 Inder Paul Singh, MD

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When it comes to understanding who is affected by 

, 1975 was a time of great confusion for those interested in the disease. The confusion persists.

Six years earlier, Mansour F. Armaly, MD, showed that without treatment few ocular hypertensive patients developed visual field loss over 5 years. 

Prior to the study, widespread agreement that glaucoma was present when the IOP was over 21 mm Hg led ophthalmologists to recommend treatment whenever IOP was above this number. 


Glaucoma devices: Now and in the future​ 

​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 
While prevalence surveys have dispelled the myth of 21 mm Hg, many ophthalmologists continue to believe that using an absolute level of IOP in making a glaucoma diagnosis is in the best interest of their patients. 

The distinction between open angle and normal tension glaucoma as two different disease entities remains controversial.



The majority of the world’s people with 

continue to be undiagnosed and untreated. In 1975, “correct” diagnosis and treatment were clear, and “easy,” even though often wrong. 

Today, diagnosis and treatment are less clear, with limited understanding about the variability of rates of progressive damage. 

Some tests considered essential in the past, such as tonography, are no longer used, while others, such as central corneal thickness or the retinal nerve fiber layer are used with great devotion.

IOP homeostasis in glaucoma: Looking below the surface



Angle-closure glaucoma caused by relative pupillary block was a leading cause of irreversible blindness in 1975. The development of laser iridotomy offered the possible elimination of pupillary block 

. 

However, angle-closure is still a major cause of worldwide blindness. Recent studies are clarifying who needs treatment and what types of treatment are preferable. 

Modern cataract surgery has emerged as a useful early intervention for patients with angle closure as well as for those with open angles and glaucomatous nerve damage.

The search for a workable definition of glaucomatous disease has intensified. Many acknowledge that the etiology of this optic neuropathy varies substantially between individuals and populations. 

The fixation on determining whether someone has glaucoma based upon cross-sectional information at a single time point has been questioned by some who believe there is little benefit, and perhaps harm, in labelling individuals as having or not having 

Clinical trials have shown that a large proportion of glaucoma patients randomly assigned to no treatment show no progression for many years.

Deciding on the actual need for treatment is still difficult, at least partially because of the lack of data that relates early changes to the development of actual disability caused by glaucomatous vision loss.


Funding new technologies for glaucoma treatment​ 



Fear of going blind is so great that both doctors and patients alike tend to opt for the apparent safety they associate with treatment, even in circumstances when treatment is not necessary to preserve quality of life. 

On the other hand, fear of problems caused by incisional surgery is sometimes so great that doctors and patients tend to defer surgery that is actually necessary to prevent the development of troublesome loss of vision in those with severe and progressive disease. Future studies need to focus on the long term consequences of 

In diagnostics, during the past 45 years, we have seen effort, thought and finances devoted to both functional and structural assessment of people with or suspected of having 

. Transition from manual to automated perimetry has been a true advance.

The decreased utilization of fundus photographs has likely had a negative impact on glaucoma care. Small changes in optic nerve and retinal nerve fiber layer can be better measured with a host of novel imaging technologies, but the significance of such change is often not clear. 

A diagnosis of 

is best made longitudinally; measures that change over time without validated reference parameters for comparison may not represent progress.

The efforts to show structure-function correlation with regard to optic nerve pathology have been limited by large variability using present day tools, thus limiting the use of structural change as a surrogate for present or future vision loss in individuals.



Traditional glaucoma surgery in the era of MIGS procedures

Glaucoma therapeutics has seen two great milestones in pharmacologic care: The introduction of topical beta-blockers in 1978 and prostaglandin analogs in 1996. Both, along with topical carbonic anhydrase inhibitors and alpha adrenergic agonists introduced in the 1990s, are now available as generic medications.

Nevertheless, their cost is prohibitively high for many, particularly in developing countries. Noncompliance with medications remains a large problem; missing appointments is also a great concern.

Laser trabeculoplasty, first introduced about 45 years ago, was initially slow to be utilized. 

Frequency of use increased in the 1990s with the development of more selective approaches; clinical trials indicate initiating treatment with laser is a good option for many patients with open- angle glaucoma. 

Minimally invasive surgical approaches, focused most often on increasing outflow through Schlemm’s Canal, and often combined with cataract surgery, have allowed surgical 

 to enter comprehensive ophthalmology practice. 

While these procedures have been shown to decrease the short-term postoperative dependence on IOP-lowering medications amongst patients with mild to moderate glaucomatous disease, the long term benefit that they provide requires further study.


Study results show that surgical system decreases IOP in patients with POAG

Various implantable devices designed to give trabeculectomy-like results have shown mixed results. Cyclodestructive procedures have been refined and are viable alternatives in some cases. 

Increasing use of drainage device implantation in eyes having had prior incisional surgery has been supported by clinical trials, but trabeculectomy remains the most efficacious first procedure for patients otherwise destined for severe vision loss from glaucomatous disease. Recent evidence shows improved visual function with IOP lowering in some patients.


 was and remains based on knowledgeable personalization of care, skillfully delivered. 

This includes awareness of the loose relationships between findings, such as intraocular pressure, and how patients function and feel. 

Anchoring diagnosis and treatment to what is important to patients was not well done in 1975, and there is still much room for improvement in 2020.


Articles

Innovation, change has dominated the glaucoma specialty over the years.

Glaucoma 45 years later: Much changed, much unchanged

The value of lens alignment technology for toric 

 implantation during cataract surgery is generally understood among cataract surgeons. 

However, a topic that is not as prevalent is how surgeons ensure that a multifocal IOL is centered on the visual axis during

ASCRS 2020: Assessing aberration of monofocal toric IOL with enhanced recovery, alignment



Herein, I will share how I utilize lens alignment technology, not only for toric markings but also to verify the visual axis for multifocal lens implantation. 

This approach has become critical for me to confirm proper placement and help decrease postoperative adverse events.


As cataract surgeons, we try to do our best at controlling variables so that we have more predictability with our outcomes. 

As such, there are many preoperative tools at our disposal, including topography, aberrometry, ray tracing, or various alignment systems. 

However, intraoperatively, only recently have we discovered an efficient way of applying the preoperative data we have collected and using them in the operating room. 

Trifocal IOL a key for premium cataract surgery practice


Aberrometry has also been used intraoperatively, but its benefit is in the lens power and alignment of a toric

; however, assistance with alignment and centering of the multifocal lens over the visual axis has been neglected.

My colleagues and I have a variety of technologies that provide

 calculations, identification of the axis of astigmatism, and even software that locates the apex of the lens, which is thought to be the center of the visual axis but is not always. 

Although we have an incredible amount of preoperative data, in surgery, we often find ourselves still guessing or “eyeballing” the placement of the lens. 

For instance, in the past, we have used the Purkinje reflex of the microscope to align and center the lens, which can be affected by patient gaze. We often centered the lens based on the pupil. 

However, if the pupil is irregular, we may not be placing it in the center of the visual axis, and some patients have a high-angle kappa or chord Mu (average chord mu, 0.2 ± 0.11 mm) where the center of the visual axis is not at the center of the pupil. 

 Performance of trifocal toric IOL highlighted in tests



As a result, patients can have up to 0.5 mm to 0.6 mm of difference between the center of the pupil and the center of the visual axis. 

Furthermore, if a patient has irregular or dilated pupils, it interferes with the ability to judge the location of the center of the visual axis due to the distorted pupil and iris.

What I have found revolutionary about using a biometer with lens alignment technology (IOLMaster 700; Carl Zeiss) and a digital marking system (Callisto eye; Carl Zeiss) is that it allows me to use preoperative data and apply them intraoperatively to help position the lens in an efficient and consistent way.

Lens alignment technology gives me a true understanding of where the visual axis is located using swept-source optical coherence tomography with a cross-sectional B-scan view of the eye, allowing me to visually confirm the foveal pit. 



Presbyopia-correcting IOLs: Expanding, improving last frontier



Now I have an accurate and confirmatory measurement to ensure that my preoperative data actually measure the center of visual axis. 

Of equal importance, the lens alignment technology takes images of the episcleral vessels preoperatively and can be applied to a digital marking system intraoperatively. 

I am able to send the information to the digital marking system using digital software or I can transfer the data using a USB drive. 



Striving for perfection: Creating the perfect IOL



Intraoperatively, the digital marking software will register and align the scope view of vessels with the image taken by the lens alignment technology to ensure proper alignment. 

For toric lenses this is ideal, because it allows me to apply my preferred axis of astigmatism. 

For a multifocal lens, it will give me an overlay to create my capsulotomy of desired size. For instance, a 5-mm capsulotomy will center over the visual axis. 

Also, once referenced, as the eye or scope moves so do the digital alignment markings. This can be invaluable as patients often have a hard time maintaining gaze, making it difficult to align capsulotomy and Purkinje reflexes.

Finally, at the end of the case, when I am putting the multifocal lens in the eye, there is a plus sign in the overlay that will tell me where the center of the visual axis is located, and it amazes me that this is not always exactly the center of the pupil.

 

We have found that in patients with higher chord mu values, the digital visual axis alignment is often not aligned with the center of the pupil.

There is no doubt that multifocal lenses have an inherent higher risk of causing dysphotopsia due to the multifocal nature of the design in the lens.

Physicians on quest to end dysphotopsias in premium IOLs



Glares, halos, and other dysphotopsias can be exacerbated if the patient is not looking through the center optic, especially the distant dominant optic. If the lens is not quite in the center of the visual axis and is positional slightly temporal to the visual axis, the patient might be looking through an edge of one of the rings, thus causing more postoperative symptoms. 

To minimize this adverse event, I want the center of the multifocal

 to be aligned with the center of the visual axis. The fovea, the center of the eye, should be looking right through the center of the multifocal 

. This can ensure that the quality of vision is not being compromised by the patient not looking through the center of the optic.


By using up-to-date formulas and advanced diagnostic tools, we can achieve a high probability of achieving our refractive target. Though we feel confident in achieving our targets, I can never guarantee a specific result to a patient. I always share with patients that there are risks and benefits to any procedure. 

There is always a need, potentially, for enhancement or the possibility for something to go wrong. But when I have confidence in the technology, it is conveyed naturally. 

I am not selling something; I am simply educating. And when I educate with confidence, it is easier for patients to consider the options. 




Paul Singh, MD, has no financial disclosures related to this content.

1. Zeng M, Liu Y, Liu X, et al. Aberration and contrast sensitivity comparison of aspherical and monofocal and multifocal intraocular lens eyes. 

. 2007;35(4):355-360. doi:10.1111/j.1442-9071.2007.01452.x

2. Karhanová M, Pluháček F, Mlčák P, Vláčil O, Šín M, Marešová K. The importance of angle kappa evaluation for implantation of diffractive multifocal intra-ocular lenses using pseudophakic eye model. 

 2015;93(2):e123-e128. doi:10.1111/aos.12521.

3. Tchah H, Nam K, Yoo A. Predictive factors for photic phenomena after refractive, rotationally asymmetric, multifocal intraocular lens implantation.

 2017; 10(2):241-245. doi:10.18240/ijo.2017.02.10

Alternative method ensures lens is set properly during cataract surgery


For IOL placement, location is key

Achieving the best surgical outcomes means putting as much effort into choosing a consistent and predictable postoperative steroid as surgeons do into every other aspect of eye surgery. 

We do so much to standardize surgery and minimize variability. To produce reliably positive outcomes, we focus first on the preoperative assessment and biometry, and then on using surgical tools and techniques that help us achieve micron-level precision. We optimize the 

 before surgery and refine our minimally invasive surgical techniques to improve postoperative recovery.

After surgery, we need to apply the same control-focused mindset in prescribing a postoperative steroid. There is enough variability in generic steroids to potentially affect healing and IOP, challenge compliance, and even erode patient satisfaction in the month following

. We cannot let that happen to our patients, and we should not diminish all of the careful work we have done up to that point. 

New tools for pediatric surgeons to optimize surgeries


	To me, it is certainly not worth taking a chance with a generic steroid after surgery. Older generic drug formulations only needed to match the active ingredient of an original innovator or branded drug, not demonstrate equivalence. This included corticosteroids such as prednisolone acetate.

Today, generic drops still may not be 100% bioequivalent to their branded counterparts. Manufacturers are only required to prove 80% bioequivalence, matching only in the active molecule while free to differ significantly in where they outsource the vehicle, inactive ingredients and bottle make and construction. 

When good manufacturing processes are followed, the differences between branded and generic medications are minimal in ophthalmic solutions, where all of the active and inactive ingredients are dissolved. However, the common generic ophthalmic corticosteroids used today are formulated as suspensions, not solutions or emulsions. 

Branded drugs rely on advanced vehicles that improve a drug’s therapeutic properties. It is almost impossible to accurately duplicate these important vehicles because they rely heavily on certain milling and other manufacturing processes that affect the particle size, coating, mixing, and other vehicle characteristics.

A different vehicle and variation in the manufacturing process can cause several problems. The active molecule can settle in the new vehicle, so patients do not get the desired effect unless they shake the bottle, and patients have poor compliance with shaking the bottle postoperatively.
	
	

The dropless future: SLT as a first-line treatment for glaucoma


	
	In addition, differing pH levels can affect absorption. Buffering agents can be inadequate. The ocular surface problems and other side effects of benzalkonium chloride (BAK) preservative can be greater because some generics may use higher concentrations of BAK than the branded alternative.

In short, a drop’s efficacy, safety and tolerance are affected by the vehicle and other inactive ingredients that make up most of the bottle. This relationship can be used to our advantage, such as when brimonidine tartrate 0.1% (Alphagan P, Allergan) was developed by changing the inactive ingredients in the brimonidine tartrate 0.2% drop. 

The preservative was changed, thereby increasing the pH, giving us half the concentration of active medication with the same efficacy and fewer side effects.
	
	In addition, the concentration of bromfenac (Prolensa, Bausch +Lomb) was changed from 0.09% to 0.07% while maintaining efficacy by changing the pH of the vehicle. With generics, however, we do not consistently know how and from whom the manufacturer sources the inactive ingredients. There is no oversight of the bottle’s contents, so it is no surprise that efficacy and tolerability can vary. 

It should be noted that in many cases, there is little or no savings in purchasing a generic steroid drop. Many generics are very close in price to branded counterparts, and manufacturers of new branded drugs typically offer coupons. Even if there is some small savings, to me it is not worth it to add potential unpredictability to the surgical recovery process. 

We have tried to educate our patients to provide them with enough understanding of the differences between a branded and generic medication so they can make a better decision on their own if it is worth it for them to pay the potentially higher cost. Essentially, we place value on everything we purchase, so providing patients with this knowledge is crucial for them to make an informed decision. 
	
	

Branded versus generics: You make the call in dry eye 


	In addition to sticking to the predictability of branded drops, it is important for me to factor IOP control into the selection of a steroid. I routinely perform not only cataract surgery, but also almost every type of glaucoma procedure. 

I am concerned about pressure spikes in patients with glaucoma who undergo any kind of eye surgery, but I am most worried when they have surgery that does not address glaucoma. For example, in cataract surgery without a concomitant 

minimally invasive glaucoma surgery (MIGS)

, patients can get significant pressure spikes postoperatively. 

Many years ago, a study by Armaly showed a significant rise in pressure in 95% of primary open-angle glaucoma (POAG) patients treated with steroids.

 About 50% of POAG patients had an IOP above 40 mm Hg at two weeks. I have seen pressure rise within the first week in 

patients on a certain steroids, such as difluprednate (Durezol, Novartis), an emulsion.
	
	

Genetic variants linked with onset, progression of POAG


	
	We also know that almost all low-tension glaucoma patients are steroid responders. We always need to be aware of that risk.

Loteprednol is a molecule used to minimize that risk. I have long used loteprednol for 

with or without MIGS, trabeculectomy, canaloplasty, XEN (Allergan), Hydrus (Ivantis), and other MIGS procedures because I am very comfortable with both its efficacy and its comparatively low risk for pressure spikes. There used to be a misconception that because loteprednol did not cause the same rate of pressure spikes as prednisolone, it was not as powerful as other steroids, but now we understand that this is not the case. It delivers the necessary efficacy with lower risk to IOP.


	After years of using loteprednol postoperatively, I was very comfortable trying a new formulation comprised of loteprednol nanoparticles with a mucus-penetrating surface coating (Inveltys, Kala Pharmaceuticals), an ophthalmic suspension, which offers better penetration of the mucin layer and cornea as well as less elimination with tears.
	
	The vehicle keeps the nanoparticles with their proprietary coating equally distributed in solution, playing an important role in ensuring patients get the amount of medication they need.

The drop’s improved bioavailability of active medication in the anterior chamber makes it possible to get the same results with BID dosing I had with other suspension steroid formulations with QID dosing. In my opinion, we cannot underestimate the value of a BID drug versus a QID drug for improving compliance.
	
	

Considering BID ocular steroid post-cataract surgery 


	
	As a glaucoma specialist, I always deal with eye drop compliance problems, from physical limitations to forgetfulness to ocular surface discomfort. Any time I can decrease the number of medications on the eye, I take that opportunity. BID dosing is simpler, so there’s less room for patient confusion and compliance errors. 

Patients appreciate the convenience as well. We asked our patients, three months after

 when everything is healed, if any factor negatively affect their happiness with this experience. Their top problem was taking so many drops every day after surgery. Now they can use fewer drops. And there’s no tapering-just BID dosing until the bottle runs out. 

This makes the regimen is less confusing throughout recovery, and it is an especially welcome change when patients have the fellow eye done and can follow the same schedule for both eyes.
	
	In fact, simplifying the regimen to BID dosing has actually saved us 2 to 3 minutes of staff time normally spent verifying the tapering medications for the first eye and educating patients about the dosing schedule, which, in turn, improved office flow in general. 
	
	


	Last year, I saw a patient who had used generic prednisolone acetate after cataract surgery. She was happy at one week with 20/25 vision, but unhappy at two weeks with 20/60 vision. Prednisolone was reducing inflammation, but the generic formulation was aggravating the ocular surface and affecting her vision. (See Figure 1)
	
	Inveltys had just been released, so I prescribed it after doing her second eye two weeks later. She was 20/20 and happy at one week, and the ocular surface looked much better compared to the prednisolone acetate eye. 

It is not a direct comparison-these drops have two different active molecules-but the case illustrates just how destructive the generic vehicle can prove to be.

The detrimental effects of some generic formulations are not always so pronounced and may not always be clinically significant, but the possibility is always there.
	
	By carefully choosing a branded steroid, we get an approach that works clinically, improves compliance (which can make our patients happier), and also saves us time-all while delivering the reliable control over postoperative recovery that we all want. And when significant pharmacological advances come along to help our patients, we are not limited to older generic options. 
	
	

Dr. Singh is president of the Eye Centers of Racine and Kenosha, Racine, WI. 

Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. 

Walsman AM, Antes A, Rescigno RJ, Lutz D, Lama PJ. What is in a drop? Brand versus generic prednisolone acetate formulations: A quantitative analysis.

 Investigative Ophthalmology & Visual Science

. ARVO Annual Meeting Abstract. 2007 May;48(13):5825.

Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics. I. The effect of dexamethasone in the normal eye. II. The effect of dexamethasone in the glaucomatous eye. 

Pleyer U, Ursell PG, Rama P. Intraocular pressure effects of common topical steroids for post-cataract inflammation: Are they all the same?

Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol etabonate gel 0.5% for postoperative pain and inflammation after cataract surgery: Results of a multicenter trial.

Rajpal RK, Roel L, Siou-Mermet R, Erb T. Efficacy and safety of loteprednol etabonate 0.5% gel in the treatment of ocular inflammation and pain after cataract surgery. 

Predictable, branded steroids offer control over surgery 

Although the visual outcome may be the most important aspect of cataract surgery, a more complete measure of success is patients’ happiness with their experience every step of the way. We have conducted several surveys in my practice to understand patients’ perspective of their cataract surgery journey and the factors that go into their perception of the quality of their experience. In other words, what makes them happy and what makes them unhappy.

What our studies have found is that, when thinking about patients’ satisfaction with cataract surgery, they consider the whole process. This includes the preoperative visits, the consultation, the conversations with educators and counselors, and the end result. Patients report that the key in the equation is the time it took them to arrive at their desired outcome. When patients have difficulty taking their postoperative drops, it interferes with their overall perception of how well their procedure went.

We asked approximately 100 patients who were happy with their visual outcome at their last follow-up (approximately 90 days postoperatively) to reflect on their journey. At that time, our postcataract surgery drop regimen included an antibiotic, a nonsteroidal anti-inflammatory agent, and a steroid. The No. 1 area of dissatisfaction by far was related to their drop experience.

Patients complained about the inconvenience of going to the pharmacy, challenges obtaining the right medication, and difficulty remembering to take the medications, according to the prescribed regimen. When using a tapering dose of a topical steroid, it can be confusing for patients when the first and second eyes are not on the same dosing regimen. It is also worth noting that some patients have physical limitations that make it hard for them to instill their drops.

Patients were also troubled by the time it took for their vision to stabilize—they expected to have good vision after approximately 1 week. A common comment was, “My vision is great now, but for the first few weeks, it fluctuated.” In the survey, we found that patients expected postoperative vision to be unstable to begin with, because of a suboptimal tear film and dry eye inherent to the procedure, but they also expected it to stabilize rather quickly. When we add to that with preservative-containing topical drops, it introduces additional visual instability and potential for delayed stability.

To eliminate these patient pain points, we were excited to incorporate the drug-delivery platform, dexamethasone ophthalmic insert 0.4 mg (Dextenza; Ocular Therapeutix). This preservative-free intracanalicular insert, which is placed at the time of surgery, eliminates the need for a postoperative steroid drop.

We have found that patients are very happy to have 1 less drop in their regiment. In our early experience (approximately 30 patients), we used the insert in 1 eye only and our standard regimen in the other, with prednisolone acetate. More than 90% of patients said they experienced a significant improvement in overall comfort, ease of remembering their drop regimen, and time to visual acuity stabilization with the dexamethasone ophthalmic insert.

When using a steroid suspension dosed 4 times a day, it often takes longer for vision to stabilize. The eye can become more irritated, and therefore patients tend to experience a longer journey to a healthy ocular surface. In our practice, satisfaction increased greatly when we removed the topical steroid from the equation.

Patients are well aware of the amount of time they spend in the practice and on the phone with us. Patients who use the dexamethasone ophthalmic insert reported higher satisfaction, as they did not have to call back because of drop problems. Before using drug delivery, they may have not received the drops we had prescribed because of a pharmacy switch or lack of insurance coverage, causing office calls and frustration. Not to mention the time spent in the office, educating patients on postoperative drop instructions. When we eliminated the steroid drop, we found there was an average of 4 minutes of time saved per patient per visit.

Today we have advanced technologies that benefit every stage of cataract surgery. We are refining our surgeries, honing our skills, and achieving fantastic results. Why not refine our postoperative management, as well? By eliminating the postoperative steroid drop with the dexamethasone ophthalmic insert, we can ultimately get better quality vision with a quicker recovery.

Singh is the president of The Eye Centers of Racine and Kenosha, Wisconsin. He is a consultant and speaker for Ocular Therapeutix.

The cataract surgery process continues to become more refined.

Prescribing fewer drops can lead to an improved patient experience

Adherence with lifelong glaucoma therapy demands a great deal from our patients. They must be able to afford and acquire their medications, remember the daily dosing schedule, be able to tolerate the drops well enough not to skip doses, and physically succeed in instilling the drops. That is a lot to ask of patients, especially as they age and begin to have concomitant health problems or cognitive loss.

Numerous studies have shown that adherence declines with more complex regimens of more than 1 or 2 bottles. Leung, Rossi, and others have shown us that, when you add a second or third bottle with preservatives, such as benzalkonium chloride, the incidence of ocular surface disease (OSD) increases

 ). Then, in a vicious cycle, patients with OSD become even less adherent.

More than ever, we are now beginning to appreciate the effect of compliance on long-term IOP control in our glaucoma patients. Both the HORIZON study [NCT04566445], looking at implantation of Hydrus Microstents at the time of cataract surgery,

and the LiGHT study, in which first-line selective laser trabeculoplasty (SLT) was compared with medical therapy,

 found that patients with the surgical/laser interventions were less likely to progress to incisional glaucoma filtration surgery. Even though we have medications that nominally provide the same IOP-lowering effect as SLT or minimally invasive glaucoma surgery (MIGS), we aren’t getting the full benefit of those medications because patients simply aren’t using them consistently.

More MIGS and SLT is part of the answer, but there will always be patients who need to continue topical therapy instead of or in addition to these options. In my practice, I typically prescribe a branded, commercially available glaucoma drug first, and I may make this choice for the second bottle as well. These drugs have gone through rigorous FDA trials and are marketed accordingly.

However, as the regimens get more complex with 3 to 4 medications, or if there are cost and adherence challenges with even 2 drops, I find that compounded fixed-combination glaucoma drops (Simple Drops; ImprimisRx) nicely address many of the factors that lead to poor adherence. Although we have a few dual-drug combinations in the US, none of them include a ß-blocker with a prostaglandin analogue (PGA), and none include more than 2 agents. Using Simple Drops, as the name implies, allows me to simplify the regimen for the patient to a single bottle once a day or 1 bottle each for morning and evening. These drugs are compounded in a Pharmacy Compounding Accreditation Board-accredited 503A patient-specific pharmacy that follows many of the same high manufacturing standards as its 503B facility. Every batch is tested for potency, sterility, and endotoxins, so I can be confident that my patients get a high-quality product.

For many of our patients who are still progressing or have poorly controlled IOP on topical medications, the problem is not that the drops aren’t working, it is that their pressure is fluctuating with inconsistent use of the medication. The Advanced Glaucoma Intervention Study (AGIS) demonstrated that long-term IOP fluctuation of greater than 3.0 mm Hg is associated with visual field progression.

 Among AGIS patients with low mean IOP—those patients whose pressure looks fine when we see them in the office—fluctuations increase the risk of progression more than 3-fold).

 Simplifying the regimen for these patients can boost adherence enough to stabilize them. 

In a study I conducted, switching my patients to a 3-in-1 or 4-in-1 drop resulted in lower IOP across most patient types, particularly among those who were poorly controlled on their prior regimen of 3 bottles or more.8 Four patients in the study were able to avoid planned surgery. 

One of these patients was a 43-year-old African American woman with advanced glaucoma who was still progressing on brimonidine/timolol (Combigan) , brinzolamide (Azopt), and travoprost (Travatan). Her eyes were always red, and she told me she couldn’t keep taking so many drops. We discussed trabeculectomy, and I decided to put her on Tim-Brim-Dor PF (timolol 0.5%, brimonidine 0.15%, dorzolamide 2.0%) and stop the PGA to improve her ocular surface symptoms before surgery. At the next follow-up, her IOP was down to our target of 12 mm Hg, her eyes weren’t red, and she was happy with the reduced drop burden. Four years later, she is still on this regimen and has been able to avoid filtering surgery.

Another major reason for using compounded combination drops is that I know what to expect and what it will cost the patient. If I prescribe 3 separate medications to a patient, it is very hard for me to answer their very reasonable question, “How much is that going to cost?” in any sort of accurate or transparent way. The cost to the patient could be $15 or $300, depending on their insurance coverage, co-pays, and formulary requirements. 

Moreover, they are highly likely to get generic substitutions from the pharmacy. The pH, viscosity, and other aspects of the inactive vehicle ingredients can vary widely from one generic to another, greatly affecting the bioavailability and efficacy of the active ingredient and the tolerability and safety of the drop overall.

 There can even be considerable variability in the quality of the dropper bottle, causing drops to spill out too fast and the patient to run out of a 30-day supply in a much shorter period of time. 

Finally, compounded drops also give me the ability to prescribe preservative-free formulations so the glaucoma medications are not contributing further to ocular surface toxicity. About half of our glaucoma patients have OSD,

 and those with concomitant OSD are more likely to experience adverse effects from topical glaucoma therapy, more likely to be nonadherent, and more likely to progress.

 If we can minimize the effect on the ocular surface, we also are maximizing the chances of success with later Xen implantation or filtration surgery if required.

If cost, compliance, and generic substitution were not factors at all, I might prefer separate bottles of each branded medication. But we have to recognize that patients aren’t getting what we prescribe and aren’t consistently instilling what they do receive, with resulting IOP fluctuation and disease progression. A simplified regimen of compounded fixed-combination glaucoma therapy is a very welcome solution to these real-world problems. 

Singh is in practice at the Eye Centers of Racine and Kenosha in Wisconsin. He is a consultant for many glaucoma companies, including Glaukos, ImprimisRx, and Ivantis, Inc.

Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17(5):350-355.

Rossi GCM, Pasinetti GM, Scudeller L, et al. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol. 2013;23(3):296-302.

Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: The good, the bad and the ugly. Retin Eye Res 2010;29(4):312-334.

Ahmed IK, Rhee DJ, Jones J, et al, on behalf of the HORIZON investigators. Three-year findings of the HORIZON Trial: A Schlemm canal microstent for pressure reduction in primary open-angle glaucoma and cataract. Ophthalmology 2021;128(6):857-865.

Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selectivelaser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): A multicentre randomised controlled trial. Lancet 2019;393:1505-1516.

Nouri-Mahdavi K, Hoffman D, Coleman AL, et al; Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 2004;111(9):1627-1635.

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Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol 2007;55(2):127-131.

Diagourtas A, Kagelaris K, Oikonomakis K, et al. Prospective study comparing Xalatan eye drops and two similar generics as to the efficacy and safety profile. Eur J Ophthalmol 2018;28(4):378-384.

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Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. 

Denis P, Lafuma A, Berdeaux G. Medical outcomes of glaucoma therapy from a nationwide representative survey. 

Numerous studies have shown that adherence declines with more complex regimens of more than 1 or 2 bottles. 

Simplifying glaucoma medical therapy for our patients

 surgeries (MIGS)—and the reason we push them earlier in the disease course—is their safety and the predictable postoperative recovery. In the past, we had fewer options, most of which were more invasive.

As a result, we had to delay surgery for years while patients suffered the discomfort, inconvenience, and expense of multiple medications, until finally those medications were no longer enough and surgery was unavoidable. 

Now we can skip years of suffering and better manage glaucoma by making MIGS part of the treatment equation.

MIGS helping to personalize glaucoma surgery options

Historically, we were hesitant to go into the subconjunctival pathway with trabeculectomy or tube shunt because of the often slow and variable nature of visual recovery and complex postoperative management. 

Instead, we waited until glaucoma progressed and the target pressure was aggressively low, often near the 10 to 12 mm Hg range.

Thankfully, with the options available today, we no longer need to wait so long to perform subconjunctival surgery for patients who need it, and with this earlier intervention, we have a better chance of achieving target IOPs because they are not so aggressively low.


Visual recovery and conventional pathway MIGS


With conventional pathway MIGS, such as stenting (iStent; Glaukos, Hydrus; Ivantis), viscodilating (iTrack; Nova Eye Medical, OMNI; Sight Sciences), stripping (Kahook Dual Blade goniotomy; New World Medical), cutting/GATT (OMNI), and others, visual recovery is generally not a major concern. 

Pressurizing the eye intraoperatively usually prevents intraoperative and postoperative hyphema, although if it does still occur, it usually clears up in a short period of time.

The mechanisms that make visual recovery so seamless for conventional pathway MIGS are also the reason they are not always the best option: 

The episcleral venous pressure is a floor we cannot cross, so it is hard to reach target pressures below the low to mid-teens. 

Patient glaucoma management focuses on pivotal studies

This floor, however, also means we do not get hypotony or flat chambers, which are often the cause of postoperative vision issues. Unfortunately, some of our patients need those lower target pressures. 

We also do not know where the resistance to outflow is located in our patients with glaucoma; in some, the distal channels are also collapsed or atrophied. In these cases, we are not able to achieve the IOP control we need through the conventional outflow system. 

We need to turn to a subconjunctival procedure to bypass the conventional pathway.


Vision after trabeculectomy or tube shunt surgery


Common causes of postoperative visual acuity changes are hypotony, choroidals, maculopathy, and ocular surface problems. 

With trabeculectomy and tube shunt, all of these problems are possible, so it is difficult to gauge how long visual recovery will take with each patient. 

Depending on how flat the chamber becomes and the position of the iris lens diaphragm complex, a return to baseline vision may take 1 week to 1 month or even longer. 

Restoring vision in glaucoma: more than meets the eye

A nonvalve tube might open up in a month and a half or even earlier when the suture dissolves, and that sudden change in IOP can cause a sudden shift in chamber depth and thus a change in vision. 

In addition, postoperative drops can prolong recovery by destabilizing the ocular surface.

In the case of weeks or months of recovery, patients are generally not happy with their vision. IOP can be unstable, so they require multiple office visits, and they often call the office with questions about vision problems and irritation from eye drop medications. 

The recovery process may still be going on when it’s time for the patient to schedule surgery on the fellow eye, which can make them reluctant to do so.

As an experienced glaucoma specialist, I still marvel at the high potential for variability of each step for a trabeculectomy. 

Study: Lower IOP, medication burden in OAG patients

I use various techniques to manage outcomes by controlling the size, thickness, and shape of the flap; titrating the flow by suture placement and tension; and trying to aggressively bring down the IOP yet prevent chambers from flattening postoperatively. 

It takes time to build that comfort and skill set, and not all patients have access to surgeons who have completed 1000-plus trabeculectomy procedures.

For these and a variety of additional reasons, a less invasive and more predictable subconjunctival procedure is needed to allow access for more patients than traditional surgeries.

Faster visual recovery from subconjunctival MIGS

Speed the return to baseline visual acuity—and make your patients happy.