MODERN APPROACHES TO GLAUCOMA TREATMENT

by Valery Yerichev, Dr. Sc. (Med.), Vice-Director for Research Activities, Institute of Eye Diseases, Russian Academy of Medical Sciences, Editor-in-Chief of the Glaucoma journal

Glaucoma is a bad eye disease, leading to poor vision and irreversible blindness. More than 1,065 thousand glaucoma patients are registered in Russia, while another 600,000 do not even suspect of their pathology. Glaucoma is characterized mostly by an asymptomatic course (no manifest symptoms), which impedes its early diagnosis; the treatment of far advanced stages is not always effective.

DRUG THERAPY

Our idea of this disease as a medical problem has changed over more than 150 years of observations. Previously it was associated exclusively with high ophthalmic (intraocular) pressure, this viewpoint had predominated for more than a century. Now, according to the European Society for Glaucoma, it is regarded as a chronic progressive optic neuropathy covering a group of diseases with characteristic morphological changes in the optic nerve head and the retinal layer of nerve fibrils in the absence of other ophthalmic diseases and congenital abnormalities. The increasing death (apoptosis) of retinal neurons is accompanied by visual field anomalies. The intraocular pressure is not even mentioned in this definition. But the paradox is that formulation of the new strategy of treatment-to keep the visual functions-implies that the only proven effective method is to bring down intraocular pressure. All efforts towards

this end should be considered quite justified, until we learn the true "trigger mechanisms" and components of the pathogenesis of this grave disease.

The causes of rising intraocular pressure, though seemingly obvious, are in fact not quite clear yet. Intraocular fluid, continuously produced by the pigment-free epithelial cells of the ciliary body* processes, is eliminated from the eye through drainage pathways; normally its production and discharge are balanced. Intraocular pressure increases if discharge is someway impeded within the drainage system. By the way, according to one of the theories of glaucoma development-the mechanical theory-this factor is responsible for a specific atrophy of the optic nerve leading to irreversible loss of vision.

High intraocular pressure is really one of the main causes leading to irreversible degradation of visual functions. The arbitrary normal range for this parameter is 15-26 mm Hg (tonometric-according to the results of measurements) or 10-21 mm Hg (true tone). Actually such values are individual, and treatment should be aimed at bringing intraocular pressure to a level essential for preserving the visual function in a particular patient. Such levels are evaluated individually.

The entire range of normal intraocular pressure can be divided into three zones: low normal (10-14 mm Hg)- about 21 percent patients; medium normal (15-17 mm Hg)- 73 percent; and high normal (18-19 mm Hg)- 6 percent patients. The European Society for Glaucoma

*The ciliary body, a part of the middle (vascular) membrane of the eye, responsible for the accommodation process and participating in the production of aqueous humor; it is the site of fixation of Zinn's ligament, holding the lens in place.-Ed.

recommends distinguishing two levels of intraocular pressure: high and low normal. It is important to take into account such factors as the initial pressure values, severity of vision defects caused by the disease, rate of disease progress, and probable life expectancy. This arbitrary division indicates that different people have different tolerance levels of retinal ganglionar cells and their axons for ophthalmic tone.

The initial glaucoma therapy implies a certain algorithm. Step one is to administer a local hypotensive (i.e. reducing intraocular pressure) drug, prescribed to a newly detected case. Possible side effects at the local and overall level should be also taken account of. Such drug characteristics as proven high efficiency, good tolerance and convenient use are essential to good results.

The set of hypotensive drugs (eye drops above all) is fairly large and is represented mainly by five pharmacological groups: m-cholinomimetics, prostaglandins, beta-blockers, carboanhydrase inhibitors, and selective sympathomimetics (α2-adrenomimetics). How do they work piecemeal?

M-cholinomimetics stimulate m-cholinoreceptors of the vegetative (involuntary) nervous system causing contraction of the ciliary muscle fibrils, which leads to the desired effect. The most typical representative of this group is pilocarpin (extracted from Pilocarpus leaves), suggested more than 125 years ago. Because of some untoward effects and due to more effective and safe drugs in use now it is but seldom used in ophthalmology today.

Prostaglandins (lipid physiologically active substances) are characterized by very high hypotensive efficiency. The mechanism of their action is based on a better

intraocular fluid discharge considered to be an optimal physiological process. Their side effects and contraindications are at a minimum. Thus the cost/efficiency ratio is beneficial for the patient and public health economy alike. Such factors make prostaglandins preferable in many respects.

Beta-adrenoblockers have been in use since the middle of the 1970s. Their introduction has become a most important event in ophthalmology after the discovery of pilocarpin. They block beta-adrenoreceptors* located in the ciliary body, limiting the production of intraocular liquid and thus reducing the intraocular pressure. Years of experience have confirmed the efficiency of these drugs. Just like prostaglandins, they are convenient for the patient and are available. However, if used for a long time they entail side effects, such as bradycardia (heart rate down to 60 and less per min), serum lipid increase, etc. That is why drugs of this pharmacological group are contra-indicated for patients suffering from arrhythmia and pulmonary diseases with symptoms of bronchospasm.

Carboanhydrase** inhibitors, like beta-adrenoblockers, reduce the pressure by inhibiting the production of intraocular humor; but they are less effective. Drugs of this group are preferable when beta-adrenoblockers are contra-indicated for the patient.

As for selective sympathomimetics, the mechanism of their action is based on stimulation of pre- and postsynaptic α2-adrenoreceptors limiting the production

* Adrenoreceptors, proteins through which the hormones epinephrine (adrenaline) and norepinephrine (noradrenaline) realize their biological effects on cells. Two types of adrenoreceptors are distinguished: alpha (a) and beta (β).-Ed.

** Carboanhydrase, an enzyme catalyzing the reversible reaction of carbonic acid formation from carbon dioxide and water.-Ed.

of intraocular liquid, just as drugs of the two previous groups do.

Unfortunately, only one drug for local hypotensive therapy is produced in Russia, and this is proksodolol, a binary beta-adrenoblocker.

It is assumed that glaucoma therapy at the initial stage is preferable using just one drug. This someway guarantees that the patient will fulfil recommendations at a minimum cost of comfort. However, more than 60 percent of newly diagnosed cases have well-developed or far-advanced stages of the disease. Therefore, monotherapy cannot be always effective, as a higher dose will not lead to a greater pressure decrease, and simultaneously is fraught with a higher risk of side effects. In order to do without several drugs, fixed combined forms are used. About ten drugs of this kind are used. Years of clinical observations show their obvious advantages over monotherapy.

However, intraocular pressure normalization achieved at the beginning of therapy is not yet the cure. Glaucoma is a slowly progressing disease, and therefore, the patient should consult regularly a specialist so as to keep the intraocular pressure within the individual normal range and assess the visual function, the visual field above all, and the optic nerve disk status.

One can do well by prescribing 3 or 4 different drugs which have to be repeatedly instilled daily. But most likely as good as half of all patients will neglect recommendations for some reason, and this is tantamount to no treatment at all. A protocol based on real life possibilities will work much better.

Now, how long could a hypotensive drug therapy be carried out? It is a well-known fact: the earlier glaucoma

is diagnosed, the more effective will its therapy be. But, as we have mentioned above, more than half of newly diagnosed cases have well-developed or far-advanced stages, when local therapy is not always effective.

Our studies have shown that glaucoma, detected at its initial stage progresses in 16.6 percent cases within two years. In well-developed and far-advanced stages deterioration of visual functions, takes place in 34.6 percent cases within just 11 months. Local hypotensive therapy in such cases should be long enough for a medical and psychological conditioning of the patient to surgical intervention.

LASER

Laser treatment is considered to be an intermediate stage between drug therapy and surgery. The main indication for its use in primary glaucoma is a poor effect of drug therapy and a psychological status of the patient not ready to face surgery. The mechanism of the hypotensive effect of laser exposure is rather involved and depends on laser characteristics and the site of exposure. The most frequent operation is what we call laser trabeculoplasty*: it improves the intraocular fluid discharge in the drainage zone. The degree and duration of the hypotensive effect largely depends on the clinical situation before drug therapy. An important drawback of laser treatment is that as a rule the patient still has to instill hypotensive drugs after it.

Some Russian and foreign lasers reduce the intraocular pressure by modulating the structure responsible for the production of the chamber humor. They are used in terminal or far-advanced stages of glaucoma, in order to save the eye as an anatomical organ.

Speaking of short-pulse lasers in practical ophthalmology for glaucoma therapy, let us note that this approach was first proposed in 1972 by Mikhail Kras-nov, the mastermind of microsurgery of the eye in Russia, the founder and first head of the Ail-Union Institute of Eye Diseases of the Ministry of Health of the USSR (now, the Institute of Eye Diseases, Russian Academy of Medical Sciences). Dr. Krasnov is member of the Russian Academy of Medical Sciences.

SURGERY

The first operation for glaucoma-iridectomy-was carried out by German ophthalmologist Albrecht Grefe

* Trabeculoplasty, the making (with a laser beam) of additional holes in the drainage network of the anterior chamber corner of the eye, with the intraocular fluid drained through these holes.-Ed.

in 1857, demonstrating the possibility of surgical reduction of intraocular pressure. Later, with the accumulation of experience and new data, such interventions changed, while the problem they solved remained the same.

The persistent high level of ophthalmic tone and progressive deterioration of visual functions are absolute indications for surgical treatment. Other important indications are local therapy intolerance, the impossibility of regular qualified medical monitoring, unavailability of drugs, etc.

By their mechanism of action, all surgical operations can be classified in three groups: those improving the liquid discharge via natural routes; those creating new drainage routes (surgical interventions of this kind are now most frequent); and interventions inhibiting intraocular fluid production. Each of these methods has advantages and drawbacks, and when selecting a treatment strategy, the physician considers a good many factors so as to achieve a maximum hypotensive and functional effect and minimize the risk of probable complications.

Drainage devices and implants are an important trend in the surgical treatment for glaucoma. But these operations are resorted to in most severe cases, when repeated previous attempts at pressure normalization fail.

Scientists of the Institute of Eye Diseases have made an important contribution in developing surgical methods for glaucoma treatment. In 1964 Mikhail Krasnov was the first to propose a noninvasive technique of sinusotomy, which became a base for subsequent surgeries. Ophthalmologists know very well the innovation methods suggested in the 1970s by Boris Alekseyev, Dr. Sc. (Med.), Georgy Sokolovsky, Cand. Sc. (Med.), and other eye doctors. A new trend has been formed: patho-genetically-oriented operations. The correctness of this approach is now obvious.

At the beginning of the 1940s Acad. Mikhail Averbakh, an outstanding Soviet ophthalmologist, wrote: "An operation remains the most reliable method, and all glaucomatous eyes not operated on eventually grow blind, while many of those who have been operated on sometimes do not go blind till death". These words hold today.

NEUROPROTECTIVE THERAPY

It is well known that even under stable normalization of intraocular pressure achieved through drugs or surgery visual functions degrade in about every fifth patient. This necessitates additional (other than hypotensive)

therapy-neuroprotection. In glaucoma it protects the retinal neurons and optic nerve fibrils against the destructive effects of various (and numerous) factors. In addition to the high intraocular pressure leading mainly to mechanical injuries, there are other risk factors implicated, and these are arterial hypotension, the vasospastic syndrome, diabetes mellitus (excess of sugar in the blood), myopia. The cascade of nerve fibril damage is augmented by ischemia, high levels of cytotoxic free radicals and glutamate neurotransmitter. All these factors result in uncontrolled apoptosis (death) of the retinal ganglionar cells.

The need for neuroprotective therapy is obvious; however, there are other problems: thus, it is very difficult to treat the damaged retinal cells by targeted and timely delivery of drugs. The primary neuroprotector substances used in neurology often have many side-effects and their use may inhibit physiological functions of the central nervous system.

The main indication for neuroprotective therapy is progressive glaucomatous optic neuropathy, and its mandatory condition is in total systemic normalization of intraocular pressure. In this case it is important to eliminate or reduce hypoxia (oxygen insufficiency) of the optic nerve head first of all, correct disorders in metabolic processes, and treat concomitant diseases. Neuroprotection can be indirect (reduction of intraocular pressure) and direct (prevention of apoptosis, improvement of mitochondrial functions, blocking of the cascade of reactions causing neuronal injury). The arsenal of such drugs is large, which makes the choice of an effective and safe drug extremely difficult.

Paradoxically, but even if we succeed in improving the visual functions or the optic nerve status, we still cannot be quite sure that this result is due to the drug used. The main cause of such uncertainty is the lack of absolutely reliable criteria for evaluating the efficiency of this or that neuroprotective drug.

Concluding, I would like to stress that the problem of glaucoma remains a priority for the Institute of Eye Diseases, the Russian Academy of Medical Sciences, just as for other ophthalmological centers of the world. Our scientists are continuing basic and applied research. However, the cause of this skittish disease is still unknown, though many factors implicated in its pathogenesis have been well studied. We are still treating the symptoms by and large. Hence the high incidence of cases with irreversible blindness all over the world.