INTRODUCTION

Keratoconus is generally a progressive, bilateral cone-like ectasia of the cornea that affects approximately 1 in 2,000 people in the general population, which is usually diagnosed in young adult patients ⁽¹⁾. It is characterized by localized corneal thinning and protrusion, which lead to high myopia and irregular astigmatism that reduces visual quality. The initial treatment of keratoconus is the use of glasses and/or contact lenses ⁽¹⁾. More advanced stages of the disease are treated by various surgical procedures ⁽²⁾. However, the relief of keratoconus symptoms using currently available treatment modalities may not be permanent, and it remains impossible to predict with certainty how long favorable results will persist.

The pathophysiology of keratoconus remains poorly defined, but its etiology is known to be multifactorial and it is an autosomal dominant trait with variable phenotypic expression ⁽²⁾. It is associated with many ophthalmic and systemic conditions, such as Down syndrome, eye rubbing, mitral valve prolapse, collagen vascular disease, and a history of contact lens wear ⁽²⁾. Other conditions include eyelid diseases such as blepharoptosis ⁽³⁾ and floppy eyelid syndrome ⁽⁴⁾.

Keratoconus patients present with excessive eye blinking, and usually develop a routine of chronic eye rubbing with consequent excessive manipulation of the periocular area. Augmented pressure to the eyelids may cause further topographic changes to the cornea ^(5,6), and eyelid muscular force can translate to the ocular surface and exacerbate symptoms. It was therefore hypothesized that reducing eyelid muscular force may provide a novel treatment option for keratoconus that inhibited the progression of damage to the cornea.

The use of botulinum toxin type A (BTX-A) in medicine was first reported in 1980 for treating strabismus ⁽⁷⁾. It blocks the release of acetylcholine into the neuromuscular junction, leading to temporary muscle weakness or paralysis ⁽⁸⁾. BTX-A is now a front-line treatment option for focal dystonias such as essential blepharospasm and hemifacial spasm, and it has become a major therapeutic drug with valuable applications in diverse medical subspecialties ⁽⁸⁾. The purpose of this study was to evaluate, as a potential novel therapy for patients with keratoconus, whether reducing eyelid muscular force through the administration of BTX-A into the orbicularis oculi muscles could prevent the progression of corneal damage.

METHODS

RESULTS

A total of 40 individuals (40 eyes) were enrolled at baseline. Three participants were lost due to voluntary non-participation in some of the follow-up visits, and so only 37 eyes of 37 participants were included for some of the follow-up analyses.

All of the eyes were graded according to the Amsler-Krumeich classification ⁽⁹⁾, based on each participant's refraction, mean central K-reading, corneal signs, and corneal thickness. Eyes were graded stage I, II, or III according to this classification.

Visual acuity

Both UCVA and BSCVA, measured using a logMAR chart, were similar between the two study groups at baseline and at all follow-up time points (Figure 1.

Figure 1 Uncorrected visual acuity (UCVA) and best corrected visual acuity (BCVA) on a logMAR chart. 

Topographic results

After adjusting for baseline levels, there was no statistically significant difference between the groups at the 18-month follow-up for all three topography parameters assessed with the Pentacam^® (flattest keratometry (K1), p=0.795; steepest keratometry (K2), p=0.562; and mean keratometry (Km), p=0.903), and with the Oculyzer^® (K1, p=0.783; K2, p=0.783; and Km, p=0.842) (Figure 2).

Figure 2 Topographic corneal indexes (steepest, mean, and flattest keratometry) by Pentacam^® and Oculyzer^® in the control and botulinum toxin-A injection groups.BTX-A= botulinum toxin-A. 

DISCUSSION

Various factors can result in the deterioration of keratoconus, including ultraviolet-B light, atopy, mechanical eye rubbing, and improperly fitting contact lenses ⁽²⁾. Researchers have studied genetic, histopathologic, biomechanical, and inflammatory aspects of the disease to elucidate keratoconus etiology and improve the currently available treatments ^(10,11). Elevated tension within the eyelid can be transmitted to the juxtaposed corneal surface, thereby altering the corneal topography ^(5,12); thus, reducing the muscular force of the eyelid may result in changes to corneal measurements in keratoconus patients. With the goal of developing new treatment options for keratoconus, the present study evaluated whether BTX-A injection into the orbicularis oculi muscles of keratoconus patients improved corneal topographic parameters by reducing the eyelid muscular forces that are translated to the ocular surface and exacerbate symptoms.

However, the administration of two BTX-A doses over 6 months resulted in no changes to visual acuity and refraction in our keratoconus cohort. Previous studies have reported no success in treating keratoconus by cross-linking corneal collagen matrices to stabilize the ocular tissue ^(13,14), an approach that also brought no changes in UCVA, BSCVA, SE, or keratometry. Another keratoconus intervention involves implanting plastic intracorneal ring segments to stabilize the cornea, but this brings the risk of ocular complication, requiring ca reful selection of patients appropriate for the procedure ^(2,15,16). Several factors contribute to the development of corneal astigmatism, including age, sex, tear film insufficiency, IOP, and physical pressure exerted by the eyelids ⁽¹⁷⁾. In a 2015 report by members of our research team, the magnitude of astigmatism was significantly reduced and palpebral fissure height significantly increased in the affected eyes of hemifacial spasm patients treated with BTX-A ⁽¹⁸⁾. In that study, BTX-A treatment temporally alleviated eyelid tension, thereby potentially reducing the transmission of physical forces from the eyelids to the cornea. In the present study, no statistically significant differences were observed in the corneal topographic parameters and palpebral fissure dimensions of keratoconus eyes during the 18 months following BTX-A administration. Usually, BTX-A effects appear within 1-2 days, peak at 1-2 weeks, and gradually decline after 3-6 months, depending on the patient's clinical condition ⁽⁸⁾. We observed no differences in palpebral fissure measurements 3 months after the first and second BTX-A applications, probably because the tension exerted by the eyelid on the cornea in keratoconus patients is not as high as it is in hemifacial spasm patients. Thus, BTX-A application to the orbicularis oculi muscles of keratoconus patients was not associated with significant changes in corneal astigmatism or palpebral fissure dimensions.

Methodologies for evaluating eyelid tension are not standardized and vary between studies, complicating the comparison of results from different groups. The present study indirectly evaluated the reduction in eyelid muscular force due to BTX-A application to the orbicularis oculi muscles by studying the subsequent effects on the corneal topographic parameters. Other research groups have described using a lid tensiometer instrument to assess the generation of eyelid muscular force ^(19,20). One report indicated that, under normal circumstances, eyelid tension was unlikely to adversely affect the shape and power of the cornea ⁽¹⁹⁾. In addition, it has been noted that no difference in lid tension exists between Asians and Caucasians ⁽²⁰⁾ even though Asians are at increased predisposition to developing keratoconus. In contrast, studies that evaluated corneal astigmatism changes after BTX-A injection in patients with blepharospasm concluded that eyelid-derived forces may play an important role in modifying corneal curvature ^(17,21).

The pachymetry results for the central and thinnest regions of the cornea remained similar between the groups throughout the 18 months of follow-up. This is not surprising, because we did not administer BTX-A directly into the corneal tissue. Pachymetry was assessed using two different devices, but both were based on the same principle (Scheimpflug tomography). This approach has good reproducibility in differentiating normal corneas from subclinical and symptomatic keratoconus cases ⁽²²⁾.

GAT is the gold standard for tonometry and is the most frequently used technique for IOP measurement. Eyes with corneal pathologies can present challenges for measuring IOP because of changes to the corneal thickness, rigidity, and curvature ⁽²³⁾. However, newer tonometers such as the Pascal dynamic contour tonometer (Ziemer Ophthalmic Systems AG, Bern, Switzerland) and the Ocular Response Analyzer and TonoPen XL (Reichert Ophthalmic Instruments, Depew, NY, USA) have better diagnostic accuracy than GAT for keratoconic corneas ⁽²³⁾.

We are not aware of any previous reports that have used BTX-A to reduce eyelid muscular force in patients with keratoconus. Although several studies ^(17-20) have confirmed the influence of eyelid tension on corneal shape, it appears that eyelid tension in keratoconus patients is no higher than for other conditions such as hemifacial spasm and blepharoptosis ^(18,24). In the present study, BTX-A application did not result in a significant change to corneal parameters. It remains unclear whether BTX-A application to the orbicularis oculi muscles could be a useful adjuvant approach for controlling the progression of keratoconus. Corneal changes after the application of BTX-A in orbicularis oculi muscles, if there are any, take longer to be detected than earlier eyelid morphometric changes ⁽¹⁸⁾; our follow-up period may therefore not have been long enough to detect associated corneal changes in patients with keratoconus. Furthermore, keratoconic corneas may present structural alterations that respond differently from the corneas of patients with hemifacial spasm.

We recognize potential limitations in this study. The number of BTX-A applications was limited, and the follow-up period was rela tively short. Future studies of keratoconus patients with a longer follow-up period and an increased number of BTX-A applications may help to elucidate whether BTX-A application in the orbicularis oculi muscle could be a valuable adjuvant treatment to help control the progression of keratoconus to some degree.

Keratoconus etiology and pathogenesis mechanisms remain unclear. The recent Global Consensus on Keratoconus and Ectatic Di seases ⁽²⁵⁾ concluded that keratoconus was a multifactorial disease with genetic, biochemical, biomechanical, and environmental components. The panelists found that the most important objectives of nonsurgical treatment were to halt progression and bring about visual rehabilitation.

The past two decades, in particular, have seen exciting new de velopments that, for the first time, promise to alter the natural history of keratoconus favorably to benefit patients. Scientific interest in keratoconus is likely to remain high in the foreseeable future, to avoid iatrogenic ectasia, unmask subclinical disease, and expand the rapeutic options ⁽²⁶⁾.

In conclusion, BTX-A administration to the orbicularis oculi muscles of keratoconus patients did not cause detectable changes in corneal parameters secondary to reduced eyelid muscular force during 18 months of follow-up.