Tonight we’ve got two hours of CE, I understand.
And I’m not going to talk for the whole two hours, I want to leave some time for Question
and Answer. But this is a big topic tonight and the topic is, “Adjusting the Faucet
or Opening the Drain.” Basically, what are the current and near future methods of treating
glaucoma. So by the end of this presentation, besides
having a really nice dinner, you should be familiar with the currently available and
soon to be available (we hope) methods of treating glaucoma and how they work. So you
should be aware of them all and have a pretty good idea of the mechanism.
Now this brings up something that’s rather interesting. In order to figure out how to
treat it and to talk about mechanisms we first have to discuss, well what is glaucoma? Now,
we all have an idea of what it is. It’s got something to do with the optic nerve,
it’s a progressive optic neuropathy, and it involves cupping and typical visual field
or retinal nerve fiber layer loss. Now, it’s also got something to do with pressure. We
know all of those things. But we’re finding out that it’s not so
simple. It’s the idea that high pressure is glaucoma so we have to lower it, we figured
that out a while ago that it wasn’t that simple (normal tension glaucoma, patients
with ocular hypertension but not glaucoma). So clearly there’s something else going
on. And what we’re discovering is that blood supply is important, oxidative damage may
be important, and there may be some other issues involved such as inflammation. So a
lot of the laboratory research that’s being done is actually focusing on those three things,
not pressure. But that’s pretty far into the future. Nothing that is involving non-IOP
lowering therapy is anywhere near clinical usefulness.
So we pretty much have to view glaucoma as a problem of plumbing. Even though we know
glaucoma is far more complex than flow issues, this is all we’ve got. This is what we have
to work with. And so given that, what tools do we have available to us? And just like
a good plumber if you don’t have the right tools or you don’t know how to use the right
tools for the right job you’re not going to be able to fix the faucet.
So we can think about fixing glaucoma or treating glaucoma as fixing the sink. So you’ve got
a backed-up sink, what can you do? Well you could potentially just the faucet. So if the
water is flowing and the sink is overflowing one thing you can do is simply turn off the
faucet. But with glaucoma of course you don’t want to turn off the faucet because if you
don’t have any flow then you end up with hypotony and with hypotony you can end up
with maculopathy, phthisis—things that you generally don’t want. So we can adjust the
flow but we can’t turn it off. Well the problem is that if the drain is stopped up
even turning down the flow might not be enough. So of course then we can look at fixing the
drain and if we’re going to fix the drain we have to think about, in terms of glaucoma,
the outflow pathways. And there are physiologic pathways—the pathways that are used by everyone’s
eye that doesn’t have glaucoma. And then there are the non-physiologic, so basically
those that we create. Now, in terms of the physiologic pathways
there’s the trabecular meshwork. Trabecular Meshwork – we can think of is basically
the drainage grate here. So that’s the first level at which fluid can come into a resistance.
Behind the grate is the Schlemm’s canal. So this is the canal that encircles the angle,
sitting just behind trabecular meshwork as you all know and this can be thought of roughly
as the drain that the you drain or whatever in again I’m not a plumber I use the metaphor
here of it I don’t know anything beyond that grate when it comes to the sink of my
house. Alright, so but Schlemm’s canal we know is basically a tube. And there are ways
that we can interact with Schlemm’s canal. Then there’s the Collector Channel System.
The collector channel system is rather mysterious we don’t have a way of testing it at this
point but we know that it’s really important in terms of drainage. If the collector channel
system, which takes fluid from Schlemm’s canal to the Venus collector system, does
not work then many of the treatments I will be discussing today simply won’t work.
So that brings us to the next one which is the Uveal-Scleral Pathway, which is a pathway
that was little known prior to the advent of prostaglandin analogs. Now this pathway
does not use the classical or the usual pathway of the trabecular meshwork, Schlemm’s canal
and collector channel system. It actually goes through the uvea here and we’ll talk
about that because it’s a very interesting option to take advantage of.
In terms of the non-physiologic pathways, we can shunt fluid. So whenever we’re using
a non-physiologic pathway we’re essentially creating a shunt. So a pathway, which wasn’t
there before and the standard pathway that’s been used surgically since 1968 was Trabeculectomy—essentially
poking a hole in the eye and shunting fluid from the anterior chamber into the subconjunctival
space and creating a bleb. Now, the other thing we can do now (and we’ll
get to this) is shunt fluid into what’s called the supraciliary or suprachoroidal
space which is below the sclera. So we’ve got above the sclera and below the sclera
options that are non-physiologic shunts. So what I’d like to do is review the currently
available glaucoma treatments because although you’ve been aware of many of them there
are a couple of FDA-approved treatments that are relatively new And it’s helpful to put
it in perspective of—put them in perspective in relationship to what’s been available
in the past. In terms of the currently available: medical treatments (you’re going to break
these up into) medical, laser, and surgical. Although, (technically) laser is surgery it’s
not incisional. You know most patients they take more kindly to laser than they do incisional
surgery. Currently Available Medical Treatments for
Glaucoma We can look at the FDA-approved Eyedrops and
Oral Medications. And I’m not going to spend a lot of time on this although I do want to
give it its due. In terms of the eyedrops what we’ve got available here in the US:
Beta-blockers, “Selective” Alpha Adrenergic Agonists, Carbonic Anhydrase Inhibitors (both
drops and oral) as well, as Prostaglandin Analogs, the Cholinergic Receptors Agonists
– so pilocarpine, and then the Fixed Combination Agents, of which we’ve got three.
So in terms of the Beta-blockers—Timoptic, Betaxolol (and others) pretty much, all we
use is Timoptic for most of our patients unless they’ve got some cardiovascular issues.
These have been around for a very, very long time, we know they work well, and they work
by turning down the faucet. So the Beta-blockers supress aqueous production and they do that
do that by inhibiting c-AMP (cyclic mp). Now— again we’re not going to go into
all of the scientific, and laboratory bench work on all of this because it’s a lot to
take in. And if you want that the papers are available you can break out or dust off your
old textbooks but I just want to make sure we get through everything today, which is
quite a bit. One other thing is although you’ve got some
paper there and some pens to take notes for pearls and what not, don’t worry about getting
all of these. My plan is at some point to make these slides available online and when
I do so (I will) we’ll send out a notice to everyone.
So in terms of the Beta-blockers – although they’re cheap, widely available, and tolerated
by most people there are some issues with them. They can cause ocular irritation (topically)
but more concerning is Bradycardia (so low heart rate), arrhythmia (irregular heart rate),
heart block (systemic just stop the heart), systemic hypotension (so low blood pressure)
and even heart failure. And traditionally we’ve been told well you know be careful
about using these in your elderly patients because they might be more sensitive to the
Beta-blockers. So you know think you’ve got somebody who’s young and healthy shouldn’t
be a problem. Be careful though. I once had a patient who
is in his 40s—an athlete, stocky guy— gave him a timolol, told him beforehand (thankfully)
that these were issues, he ended up in the emergency room the first night that he took
a Beta-blockers because he was—although his heart rate was reasonable for an athlete
in the 50s and 60s, when he took the Beta-blockers – because he started off so low, he dropped
down below 40. So you do need to be careful about that. Basically anyone who’s not really
healthy or really unhealthy should be okay. But if you’ve got an athlete or somebody
who’s elderly and in terms of their cardiovascular status not so strong, you should be worried.
Now they’re also non-cardiac issues: Central nervous system depression, impotence – if
you’ve got somebody who’s taking the blue pill probably not a great candidate for Beta-blockers
(by blue pill you all understand Viagra or its fellow agents). More importantly than
that, it may mask signs of hypoglycemia. So if you’ve got diabetic patients who fluctuate
a lot and occasionally have hypoglycemic episodes, you do not want to use Beta-blockers. It can
also exacerbate asthma and you know from the things that I just mentioned, I think it’s
pretty clear to see it can also result in death. We don’t see it very often but it
does happen. Selective Alpha Adrenergic Agonist is the
next class I’m going to look at and that’s basically Brimonidine works by turning down
the faucet and the selective one such as Brimonidine also opened the drain. So it’s nice this
particular agent actually does both. But as we’re aware it causes ocular irritation
and more worrisome than ocular irritation is the Follicular Conjunctivitis – this
can happen up to 15% of the time and when it happens it could be whopping and you have
no choice but to discontinue. Of interest is you can also see eyelid retraction, contact
dermatitis and occasionally, although, we don’t think of it that often a headache.
Other things: dry mouth, systemic hypotension, so it’s not just the Beta-blockers. Bradycardia,
Arrhythmia, Death – it’s unlikely but we can see it. But with regard to these last
three here it’s most worrisome in infants and small children. The adrenergic agonist
should not be used in infants and small children because of the risk of central nervous system
depression and death. Now interestingly there are a couple of potential
benefits of the selective alpha adrenergic agonist such as Brimonidine. One is if you’ve
got somebody with a small ptosis of approximately one millimeter, Brimonidine is a great medical
way to treat a small ptosis. It’ll lift the eyelid by about a millimeter. Also in
terms of normal tension glaucoma there is evidence that between a Beta-blockers and
an alpha adrenergic agonist (Brimonidine), that even with the same amount of intraocular
pressure lowering, patients do better with Brimonidine. So in other words their visual
fields are more stable – less likely to get worse over time.
The Carbonic Anhydrase Inhibitors (the next class that we’ll talk about) so basically
the Azopt® Brinzolamide and & Trusopt Dorzolamide. These work by turning down the faucet – decreasing
aqueous production. Carbonic anhydrase is present in the ciliary epithelium. Now, the
problem is that you have to actually block about 90% of the enzyme in order to get the
effect that you want. So the problem with these is that they don’t actually work all
that well. Of the drops we’ve talked about so far, they’re the least likely to work.
Fortunately they don’t have too many side effects – irritation (that seems to be pretty
common with anything that you’re going to use), punctate keratopathy, some blurred vision
and some bitter taste. As I was saying 90% blocking has to occur to get an effect 15%
reduction pressure – not that impressive. Now importantly, carbonic anhydrase is also
used by the corneal endothelium in order to pump fluid out of the cornea. So if you’ve
got somebody with a corneal endothelial dysfunction this may not be the best choice. Lower pressure
but might swell the cornea up a bit. Prostaglandin analogs – there’s a whole
bunch of them available now. They open the drain but not through the regular drain. They
open up the drain through the uveal scleral outflow. They work quite well but they do
have some local side effects that can be—depending on the patient—either desirable or bothersome.
Conjunctival Hyperemia almost always bothersome, iris color change almost always thought bothersome
and it only happens in the pigmented areas so if you got somebody that has blue eyes
and there’s no pigment they’re going to stay blue. If you’ve got somebody that’s
got blue with brown spots the spots are going to become more noticeable. Hazel eyes become
more brown. If you’ve got somebody with a dark brown iris it’s not going to matter.
Lash growth most people appreciate that although some of the prostaglandins do tend at least
under this Slit lamp to provide more of **** spidery, unruly lash growth which isn’t always appreciated.
And men don’t always appreciate it but the other thing we’ve been seen recently is
prostaglandin associated periorbitopathy (that’s a mouthful), which is essentially a reduction
of the tissue around the eye now early on again it can be rather desirable right so
you’ve got somebody with some excess bags under the eyes, apply the prostaglandins things
seem to tighten up a little bit like they’ve had a little laser surgery tightening or sometimes
it even looks like they’ve had a lower lid Bleph. That’s great early on but if it progresses
too far it can actually tighten the lid so much that it’s difficult to obtain a pressure
measurement using Goldman applanation tonometry so this can actually get in the way of your
ability to monitor glaucoma. Now there’s some other things you can get intraocular
inflammation. This is controversial but the prostaglandins are part of the inflammatory
cascade. So it makes perfect sense that they are pro-inflammatory and indeed there’s
evidence that they can increase the risk of macular edema at least in those patients who
are already at risk for macular edema, herpes virus reactivation can be an issue so you
should generally not use this particular drop to lower the pressure in somebody who has
a history of herpes virus infection at least of the eye, and then headaches— there have
been reports of pretty severe nocturnal headaches. Speaking of headaches, Cholinergic Receptors.
Pilocarpine that’s the one thing we all think about with pilocarpine is headache.
Now these are still around because they can still be quite useful for those of our patients
with narrow angles but there also still worth being aware of just in terms of general practice.
Because they do work pretty well — they open the drain through a different mechanism
than the ones we’ve talked about. Essentially they provide some tension on the posterior
trabecular meshwork and allow increased outflow. But brow ache poor night vision due to the
meiosis induced myopia and then there are these other issues—retinal detachment more
of an issue with high myopias but of course if you’ve got a retinal detachment and somebody
who has a small pupil that you can’t dilate, that’s an issue. And then less likely but
something that was more commonly seen with the older agents in this class and also when
we were using this drop a lot more, cicatricial conjunctival pemphigoid, corneal endothelial
toxicity, so it’s not just the carbonic anhydrase inhibitors that can give you issues
with the corneal endothelium it’s also pilocarpine. And then band keratopathy.
Fortunately we now have these Fixed Combination Agents. We have three of them here in the
US Cosopt® – Timolol + Dorzolamide, Combigan® ® – Timolol + Brimonidine, Simbrinza®
which is Brimonidine + Brinzolamide. My current favorite is Simbrinza® simply because it
doesn’t have a Timolol component. Now the other thing to keep in mind here is
that these agents, Cosopt® and Combigan® , the two that are Fixed Combination Agents
which do have Timolol in them, you’re using these twice a day. It’s a twice a day agent
where you’re using timolol twice a day which really is best used once a day in the morning
because the night-time dose doesn’t really help you all that much in terms of the aqueous
production which drops at night anyway. But the other thing is we now know that using
Beta-blockers at night can potentially put patients at risk for what’s called dipping,
which is where their blood pressure drops by 10 points patients who dip are at a much,
much higher risk of progression with their glaucoma. So why in the world would you want
to use a drop that places a beta blocker in the eye but then moves systemically in most
patients at night? Now the other issue here is we’re dosing these twice a day Cosopt®
and Combigan® . Well, Dorzolamide and Brimonidine both work best three times a day. So the Cosopt®
and Combigan® — I’ve almost entirely eliminated from my practice because in my
mind these are just bad compromises. You’re not getting the right dosing on the Brimonidine
and the Dorzolamide and you’re getting too much Timolol and potentially actually putting
your patient at risk if they’re a dipper. Now if you’re worried about dipping, you
can get a 24-hour blood pressure monitoring. It’s not that expensive. It’s not that
much of a hassle. Generally you work with the internist. Most internists are happy to
do it because it’s information they’d like anyway but for that reason I’ve really
moved to Simbrinza® using— recommending it three times a day. The patients don’t
get that middle of the day dose so I tell them don’t feel guilty about it just try
to do it. We’ve all got more guilt than we need. So those are the drops.
Currently Available (FDA-approved) Medical Treatments (Oral Medication)
The Carbonic Anhydrase Inhibitors (CAIs) – Again, they turn on the faucet. But the oral ones
are far more effective than the topical ones. So the oral ones, again, are Acetazolamide
and Neptazane. The issue with the oral ones, though, is systemic side effects: transient
myopia, frequent urination, light-headedness, paresthesias/Paresthesias – extremity tingling.
These are all bothersome but they’re not horrible. What’s horrible is potentially
(in your older patients) dehydration leading to falls, malaise, weight loss, GI symptoms,
and hypokalemia. So we all say to our patients, “eat bananas” — bananas actually aren’t
the best source of potassium. Much better would be pomegranates, which we now have in
abundance here. And soon enough bananas won’t be available anyway. So you might as well
start recommending pomegranates before bananas go extinct, metabolic acidosis, kidney stones,
aplastic anemia, and death. So this is why you don’t see patients on Diamox chronically
at least not too many of them. So those are medical treatments.
Let’s move on to the Surgical Treatments. You’re going to start with the FDA-approved
surgical treatments— laser and incisional is what’s available here. In terms of laser
treatments, we’ve got Iridotomy, Iridoplasty, Trabeculoplasty, and Cyclodestructive Procedures.
Iridotomy, I’m not going to spend a lot of time on that – we poke a hole on the
Iris, allows fluid through and out the natural drainage system.
Iridoplasty – It’s Plasty. So instead of making a hole you’re basically shrinking
the Iris. This is used in plateau iris and what you see here in this picture is here’s
the Iridotomy. When Iridotomy doesn’t work in plateau iris you then do a Iridoplasty.
So you do is you make a whole bunch of little spots here that pull the iris away from the
angle. But what I really want to talk about here
is the Open Angle Glaucoma treatments because narrow angle is pretty straightforward. So
not that interesting—there’s not that much going on right now. Whereas with Open
Angle Glaucoma there’s a lot. We can split Open Angle Glaucoma surgeries
into categories: the non-invasive laser, the minimally invasive, which is the most exciting
and then the penetrating which is, for the most part, the older style of surgery.
Now, we can also think about glaucoma surgical treatments in terms of how they work. They
can SHUNT, they can ENHANCE–So they can shunt fluid out of the eye. They can enhance
the natural outflow, or they can ABLATE – they can basically destroy tissues. So mostly when
we’re talking about destroying tissue we’re talking about destroying the ciliary body.
So I like to think of this in terms of mnemonics as SEA. Let’s look at Enhancing here.
Laser Trabeculoplasty – you can split this up into Argon, Selective and Micropulse.
The Argon Laser Trabeculoplasty or ALT has been around for a very, very long time.
Quick aside—of interest, I always love to hear the stories about how scientific discoveries
are made. In the case of Laser Trabeculoplasty, this was actually an accident. They were studying
monkeys, when those laser treatment came about and they thought well let’s poke little
holes in the trabecular meshwork so that fluid can get through the trabecular meshwork, which
tends to be the primary location of restriction of flow and shunt it directly into Schlemm’s
canal. So they did it. But the problem with the monkeys is that they scarred down. So
then they thought, “ah we can use this laser instead to create a monkey model of glaucoma”.
So instead of poking holes we’ll just use a lower energy, will shrink or scar down the
trabecular meshwork and now we’ll have these monkeys that we can study glaucoma treatments
on because we will essentially have created glaucoma in these monkeys. Well, lo and behold,
after the monkeys healed up from the initial inflammation, what happened?! Their pressures
went down. So that’s how ALT was discovered. Then it was used in humans to essentially
create small micro burns in the trabecular meshwork and the thinking was that in between
the burns you stretch open the trabecular meshwork. Nobody really knows. It can only
be used in open angle glaucoma, performed in one or two sessions, may result in microscopic
scars — you are actually coagulating tissue, and it may limit future surgical options,
in particular some of the newer options that are becoming available. So for that reason
it’s not the best choice. Selective laser trabeculoplasty is becoming
more commonly recommended primarily because it doesn’t destroy tissue. And because it’s
now becoming affordable. When this first came out it was $70,000 to buy the laser, who other
than glaucoma specialist are going to be able to do that but lately the laser cost has come
down into the 20,000-40,000 range. This uses a Q-switched frequency-doubled Nd:YAG laser
(not that anybody need to know that). It can be performed on its own or even after ALT.
It’s less traumatic because it doesn’t coagulate tissue, less damage, it’s quick
and it’s usually painless. And interestingly enough, it can be performed either using a
gonio mirror (as with the Alt) or a recent study that was just published showed that
you can actually do this Transscleraly. So you can just sit the patient at the slit lamp,
aim the beam at the limbus and place 100 spots around the limbus and it works. Perhaps not
as well — we don’t know—but it does work. So there it is. There’s a laser spot
and it’s lasering. Fascinating. Micropulse® Laser Trabeculoplasty (MLT) – This
basically uses micropulses—really, really, really short pulses. And the idea is if you
separate the pulses into tiny little pulses followed by a little pause and then another
little pulse and then a little pause what happens is you get what’s called “thermal
relaxation”. So the tissue heats up and then cools off and then heats up and cools
off and you do not get coagulative damage when you do this. Basically this is a newer
version of SLT. It’s a cheaper version of SLT, seems to work as well as SLT and so there’s
some benefits to having this. Currently Available (FDA-approved) Laser Treatments
(“Cyclodestructive” Procedures for Glaucoma) Continuous Wave Cyclophotocoagulation
Ab-Externo Continuous Wave Cyclophotocoagulation This is, traditionally been, reserved for
those patients who have end-stage glaucoma where there’s no potential for vision. It’s
just a blind, painful eye. And you’d place this laser spots transscleraly, you destroy
the ciliary body and you’d lower the pressure. But you could also lower it too much—you
could essentially destroy the aqueous production and end up with a hypotenuse or even Phthisical
Eye. So this is not really used for too many patients. But it did have its use.
Then there’s the Ab-Interno – the newer version, the EndoCycloPhotocoagulation (ECP)
and the most exciting (I think) is the newest iteration of this is Micropulse® Cyclophotocoagulation
(MP3). So the Ab-Externo which is from the outside
of the eye, continuous-wave cyclophotocoagulation— we just talked about that. It was pretty uncomfortable.
Nope, it was downright painful. You actually had to block the eye or put somebody under
anesthesia. And then not only— this is the other thing—not only could you get hypotony
but there was even the possibility that you could get sympathetic ophthalmia from the
severe inflammatory response. So you treat one eye and the other eye would go blind.
Not ideal. So this is why we didn’t see much of this but because it did have its use
it stayed around for a while. And eventually people figured out how to use this technology
in a safer way that was still effective. And so EndoCycloPhotocoagulation was developed.
This can be used for mild to moderate glaucoma it has to be done at the time of or after
cataract surgery and it’s relatively low-risk glaucoma but it’s also you know relatively
modest in its effect. And it does, as with anything you do with the iris or the ciliary
body, it’s going to result in some inflammation. So here is an animation of the ECP. A viscoelastic
is placed in the in the eye a probe is then inserted and the individual ciliary body processes
are then lasered and the trick is to shrink them. You have to shrink them enough that
the epithelium stops producing aqueous. But you don’t want to actually pop them. And
what happens is you see them shrink and if you go beyond the shrinking they pop like
popcorn. And unfortunately that pop is so incredibly pro-inflammatory that this procedure
is very much surgeon-dependent. So if the surgeon understands the nuances of the procedure
you can get a nice effect without too much inflammation. If they’ve got a heavy hand
or heavy foot, as the case may be it, it can actually result in a lot of inflammation.
This is, I think, as I said the one of the most exciting laser treatments that’s available.
This uses, as we talked about before, micropulses. You’ve got tiny little pulses followed by
a pause allowing for the thermal relaxation. So this was thought of as a gentler form of
Cyclophotocoagulation. Nobody really knew how it worked. I mean if you’re not destroying
the ciliary body process how in the world are you getting any reduction in aqueous.
Well turns out you’re not. It doesn’t work by reducing aqueous. It works by pulling
on—on the posterior trabecular meshwork and essentially enhancing outflow just like
pilocarpine. Nice thing about this is although it is uncomfortable
and you still have to either block or put some of the– quick five minutes of IV sedation,
it’s generally comfortable afterwards, very low risk, and it works— works well as we’ll
see in a moment. So this is the slow application. The lasers
chopped in the micropulses. The early studies looked at patients who just like with Transscleral,
continuous wave Cyclophotocoagulation were kind of end-stage patients —you can see
these are patients with pressures in the 40’s. And they come down in the mid 20’s. Since
that time, they’ve also studied patients who have more reasonable pressures and the
studies seem to indicate that they do (about) as well, in terms of the percent reduction.
And this is the procedure it’s an external procedure… There’s no incision it does
not have to be done under sterile conditions, and essentially you make about nine passes
superiorly, nine passes inferiorly of this laser. And it’s not technically challenging
although it can be somewhat challenging in patients who have small palpebral fissure
because if you don’t get the laser posterior enough you can end up with a change in the
pupil size and potential inflammation. And that’s probably the reason why pupil dilation
is relatively common. Currently Available Incisional Treatments
for Glaucoma (Traditional “Penetrating” Surgical Methods)
These are what we can basically split into Penetrating (the more traditional ones) and
the Lower Risk Surgeries, which are called “minimally invasive glaucoma surgeries”
or “Micro Invasive Glaucoma Surgeries”—basically MIGS.
And we’ll go over how well MIGS go, in a second, because you may have heard the tongue-
in-cheek term, MEGS— M-E-G-S for Minimally Effective Glaucoma Surgery and we’ll see
whether or not that’s case. We all know about trabeculectomy— you create
a fistula, so a shunt creates a bleb, the issues of bleb failure, lifetime risk of infection
and lifestyle limitation. You can’t wear contact lenses; in general, you can’t go
snorkelling or scuba diving— things like that. For our active baby boomer patients,
this can be an issue. There’s also other issues—you can have cystic blebs, resulting
in ocular surface disease, you have scarred bleb, which is quite (you know) in five years
after trabeculectomy, its more likely to have a cataract from the trabeculectomy than you
are to have a working bleb. You know, they’ve been around since 1968 and they’ve really
not changed much in that time so I think that we can all agree it’s time to move on. And
we’re going to be talking about the potential methods by which we can move on.
Traditional penetrating surgeries also include the Glaucoma Drainage Devices.
Essentially there are two that are commonly used here in the in the US — the non-valve,
which is the Baerveldt® versus the valve, which is the Ahmed™ and these have a number
of issues along with — that are shared as well as somewhat unique from Trabeculectomy.
And in the case of the Trabeculectomy and Glaucoma Drainage Devices the main risks are
pressure elevation and hypotony—so both extremes there. In the case of the Glaucoma
Drainage Devices, you’ve put an implant on the surface of the eye, underneath the
conjunctiva, so not surprisingly the implant can sometimes move, you can give them the
trouble with that, you can get an infection — if you get an infection on an implant,
whether it’s an implant in the eye or anywhere else, that’s a big issue. You generally
have to remove the implant. It’s very hard to eliminate an infection on any non-biologic
tissue. Scarring can cause double vision. And then there are other things — the implant
itself — the tube can erode. With Glaucoma Drainage Devices as well as Trabeculectomy,
if you end up with a sudden drop in pressure, you can end up with a suprachoroidal hemorrhage—
a bleed in the back of the eye that can lead to a total loss of vision or at least put
you at great risk of that. So essentially after incisional glaucoma surgery
that’s the only time I will ever tell my patients that not only can they use a laxative
or stool softener but I want them to. Because I want them to avoid any Valsalva maneuver,
anything that could cause an increase in venous pressure resulting in back flow into a hypotenuse
eye. So given those risks and given the fact that with glaucoma, we’ve got patients that
generally can see and we’re trying to keep them from losing vision. I don’t like offering
surgical treatments that have a high risk of loss of vision.
So this is where the newer, lower risk surgeries are really exciting. The question is, are
the lower risk surgeries as effective as the higher risk, older penetrating surgeries?
so we’re going to look at the Ab-Externo (from the outside) and the Ab-Interno.
Of the Ab-Externo, the main one is Canaloplasty. This is a develop— this is essentially a
modification of a surgery that’s very commonly done in Europe, which is called Deep Sclerectomy
or ViscoCanalostomy (this is another version of that). And they use it in Europe because
it’s safer than Trabeculectomy. Well in the case of—when we’re talking of ViscoCanalostomy
or Canaloplasty, these are non-penetrating. So you’re not actually creating a fistula
from the anterior chamber into the subconjunctival space. So there’s no hole, no bleb… but
they work well. So, you do lower the pressure, you have fewer drops in general, they’re
safer than traditional surgeries, and this is key for our patients who like to be active:
you, generally, do not have to adjust your lifestyle.
And so, showing you what Canaloplasty looks like here. You do—and this is just going
to go through (sorry) the normal pathway of aqueous being produced by the axillary epithelium,
going out through the trabecular meshwork but in the case of glaucoma patients there’s
a blockage in either on the Trabecular Meshwork or the Schlemm’s canal…So with canaloplasty,
you do create a partial thickness scleral flap; so it’s not a full thickness scleral
flap. It’s a partial thickness. And a catheter-the world’s smallest catheter, it’s incredible
little 250 micrometer diameter catheter is threaded through the canal, which is pretty
neat to see. Once it’s through, you tie a suture to it and pull the suture back through
the canal. Now why would you do that? The idea is as you’re pulling it back through
the canal you’re actually injecting viscoelastic to dilate the canal. So it’s kind of like
angioplasty for the eye. Now once you’ve pulled the suture back through you tie it
to tighten the inner wall of the canal kind of like you tie a hoodie to bring it down
and you can see that pulling down on the inner wall. Now what happens is you dilate the canal
and you stent it open so you get better flow into the Schlemm’s canal and then out through
the collector channel systems. Aha! But you have to have an open collector channel system,
which there’s unfortunately no way to detect beforehand and this is going to be a theme
through the rest of this talk. So how does it work? Well it turns out it
works pretty well, okay. And one study that looked at the two surgeries Trabeculectomy
versus Canaloplasty there was not a significant difference between the final pressures: 13.4
with Trabeculectomy (and this is one year out) versus 12.3 (sorry) 13.4 with Canaloplasty
(I correct myself) versus 12.3 with Trabeculectomy and mitomycin. So yes Trabeculectomy had a
tendency to be lower but it wasn’t a statistically significant difference.
What was different importantly is the risks. Patients had better vision with Canaloplasty,
they had lower risk of hypotony, they had no issues with blebs… I could go on. Anyway
the three year results are quite good in terms of the reduction. So if Canaloplasty only
there was a 34% mean IOP reduction from baseline and a 53% reduction in drop use. So not only
did the pressure drop, but the number of drops that were required to keep that pressure dropped
as well. If you combine Canaloplasty with phacoemulsification (so cataract surgery)
it gets even better 42% mean intraocular pressure reduction. 81% mean reduction in drops and
90% (eighty-eight% of patients) were drop- free three years after surgery today without
the risks of Trabeculectomy. So this is a really, really exciting procedure.
The doctor who developed Canaloplasty, Dr. Robert Stegmann in South Africa, is an absolute
genius. I think this quote pretty much sums it up, “it’s vital to find a safer more
predictable operation with preferably no complications at all (and he felt that) canaloplasty is
the closest that (he) has ever come to that”. And that’s another point that I didn’t
make earlier; with Trabeculectomy/Glaucoma Drainage Devices it there’s no coupling
between surgeon skill and the outcome. You speak to experience glaucoma surgeons, they
will tell you “I will finish what I think is a perfect Trabeculectomy and have no idea
how this patients going to do because it’s so dependent upon the body’s healing response.”
And that’s not the case with Canaloplasty. So moving on to the minimally invasive glaucoma
surgeries, which is really an exciting area right now—but the question is, “are they
also minimally effective?” So the ones we’re going to go over are the
ones that are FDA-approved: Ab-interno Canaloplasty (ABiC)—so this is Canaloplasty from the
inside of the eye, Trabeculotomy, iStent®, Cypass®, Xen Gel Stent, and Cataract Surgery.
And you may say, “well, why’s cataract surgery up there?” We will get to that.
So interestingly enough, with the Ab-Externo Canaloplasty (coming from the outside) they
separated the results in those that had the stent and those that didn’t have the stent.
And what they saw was that, although they generally did better with the stent (even
if you couldn’t get the stent in) the pressure is still dropped. And you can see in this
here three-year results of those with Ab-Externo Canaloplasty but without the suture the average
pressure dropped from 25.2 mmHg to 16.2 mmHg. This is a pretty decent reduction and the
mean number of medications from 2.1 to 1.1— so by one medication on average.
So, Dr. Mark Gallardo in El Paso Texas thought, “well this is interesting. Is there a way
that we could do this from the inside of the eye without making the incision from the outside
the eye, which would make it much less complex of a surgery and also a much faster surgery.
And it turns out you can and the neat thing about it is that by doing this you treat the
trabecular meshwork—because you create an opening in the trabecular meshwork, you open
Schlemm’s canal, you potentially dilate the collector channels— so you get better
aqueous outflow, and there’s no permanent stent or implant. And that’s the key point
of the Ab-Interno Canaloplasty— no permanent stent or implant.
What we’ll do here is I’m going to take us through—this here, so essentially this
is after cataract surgery. So, what’s going to be done is— you can see over here that…here’s—the
catheter is being inserted into the anterior chamber and it’s basically being rested
against the angle here. Then what happens is a gonio lens is placed on the eye—and
here again you can see that the catheter is resting there so you’re looking at the angle
of the eye—and either a blade or Cystitome is used to actually pierce the trabecular
meshwork, opening up into Schlemm’s canal, which also—which often results in a little
blood reflux—so you can see a little blood there. And then this is what is so cool about
this procedure—micro forceps are used to thread this catheter through and you can see
the tip of the catheter (it’s a blinking red catheter), you’re going to see it coming
around here in a moment—so these—he’s threading it around the Schlemm’s canal.
So he’ll thread it all the way around and then place another instrument in the eye to
essentially hold the catheter up against the angle and he pulls it back through. As it’s
being pulled back through, viscoelastic is being injected into the canal—dilating the
canal. So how does it work? Well, the initial studies,
looking one year out basically showed—there’s two: one was by Dr. Khiami, showed a reduction
of from 19.5mmHg to 13.9mmHg. The reduction of average medications from 2 to 0. Dr. Gallardo,
showed a reduction of 18.6mmHg to 12.9 mmHg. You get 12.9 mmHg! I mean, that is in the
range of what the Trabeculectomy studies are showing, right? And mean reduction from 2
medications to 1. And if you actually combine the studies—mean IOP from 19 mmHg to 13.3
mmHg, 2 meds to 1. You know these are very impressive results for very safe and very
fast surgery. What else can we do? Well one thing we can
do is dilate the canal, the other thing we can do is say, “well, if trabecular meshwork
is the primary area of restriction, why don’t we just rip it out or tear it open?” And
so, we can do that. It turns out that if you’ve had a patient who’s had Ab-externo Canaloplasty
and at some point the pressure is no longer controlled— if they’ve had the Stent — so,
if they’ve had the suture placed in the canal, you can go in with micro-forceps or
another instrument and pull the suture through. Pulling the suture through rips open the Trabecular
meshwork— that’s called Micro-invasive Suture Trabeculotomy. And in a two year study
it showed a 45% reduction in intraocular pressure. So, low-risk procedure.
Basically, the main risk you have is hyphema (system bleeding in the front of the eye as
you open up the trabecular meshwork). That generally goes away on its own. There’s
very low risk with any of these angle procedures of cyclodialysis, which can result in hypotony.
That’s pretty low risk. So you know the nice thing about canaloplasty is that you
can potentially get a double benefit: you can get the initial opening of the canal and
then if you need to you can you know pull the suture through the trabecular meshwork.
So, there’s also if you’ve got somebody who has not had Canaloplasty you can perform
what’s called Gonioscopy-Assisted Transluminal Trabeculotomy. That’s essentially taking
that catheter we saw before but instead of just dilating the canal you move the catheter
or some people will use a aid…a suture if you want to (you know) get really cheap you
don’t want to use an instrument that’s been designed for this it can be done it’s
a bit more challenging but in any case you move the suture around the canal and then
you take the two end of the suture and you pull through and you rip through the trabecular
meshwork. And it also shows a pressure reduction around 40% at two years.
You can get more sophisticated and a whole lot more expensive; Ab-Interno Trabeculotomy
has been done using a device called a Trabectome, which has to be done with or after cataract
surgery. As with all of the Trabeculotomies, they do limit the potential for future canal-based
surgeries but the most—the biggest issue with Trabectome is it’s just—it’s darn
expensive. This is the instrument here. And it’s a
pretty cool looking instrument… it has a foot plate to protect the posterior wall of
the canal and essentially it’s got these electrodes that produce plasma and then it
sucks up the trabecular meshwork tissue as it opens up the canal there. So it’s about
a fifty-thousand-dollar instrument and then they make you purchase each of the hand pieces
so it’s not been that popular when you’ve got these other less expensive options.
And one of the more interesting, less expensive options is the Kahook Dual Blade. Basically,
it’s like a poor man’s Trabectome. But instead of using a plasma blade, it’s got
this neat (I’ll show you) this really neat, design of this blade. There we go… that
allows you to safely remove the trabecular meshwork as kind of a strip. So it strips
it off. And here you can see the tip of the blade there and it’s got a kind of foot
plate and then these two side blades, so you get a sharp tip to get into the trabecular
meshwork. And boy, don’t I wish the trabecular meshwork looked that clear and easy to find.
Angle base surgery is technically challenging. There’s a high learning curve but once you’ve
got it, it can be quite fast and really gentle in terms of the patient experience.
So this is a video of the Trabeculotomy using the Kahook dual blade. And you can see the
blades in the angle—It’s getting in the trabecular meshwork. Now is going to come
around from the other way and it’s pretty you actually end up with this little strip
of trabecular meshwork that if you were interested in it for research or other purpose you can
actually take it and send it to pathology. So you can see there’s a little strip on
the edge of it. They’ll actually remove that in second.
So other angle based surgeries… The first micro invasive surgical implant
to be FDA-approved is the IStent®. For use with ocular hypertension, mild Open Angle
Glaucoma—to be done with cataract surgery. And you can see, it’s pretty neat device—
it’s this snorkel that is meant to be implanted through the trabecular meshwork, into the
canal. The problem is that it limits future surgeries.
If you do this you can’t do canaloplasty or other procedures that require access to
that area of the canal. And it’s damn expensive! I mean this device is the smallest FDA-approved
surgical implant – ever. It’s made of titanium and per ounce this is the most valuable
expensive thing you could ever purchase. I think that you know some rare man-made elements
that you have to create in the Hadron Collider, maybe more expensive than this—but per ounce.
But this is well-reimbursed. The implant itself is a thousand dollars and that’s about what
the surgeon is paid for implanting one of these. So they become quite popular.
The question is do they work and here’s a video from Ike Ahmed, who is just a truly
expert, expert surgeon and has had the ability to be involved in a lot of these new surgical
procedures. Have done a lot in terms of, you know, figuring out how best to do these things
and this is him performing the surgery and as with all of his surgeries it’s just elegant
to watch. You can see him implant the stent and he makes everything look so easy but one
of the things about this particular video which underscores the issue with the iStent®
is – you’re going to see in this video, that he does not implant one. He does not
implant two. He implants three of these in the eye. Now if you implant three of these
in the eye you should get an effect. The problem here in the US (separate from Canada) is you’re
only going to get paid for one and at a thousand dollars each good luck finding a surgery center
that’s going eat the extra two thousand or patient who’s going to be willing to
pay for the extra two thousand. You can see how this goes into the canal through the trabecular
meshwork and I just love watching his videos. I can’t think of too many too many eye surgeons
who don’t. His work is so nice. Anyway, so… his surgical technique—absolutely
fantastic! How about the results of the iStent®? Do
they match his surgical technique? No they don’t. The one year result of the iStent®—cataract
surgery alone is done the pressure is reduced by…. the percentage of patients who achieved
a pressure lower than 22 mmHg? 50% – so half of the patients, just from cataract surgery
alone, will achieve that pressure under 22 mmHg. How about if you put the iStent® in
with cataract surgery? 72%. Okay— so yeah you do get more but the majority of the reduction
there is from the cataract surgery. Say, “okay well you know that some of these drops can
be pretty expensive right?” I mean we’ve all got patients who are saying, “doctor
that drop that you prescribed me the Simbrinza, it’s $250 a month.” Well a year of Simbrinza®—and
you know this is paid for itself. So maybe not so impressive when you’re looking at
the difference between cataract surgery alone and cataract surgery plus the iStent® but
taking a bigger picture it can be a useful option. But two years after surgery there’s
no statistically significant difference between those who had cataract surgery alone and those
who had cataract surgery plus the iStent®. So it’s easy to put in, it’s currently
paid for by insurance, but is it really going to give us a long-term benefit? Probably not.
So what other options are there, well just recently at the end of 2016, the FDA approved
the Cypass® Microstent. Now this is exciting because this is using
an outflow shunting method that has not been available to us before. That is, it’s also
like with the iStent®, only approved for those who are also having cataract surgery.
The nice thing about this is because it uses a separate outflow it can be used even in
patients who have had or may need to have other glaucoma surgeries.
I want to show you this this video here…so this is showing the outflow pathway, showing
essentially both the pathway through the trabecular meshwork as well as through the through the
uvea scleral outflow. You can see that this is an essentially a tube. But it’s a tube
is designed in such a way that it can atraumatically sit in the supraciliary space. So you can
see that right in the angle, above the ciliary body and shunt fluid into that space. And
it’s a very quick procedure. Basically you make an incision, just like you would with
cataract surgery. You fill the eye with viscoelastic … (I’m sure we don’t need to see all
the details of this) and you have this injector. It’s placed into the angle and then simply
inserted into the supraciliary space. And there it is…
So the question of course is how well does it work? So if we look at 2-year results (and
we do have two year results on this), they looked at patients whose diurnal curve was
between (i think it was) 18 mmHg or 6 mmHg. That’s right – 6 mmHg and 18 mmHg and
61.2% patients of the Cypass® maintained this range versus 43.5% with cataract surgery
alone. So again, what you see here is that, cataract surgery alone does have a beneficial
effect in treating glaucoma. So more however experience this range of diurnal curve with
combined cataract surgery and Cypass®. if we look at the absolute pressure reduction
7 mmHg with a Cypass® versus 5.3 mmHg on average which cataract surgery – really
doesn’t look that impressive, alright. Less than 2 mmHg but if you look at the percentage
difference it was 32% and again what we’re going to find is that with all of these lower
risk micro invasive surgeries we don’t necessarily have to think of just one. We could potentially
think of building up on different surgeries using different outflow pathways in order
to achieve a reduction that could potentially end up in the same range as trabeculectomy
or glaucoma drainage devices but without the vision threatening complications. And if we
look at the two-year results in terms of the percentage of patients who achieved a non-medicated
pressure of 20mmHg or less… so 20mmHg or less without drops, 72.5% of patients for
Cypass® achieve this versus almost 60% with cataract surgery alone. In terms of adverse
events, there really weren’t that many when you look at the comparison of the combined
Cypass® with cataract surgery versus cataract surgery alone, overall, quite similar. So
it seems to be a pretty safe, safe device. Also approved— at the end of 2016 by the
FDA, the Xen® 45 Gel Stent. This is a chemically treated gelatin tube. It’s basically what
it is – it’s a tube but it’s been designed so that the aqueous flow through it is restricted
in such a way that it reduces the risk of hypotony. So, this is essentially an Ab-Interno
method of trabeculectomy. You’re shunting the fluid into the subconjunctival space.
So it still requires a bleb to achieve intraocular pressure lowering and as such it still has
all of the potential complications or most if not all, that trabeculectomy would.
The issue with this is that although it shares many of the complications with Trabeculectomy
and although it’s much faster and in some ways easier to do, it doesn’t seem to do
quite as well as Trabeculectomy in terms of pressure reduction. So the average drop of
30% from 20.8% to 14.4% at 1 year – not quite as impressive as trabeculectomy. Three
year results looked pretty good 40% reduction, 75% medication reduction, and about 5% of
participants needed to go on to additional surgery, which is pretty typical for glaucoma
surgeries. But as I said (was saying) earlier you have these issues of short and long term
hypotony, potential for loss of vision—that’s not insignificant, right? 6.2 % long-term
loss. So that’s on par with, really, trabeculectomy. Cataract surgery – I’m not going to belabour
on this point. You’ve seen already from the studies I showed earlier that cataract
surgery alone can be effective with glaucoma. So for many of our patients who are kind of
doing pretty well with their glaucoma – we’d like the pressure to be a little bit lower,
they may be having some progression. If they’ve got cataracts or cataracts that are ready
for surgery, and they’re not maxed out on medications, then cataract surgery alone,
for many of these patients, is perfectly reasonable. The issue though is, if they are maxed out
on medications and you perform cataract surgery and they have a pressure spike, which is not
uncommon among glaucoma patients of cataract surgery, then what are you going to do? Then
your only option is Diamox. So patients who are on max-tolerated medical therapy and need
cataract surgery, we will generally consider combining the cataract surgery with one of
these MIGS procedures. But if they’re not maxed out it’s perfectly reasonable to consider
just cataract surgery alone in those who have mild to moderate glaucoma.
So what’s in the pipeline? Next-generation medications and surgeries in the pipe line.
Quickly, the medications that are—that you’re going to see—some of these are already available
say in Japan and elsewhere but hopefully we’ll see these in the US. There’s essentially
three new classes of medications: The Rho-Kinase or the ROCK inhibitors—they
open the drain by relaxing the trabecular meshwork. The Norepinephrine Transporter Inhibitors
or the NET Medications—they “turn on the faucet”. There’s one an FDA trials right
now, which is a ROCK/NET. So it uses both of these. Just like the alpha-2 agonists,
you could potentially get both a reduction in the flow (reduction in the production of
fluid) as well as an improvement in the outflow—so that’s very exciting.
Adenosine Receptor Agonists They work by increasing the outflow through
the trabecular meshwork. Modified Prostaglandin Analogs
Now, these are basically Prostaglandin Analogue plus a Nitric Oxide. So they’re generally
(you can think of some of these as) Prodrugs. They enter the anterior chamber, they’re
split up into the prostaglandin and a nitric oxide. Nitric oxide relaxes the trabecular
meshwork and Schlemm’s canal increasing outflow.
Next Generation Plumbing | What’s “In the Pipeline” of Medications and Surgery
But what’s really exciting and what I’m going to end on here is the next generation
of plumbing – the surgeries. The iStent Supra® is basically the the Glauko’s
version of the Cypass® and it’s exciting but we’ve seen Cypass®—this isn’t that
different. I’m sure there’s some nuances and one may end up working better than the
other—have fewer complications—but what interests me is what follows.
The Hydrus™ Microstent – this is actually a way of stenting the canal. So we’ve seen
with the Ab-interno Canaloplasty (ABiC) how we could dilate the canal but the problem
is: you’ve dilated—that’s nice—angioplasty of the heart remember, many times the vessels
would scar back down. So then they started putting stents in the vessels in the heart.
Well, the same thing (we hope) we’ll be able to do with the Schlemm’s canal: dilate
the canal and leave a stent. So, in this case, it’s a small little stent, only as long
as an eyelash. It’s done with cataract surgery, seems quite promising. Another Ike Ahmed video,
which is again fun to watch but given the time I think that we’ll hold off unless
somebody wants to see it after the talk. I’m willing to stay around and do some theatre
here. The other is the InnFocus MicroShunt®—These
things are not yet FDA-approved but they’re in trials and then maybe. The InnFocus MicroShunt®
is essentially— it’s an Ab-externo, unfortunately. It’s essentially a controlled trabeculectomy.
So instead of creating a flap and punching a hole, you essentially place this device
that limits flow. So very much like the XEN® Gel Stent, which you could do from inside
the eye. This is similar but requires that you come from the outside of the eyes. Now,
personally, now that the XEN® Gel Stent has been approved, I can’t imagine why anybody
would want to take the trouble to use this but it might have… it might have a following—we’ll
see. The Xen® Gel has the advantage of both being an Ab-interno – so quick and easy
to do, as well as the fact that it’s already FDA-approved. So it’s kind of you know first
one the market. So, if I was an investor I would not be investing on the InnFocus but
I’m not. This is the one I’m most excited about and
I think you’ll see why. We’ve been talking about minimally invasive
glaucoma surgery and the problem with it; potentially, being minimally effective specially
when you compare it to cataract surgery. So Dr. Stegmann, who created Canaloplasty thought,
“this is great stuff but can we make it better?” And so, in terms of what we just
talked about—with the Hydrus as a scaffold from the inside—If that will…“can I
create a scaffold that can be used with canaloplasty?” So he created this tube-shaped scaffolding
device that’s placed in Schlemm’s canal and can keep —and this is the key: the Hydrus
and these other scaffolds are very, very small (only a few clock hours). In the case of this
device, it can keep—up to half the canal open permanently. And this video (I think)
is worth seeing. And this is by Dr. Matthias Grieshaber, who
is an outstanding glaucoma surgeon (overseas). And you can see, this is actually—he’s
already done the canaloplasty. He’s pulled the catheter back and you saw the viscoelastic
gel at the end of it. So he’s dilated the canal. Now here is this stent. You can see
it’s a pretty long stent. What he’s going to stent is on… it’s essentially a guide
wire. So what he’s going to do is he’s going to thread this guide wire back through
the dilated canal and now you can see at the end of this guide wire is this stent – he’s
going to place this stent, again using the guide wire to help it move along. He’s going
to move this into the canal. Now this is such a long stent that he wouldn’t be able to
do this without the guide wire. And now he’ll pull the guide wire out, holding on to the
stent, and then once this is done he’ll then do the same thing on the other side but
then close up as he would any canaloplasty. So is it successful? It certainly looks like
it should be. Well, we now have two year results and if
we look at the success—recall earlier, I was talking about success rates with the different
minimally invasive glaucoma surgeries in terms of the percentage of patients who had pressures
at or below 20-21mmHg—the problem with these studies, of value is kind of a different outcome
but if you recall those compare that to this: For those had a final intraocular pressure
of less than or equal to 21mmHg, there is a 98% success rate. Almost a 100% of those
who had the surgery had a final pressure of