Refractive Surgery and Frivolous Lawsuits

Pharmacological management of myopia
The quest for safe and effective drugs to retard progression of the condition

ALTHOUGH the development of surgical procedures for the correction of myopia has continued over the last two decades, there have been increases in the prevalence of the condition in Europe, the United States and Asia in the same period. Increases in the frequency and severity of myopia have been particularly pronounced in Asia.

Our understanding of the mechanisms by which myopia grows has improved with the development of animal models. These models have facilitated the determination of how the visual environment guides ocular growth for successful and unsuccessful emmetropisation.

Although clinical data led to the hypothesis that excessive accommodation directly caused myopia, experimental results subsequently demonstrated that axial length is regulated by the retina, involves active control of the scleral extracellular matrix and depends on image clarity and location of the focal plane.

Many pharmacological agents have been evaluated in the quest for a drug capable of safely and effectively treating or preventing myopia. Most initial studies on the use of muscarinic receptor antagonists, such as atropine, to prevent the progression of the condition were based on accommodation theories.

Some studies dating back to 1932 used atropine as a cycloplegic agent to prevent myopia, which was hypothesised to result from tension in the extraocular muscles during prolonged convergence.

In 1995, Sek-Jin Chew MD and collaborators in Singapore analysed the efficacy of unilateral atropine 1% eye drops in the myopic eye once a day in the morning in 47 patients between the ages of four and 17 years. The mean age was 10.

Their findings in Asian patients showed the drops were even more effective than in previous studies in Caucasians. A significantly greater increase in myopia was found in the control group after periods ranging from six months to one and a half years.
They demonstrated a mean increase of -2.0 +/- 2.06 D in myopia in the control group and a mean reduction of +0.17 +/- 0.97 D in the atropine group.

Control eyes increased in axial length by 1.18mm (SD, 1.56mm), while the treated eyes decreased in length by 0.017mm (SD, 0.22mm). Rates of change in globe length were 0.049 +/- 0.038mm/month of elongation in controls and 0.016 +/-0.05mm/month of shortening in atropinised eyes.

Dr Chew postulated that the reduction in axial length following treatment probably represented an expansion of the choroids, as demonstrated in chick eyes during recovery from myopia. He also suggested that atropine blockade of growth stimulation by the retina may have permitted collagenase-mediated remodelling of the sclera toward an emmetropia eye size.

Dr Chew cautioned that chronic use of atropine may be necessary until at least age 16, since the effects were reversible and myopia progressed at its previous rate following cessation of treatment.

Although only one patient stopped the drops because of a contact allergy, Dr Chew noted the side-effects of mydriasis, cycloplegia and photophobia and the long-term concerns regarding retinal phototoxicity. Atropine is a non-selective antagonist of muscarinic receptors.

Experimental studies clarifying the important role of the retina, rather than of the ciliary body, led to the search for muscarinic receptor subtype-specific antagonists which could reduce myopia while sparing muscarinic receptors – particularly the M3 subtype in the ciliary body.

Muscarinic receptor subtypes were demonstrated to have specific localisations within the eye. The M1 subtype, predominant in the retina, prevented experimental myopia in studies by Chew, Mazani, Stone, McBrien, Rickers and others.

One of the selective M1-muscarinic antagonists is pirenzepine which has little M3 activity and causes minimal cycoplegia. A topical gel formation of pirenzepine has been developed and is undergoing FDA clinical trials as the first pharmacological therapy for the treatment of myopia. Atropine is not approved by the FDA for that indication.

The US FDA Phase II multicentre, randomised clinical trial was conducted in 174 patients aged eight to 12 years. The patients were assigned in a 2:1 distribution to receive either 2% pirenzepine gel or placebo twice a day. Results to date have been very significant.

Progression of myopia
Progression of myopia was reduced by 50% in the pirenzepine-treated patients compared to the controls over the first year of the study.
Many questions still remain. The next phase of the FDA trials needs to address at what age and for how long the gel must be administered to prevent regression. If the medication is shown to have an excellent safety profile and minimum side-effects, it may be very useful even if it reduces but does not eliminate myopia.

The results of the pirenzepine clinical trial in Asia, where myopia is endemic and severe, will be of great interest. Our refractive surgical techniques are still much more effective and safe for lower levels of myopia than for very high myopia.

Pharmacological agents such as M1-muscarinic antagonists are not the only non-surgical approaches under investigation. Molecular genetic and epidemiological studies may ultimately provide the necessary information for successful gene therapy. In the meantime, improvements in surgical and pharmacological therapies must continue to be pursued actively.

Unfortunately, all too often these days, surgical and pharmacological treatments are advocated using pseudoscientific arguments or incomplete evidence or sometimes even complete disregard for any scientific basis.

Hopefully, the myopic foresight and quest for immediate financial gain of many in the ophthalmic industry will not prevent or delay the development of truly effective and safe pharmacological and surgical treatments for the management of myopia.

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