, avoiding the excess of constriction of the pupil. Naphazoline increases the release of acetylcholine and reduces the release of norepinephrine, enhancing the relaxing effect of pilocarpine in the dilator muscle of the pupil, thus relieving its side effects, and the lubricating effect of polyethylene glycol protects against the typical burning sensation caused for most of these compounds and improves the tolerance of use of these eye drops. The study included 14 patients who experienced an improvement of the near visual acuity without correction of 2-3 lines for about 5 hours, without deterioration of the far visual acuity without correction, being very satisfied with the efficacy and tolerance of the medication¹⁵. In summary, it could be concluded that there are few studies, with short series, few published in peer-reviewed journals and results presented only in congresses that have not been published. The evidence of their effect is therefore scarce. In most cases a combination of several drugs is needed so that some counteract the side effects of the others. Drugs would be required to induce a miosis of sufficient duration, with minimal or no myopic change, and free of side effects. In view of the scarcity of studies and variety of combinations, this approach, although attractive, is far from being able to be implemented in clinical practice^4,5.

1.2. Lens softening

The process of increasing the rigidity of the lens with age is complex. One of the mechanisms involved seems to be the increase of the disulfide groups. The hypothesis was then raised that a treatment with an exogenous antioxidant increases the elasticity of the lens. Since both cortical and nuclear fibers have glutathione reductase, and thioredoxin reductase, R-lipoic acid was selected for investigation. This acid is an oxidized disulfide whose reduction by glutathione or thioredoxin produces the potent antioxidant dihydrolipoic acid (DHLA)¹⁶.

An experiment was carried out in mouse lenses showing that the in vitro treatment with lipoic acid reduces the disulfide bridges between the lens proteins, making it more elastic. This occurs in a concentration-dependent manner¹⁶. Subsequently, acid was synthesized and the colloidal ester of lipoic acid (LACE) was purified, demonstrating a greater penetration in the eye of this compound than lipoic acid. 8-month-old mice were treated with this compound 3 times a day in one eye for 5 weeks. After the treatment, the crystalline lenses were extracted, and their elasticity was evaluated with a computerized instrument. A control group of 8-week-old untreated mice was included for comparison. It was possible to objectify that the crystallines of the treated eyes were more elastic than the crystallines of the contralateral eye and most of the time, even more elastic than those of the 8-week-old mice of the control group without treatment. The study concluded that this treatment could be used to improve the amplitude of accommodation in humans¹⁶.

The Encore Vision company conducted a prospective, double-blind, randomized, multicenter, placebo-controlled phase I/II study in humans with the compound EV06 (LACE). Patients between 45 and 55 years received treatment for 90 days with 1.5% EV06 every 12 hours in the treatment group (75 patients) and placebo treatment in the control group (25 patients). The drug was well tolerated, did not induce changes in distance visual acuity and no adverse effect was detected. There was a statistically significant improvement in near visual acuity with correction for far¹⁷.

Probably, among the medical treatments with eye drops, this approach of softening the lens is the one that makes the most sense and has more possibilities of success, since it deals with the cause of the problem, unlike the treatments that try to induce miosis. However, studies with more patients and longer term will be needed before their clinical application.

2. PULSED MICRO-ELECTROSTIMULATION OF THE CILIARY MUSCLE

Very recently, the results of a study on a new non-invasive alternative to reestablish accommodation in patients with incipient presbyopia have been published: the pulsed micro-electrostimulation of the ciliary muscle¹⁸. This technique intends that the muscle recovers its contraction and power, in the same way that it has been seen that the pulsed electrostimulation has a beneficial effect on other atrophic muscles.

In the prospective and non-randomized study, 27 emmetropic patients aged 40 to 51 years and 13 control patients were included. The protocol included 4 sessions of pulsed micro-electrostimulation (2 seconds on; 6 seconds off) with 26 mA for 8 minutes, with an interval of 2 weeks. For this, the Ocufit medical device (Sooft, Montegiorgio, Italy) was used. It consists of special contact lenses, and a generator, to which they connect. The treatment was performed under topical anesthesia. The device consists of a 20 mm polycarbonate scleral contact lens equipped with four microelectrodes placed 3.5 mm outside the limbus area, corresponding to the region of the ciliary body. The four electrodes are connected to the electric generator. During the 8 minutes of treatment 60 cycles of electrostimulation are applied.

At the end of the procedure, two drops of steroid and antibiotic combination are instilled, and no other treatment is necessary. The treatments are performed sequentially in either eye during the same session. The postoperative examinations were carried out two weeks after each treatment and therefore, the last one, two months after the beginning.

Improvement in near vision and in the reading speed was observed without correction, compared to the preoperative values. In the control group all measurements were similar to preoperative. Examination by ultrasonic bio-microscopy showed an increase in the thickness of the lens during the accommodation and a decrease in its anterior and posterior curvature radii. A questionnaire on satisfaction at the last exploration showed a 96.3% satisfaction. The only adverse effect detected was ocular dryness shortly after the procedure, which resolved 48 hours later with artificial tears.

The published study is the first and only of its kind that has been performed, although the effects of electrostimulation to reduce intraocular pressure were already known^19,20. More studies will be required to optimize the parameters of the sessions. In the case of stimulating a muscle, it is expected that the treatment will be applied in young presbyopic patients, who still do not have a totally rigid crystalline lens. And because it is a passive stimulation, it will be necessary to repeat the sessions with a pattern adjusted to the individual response of each patient.

The possibility of associating this treatment that stimulates muscle contraction with medical treatment with lipoic acid eye drops that soften the crystalline lens has been proposed, resulting in a synergic treatment at least theoretically, since there is no experience with this association.