As an individual withSeems pretty simple, right? Shouldn’t every patient know the answer to this question? Yet anyone who has been to more than one glaucoma specialist knows that they will often get told “moderate” by one specialist whereas another will say they have “severe” glaucoma. What gives? Is one specialist ignorant? Possibly, but more likely they are both “correct” in their relative assessments, just using different systems to classify the severity of glaucoma.

So, why don’t all glaucoma specialists use the same system for consistency?

Simply put, because no one can agree on what parameters are most important for assessing glaucoma damage.

“Duh, visual fields”, you say?

OK, what part of the visual field? Mean deviation (MD)? Pattern Standard Deviation (PSD)? Visual Field Index (VFI)?

What about where the visual field defects are located? Shouldn’t more central defects be weighted more heavily than more peripheral defects?

All of it? OK, show me a physician that has time to enter (or has the budget to pay staff to enter) all that information into a “staging software package”–which would very likely not be free or its use reimbursed by insurance.

Then there’s the structural aspect of glaucoma (visual fields are “functional” tests, whereas OCT/photos are “structural”).

Doesn’t that have a role to play in staging? Depends on who you ask. Neither the government nor private insurance companies give two cents (literally or figuratively) about the structural staging of glaucoma. Given the limited time available to physicians, this means that both the financial and time-based incentives are for physicians to stage solely according to how billing codes define severity.

But is this clinically in the best interests of the patient? Probably not, which is why a LOT of effort has gone into creating a more relevant and nuanced method of staging glaucoma.

Take a look at just a few of the more commonly recognized methods of staging glaucoma severity:

Glaucoma – Classification of Severity

Most of the proposed systems of classification that primarily vary according to:

• Use of functional (visual field testing) versus structural (optic nerve photos or OCT) metrics
• Complexity (number of parameters needed to stratify)

Staging according to Pathophysiology

Staging according to Functional Damage

Mean Deviation Severity Staging

Informal “quick and dirty” staging “system” used by many general ophthalmologists and not infrequently used to stage glaucoma severity in clinical trials

Staging based on:

• Visual Field Mean Deviation (MD) Value
• The higher the absolute value of the MD, the worse glaucoma—yep, that’s it! Easy peasy.

Strength(s) of Mean Deviation Severity Staging:

• Only requires a visual field test
• Fast (only one metric to evaluate)

Major weakness of Mean Deviation Severity Staging:

• Mean deviation can be reduced by ocular pathology other than glaucoma
• Does not correlate well with visual disability

Glaucoma Staging System 2 (GSS2)

Uses BOTH Mean Deviation (MD) and Pattern Standard Deviation (PSD) from visual field printout

Strength(s) of GSS2:

• Relatively simple (can be mentally “ballparked” without referring to reference graph)
• Addresses some of the weaknesses of the Mean Deviation Severity Scale

Major weakness of GSS2:

• Not as nuanced as the systems that use more parameters to stage
• e.g., does not take into account location of visual field defect(s)

International Classification of Diseases (ICD) Staging of Glaucoma

Allows for staging of glaucoma into mild, moderate and severe disease _based simply on the physician’s analysis of the printout of the visual field_ in the patient’s worse eye.

Because this system has been forced upon physicians in both the US and Europe by both government and private insurance systems it is by default the system that is in most commonly use (at least by eye doctors who are not glaucoma specialists)

Mild

• No visual field abnormalities on any white-on-white visual field test or** abnormalities present only on short-wavelength automated perimetry or frequency-doubling perimetry

Moderate

• Visual field abnormalities in one hemifield, and not within 5 degrees of fixation

Severe (Advanced, End-Stage)

• Glaucomatous visual field abnormalities in both hemifields, and/or loss within 5 degrees of fixation in at least one hemifield

Strength(s) of ICD Classification:

• Simple and easy to determine

Major weakness of ICD Classification:

• Does not take structural damage into account
• Cannot stage in patients who are unable to perform high-quality visual field testing

Hodapp–Parrish–Anderson method

Staging based on:

•  Visual Field Mean Deviation (MD) Value
• Number of depressed points in the pattern deviation map
• Proximity of defects to fixation point

Strength(s) of Hodapp–Parrish–Anderson method:

•  More nuanced and likely more accurate representation of clinical severity of glaucoma

Major weakness of Hodapp–Parrish–Anderson method:

•  Cumbersome & time-consuming

Mills et al. Staging System

Staging based on Hodapp–Parrish–Anderson method but uses five parameters instead of three

Strength(s) of Mills et al. Staging System:

• More nuanced and likely more accurate representation of clinical severity of glaucoma than even the Hodapp–Parrish–Anderson method

Major weakness of Mills et al. Staging System:

• Even more cumbersome & time-consuming than the Hodapp–Parrish–Anderson method
• Because of that is it rarely used by anyone outside of an academic glaucoma practice

AGIS Method

Staging based on the number of depressed points in various areas in the central visual field

Strength(s) of AGIS Method:

• Provides a score between 0 and 20
• Easy to compare scores

Major weakness of AGIS Method:

• Although the score is easy to compare, it is still a bit cumbersome to calculate

Systems for Staging Glaucoma based on OCT

Multiple systems have been proposed in the literature. None are widely in use or agreed upon.

Elbendary and Elal Three-Stage Method

Uses OCT RNFL measurements to stage

Strength(s) of Elbendary and Elal Three-Stage Method:

• Relatively simple

Major weakness of Elbendary and Elal Three-Stage Method:

• Requires OCT (expensive technology not available in all practices)
• Not glaucoma-specific (any optic neuropathy will increase severity scale)

Six-Stages OCT glaucoma staging system

Uses OCT RNFL measurements to stage

Strength(s) of Six-Stages OCT glaucoma staging system:

• Likely more sensitive and specific related to diagnosing/staging glaucoma than the  Elbendary and Elal Three-Stage Method

Major weakness of Six-Stages OCT glaucoma staging system:

• Requires OCT (expensive technology not available in all practices)

– More involved than Elbendary and Elal Three-Stage Method so less likely to be used by busy clinicians

Systems for Staging Glaucoma based on BOTH Function and Structure

Complexity of system is the main drawback of any system using both function and structure

Global Glaucoma Staging System (GGSS)

[Website](https://www.mdpi.com/2077-0383/10/19/4414)

“plots structural and functional damage data on an x-y diagram in order to provide a standardized classification of the entire glaucomatous damage”

– Uses both OCT RNFL data and visual field data

Strength(s):

•  Uses only 5 readily available parameters for patients with glaucoma:
  
  • Age
  • Mean Deviation (MD)
  • Pattern Standard Deviation (PSD)
  • Superior Quadrant RNFL thickness
  • Inferior Quadrant RNFL thickness
• The only system to incorporate _both_ structural and functional damage metrics
• Uses objective measurements of optic nerve (OCT)
• Likely the most useful system of clinical staging

Major weakness:

• Requires OCT technology which may not be available in every practice
• Requires use of reference chart or proprietary software in order to stage individual patients
• As this system was first published in late 2021, most physicians are unaware of this method of staging
• Patented system so will likely require licensing software to implement which will effectively limit its use to academic centers or practices with large budgets for capital equipment

Summary

So as you can see, staging the severity of glaucoma is a hot mess with no universally agreed upon system of classification. Even were one system to be determined to be the “best” one, getting physicians to all use the same system is about as likely to be successful as herding cats. Add time demands and financial constraints and even the most “perfect” system will be left to collect metaphorical dust if it’s not fast and easy to use.

Thus, my expectation is that if you were to really press most eye doctors (not glaucoma specialists, but general ophthalmologists, cataract surgeons, and optometrists) about how they stage glaucoma, they’d probably shrug and answer something along the lines of, “I don’t know, I just look at the visual field, OCT, and optic nerve, and have a sense of how severe it is.” And, given our mind’s amazing ability to incorporate “fuzzy” data and recognize patterns, this system could very well beat out many of the more complicated systems described above in terms of meeting the demanding balance of efficiency and clinical relevance.

It’s not perfect, but at least for now, it seems to provide a ballpark assessment of glaucoma severity sufficiently close to the more formal system that have been proposed. After all, an imperfect system is far better than a “perfect” system that will not be universally implemented due to complexity, time, or cost.

References:

Brusini, P.; Johnson, C.A. Staging functional damage in glaucoma: Review of different classification methods. Surv. Ophthalmol. 2007, 52, 156–179.

Alpha Agonists – Glaucoma Medications | Driving with Dr. David Richardson

Hello, my name is Dr. David Richardson. I’m a cataract and glaucoma surgeon in Southern California. Today I’d like to talk about a class of glaucoma medications, called the alpha agonist class.

So let’s get going!

Now the alpha agonist class has been around for many decades and it works primarily at the ciliary body which is where fluid in the eye is produced. So what the alpha agonist class does, like most of the topical or eye drop glaucoma medications, is to actually reduce the amount of fluid that’s produced by this tissue, called the ciliary body. Now the interesting thing about the alpha agonist class however is that that’s not the only mechanism that it uses like the prostaglandin analog class, it also allows fluid to leave the eye through what’s called the uveoscleral pathway which is what we’d consider to be an accessory pathway. It’s not the main pathway. The main pathway is through the traumatic meshwork and that’s actually where the problem with most open angle glaucoma tends to be. It’s at the trabecular meshwork so this eye drop not only reduces the amount of fluid that’s produced, but it also allows fluid to escape the eye around the primary problem, the trabecular meshwork. Now the other interesting thing about this class of medications the alpha agonist is that there’s some evidence that it may actually provide what’s called a neuroprotective effect, so an intraocular pressure or iop independent separate benefit to the optic nerve which is a central nerve. The evidence for this is based on a mouse laboratory mouse model in which mice had their optic nerves crushed. So pretty awful those mice who were treated with an alpha agonist had less damage to their optic nerves than those mice that were not treated with the alpha agonist. Now crushing an optic nerve is pretty different from what happens with glaucoma which tends to be kind of a slow progressive damage to the optic nerve over many years but, nonetheless, one might posit that if this class of medications can help the optic nerve survive a traumatic damage, then perhaps the class of medications can also help with longer term damage. We don’t know for sure but there is some other evidence that suggests this may be the case and I’ll talk about that in a bit.

Now then the question arises. Okay well, it’s got all these mechanisms. That’s nice but, how does it really work? So in humans who use this drop, does it work well?, and indeed it does. The brimonidine which is the primary alpha agonist drug available in the United States actually works about as well as timolol but, without many of the systemic side effects of timolol, but not quite as well as the prostaglandin analog class which is the most effective topical medication class for treatment of glaucoma. So that’s actually very effective which makes it a very commonly prescribed eye drop. Now how is this prescribed? In terms of what’s the opportunity where a physician might say let’s prescribe this class of medications. But although it works quite well, it tends not to be what you would call a first line therapy. Most of the time brimonidine is prescribed as a second line. So after someone has been started on, saying a prostaglandin analog or perhaps timolol and the primary reason for that is the dosing that we’ll get to in a little bit. 

Now as far as how it’s supplied, brimonidine in the United States is available in the branded name alphagan P which is a 0.1 percent concentration and also available generically as 0.15 and 0.2 percent. Now the brand is preferred because the lower the concentration, the lower the risk of side effects. And we’ll talk about those in more detail later. But also the elf alphagan P uses a special preservative, called pyrite which essentially keeps bacteria from growing in the bottle once the eye drop hits the tear film. The preservative is inactivated, so that decreases the amount of potential damage to the corneal surface which is possible over time with the most commonly used preservative benzyl comanium chloride. Or back the other thing with bak is that it can potentially cause damage to the trabecular meshwork which is the part of the drainage system. That’s already damaged in open amino glaucoma so you certainly want to avoid damaging it further with a drop that’s meant to actually prevent damage. So most of the available alphagan or brimonidine rather comes in multi-use bottles and is just brimonity. But you can also get brimonidine in what’s called a fixed combination. A fixed combination is essentially two or more individual medications in one bottle, so you can get brimonidine combined with timolol and the brand name for that is combigan. You can get brimonidine combined with brinzolamide which is a carbonic anhydrase inhibitor that goes by the brand name simbrinza and that’s a nice combination because there’s no real systemic issue since there’s no timolol or beta blocker in it. And then there’s brimonidine, plus dorzolamide which is available through a compounding pharmacy in New Jersey called impromise. The nice thing about this particular formulation is that it’s preservative free, so no preservative, no damage to the surface of the eye or the trabecular meshwork. 

So I’ve already arrived at the office. It seems that I am always talking too long here but there’s still a fair amount to go over in this class. So let me go through that and then sum it up so we’ve gone over the issues of preservative, how this class of medication is supplied. Now, of course, one of the other issues that comes up within a prescription is cost. Now cost is very much dependent on one’s insurance. If the brand is covered by insurance, then that’s really what I recommend because of the advantages that we’ve already talked about. If the brand is not covered, then the two generics that are available the 0.15 percent and the 0.2 have very different coverage among insurance companies. Most insurance companies will not cover the 0.15 which makes it almost as expensive as the brand. And between the two, I would definitely choose the brand over the generic 0.15. The 0.2 percent is almost universally covered but, it does have a higher rate of the side effects that we’ll discuss in a moment.

If your insurance does not cover even the 0.2, then I recommend that you search for a good price through one of the online sites that can help guide you with cash prices. I recommend goodrx.com to my patients as well as to you know anyone on these videos. I have no financial relationship with goodrx. It just seems to work to save my patients a lot of money so highly recommend that if you’re going to pay cash prices and if you have a high co-pay, it’s worth checking just because your cash price could potentially be less than your co-pay. Now how is the brimonidine class or the alpha agonist class? Primarily brimonidine in the US is used well generally. It’s prescribed twice a day and that’s true whether it’s in the brimonidine only or the fixed combination. There is some evidence that it works better three times a day but that third-time-of-the-day dose which is generally the middle of the day is really hard to get in and during our busy lives. So I generally recommend that my patients take it twice a day if you remember a middle-of-the-day dose, then bonus. But don’t feel guilty about it if you don’t get it in because it will still work twice a day. Now I’ve talked about or alluded to side effects. It’s important to know about side effects with every medication. Of course most side effects don’t occur or are quite mild and you know we’re always looking at the risk benefit trade-off the risk of permanent loss of vision with glaucoma versus the side effects. So let’s go over the side effects. 

Some of which are pretty mild and some which could be potentially quite bothersome or even serious depending on the individual. So local side effects include irritation or a sense of dryness. That’s true with almost all of the preserved glaucoma medications hybrimia which just means that the white part of the eye gets red or congested and that is more common with the higher concentrations. The 0.2 percent generic has a higher likelihood of resulting in a red eye than the purity preserved 0.1 percent branded alpha again P. I’m an allergic reaction. There’s about a 10 to 15 percent chance of developing an allergy to this class of medications, at some point, over the course of the therapy. And this risk is higher with the higher concentrations. Another reason why preserve, I prefer the pure right preserved alpha again P 0.1. Alright dry mouth can be an issue and then a mild pupil dilation. It’s not usually notable in those with dark irises but in those who have light irises, mild asymmetry can be noted if brimonidine is taken just in one eye. If it’s taken in both eyes most people don’t notice it at all and then the other interesting thing is it can actually lift the eyelid just a bitu, usually by only a half a millimeter to a millimeter which can actually be advantageous. So for many older adults who have a bit of a ptosis which means a drooped lid by often a millimeter or two, this can actually help the cosmetic appearance of course if it’s not desirable. Then if it’s used again in just one eye, that can be an issue and then there are the issues of systemic side effects. Now, fortunately, for the bra monitoring class, unlike the beta blocker class, systemic side effects are quite rare in healthy adults but they can be a bit more common in the elderly and glaucoma being more common as we get older. That’s important to be aware of but they’re especially worrisome among children. So these side effects include a headache, again quite rare but occasionally seen low blood pressure. So just like the beta blocker class, the alpha agonist class can lower blood pressure but the really worrisome things are lethargy. And apnea apnea means discontinuation of breathing. So breathing just stops and those two things are actually a pretty high risk among infants and young children. So brimonidine is generally what we call contraindicated in children under five years old. 

Now how can you minimize the side effects? Well, of course, try as much as possible to prescribe just to healthy adults. It’s not always possible. So be aware of the side effects. Avoid it in young children. But then there’s also the issue that we’ve already talked about and that using the lower concentration forms of brimonidine will reduce the likelihood of all of the side effects, unfortunately the side effects of red eye. And an allergy are not going to respond to the same kind of treatment, the either punctal occlusion or the balled up tissue that would benefit those systemic side effects. Now one other thing that’s worth discussing is interaction with other medications. Fortunately with brimonidine, there aren’t a lot of interactions with other classes of medications and the one class that it is known to interact with which is the monoamine oxidase or mao inhibitors are hardly prescribed anymore. Those are actually the first class of antidepressants, approved by the FDA in the US but we’ve pretty much moved away from the maois with the SSRIS and tricyclics and things like that. So, it’s unlikely that interaction would occur now. But it’s worth stating that the brimonidine or alpha agonist class should not be prescribed with mao inhibitors.

So in summary, the alpha agonist class is an effective class that works through multiple mechanisms. May have a neuroprotective benefit which is generally prescribed as a second line treatment although there is an exception to that that I neglected to mention and that is that those who have what’s called normal tension or low tension glaucoma may actually enjoy an added benefit in terms of protecting them from progressive loss of of their visual fields over time compared to say timol. So both timolol and brimonidine were studied and even though they both lowered the intraocular pressure about the same amount, those with normal tension glaucoma who were given brimonidine actually did better over time and so that is one case where brimonidine may be a good first line agent that is for someone with normal tension glaucoma. 

So to continue the summary, back to that, the side effect profile is usually mild and well tolerated with the exception in children and it can be quite affordable depending on the insurance coverage as there are generics available although the brand is definitely preferable in this class of medications. So anyway I know this has been a very long video but again I feel that the topics of intraocular pressure lowering classes of medications is so important because almost everybody who has glaucoma is taking one or more of these medications. And it’s important to be aware of the pluses and minuses of each class, the nuances, the costs, all of these things. So I think that it’s probably worthwhile spending 15 plus minutes together on this topic anyway. I hope you agree and if so, I’ll keep making these videos and hopefully providing some useful information that clearly there’s no time in a typical office visit with an ophthalmologist to have a 15 plus minute conversation on one class of glaucoma medications.

So this is my commuting opportunity and parking lot opportunity to share this with you all right have a good day!

1. Beta-blockers-glaucoma-medication-driving-with-dr-david-richardson-series-5-ep-01
2. Oral-carbonic-anhydrase-inhibitors-glaucoma-medications-driving-with-dr-david-richardson-series-5-ep-03

1. Alpha Agonists – Glaucoma Medications _ Driving with Dr David Richardson – Series 5 Ep 02 
2. Oral-carbonic-anhydrase-inhibitors-glaucoma-medications-driving-with-dr-david-richardson-series-5-ep-03/

The Prostaglandin Analog class of glaucoma medications is generally well tolerated, but there are a number of cosmetic side effects that can be associated with their use.

For more information about prostaglandin analogs read the following:

http://new-glaucoma-treatments.com/medical-therapy-for-glaucoma-prostaglandin-analogs/

To learn more about Dr. Richardson read the following:

http://david-richardson-md.com/