Download Schlemm canal Surgery

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Schlemm Canal
Surgery
Why you may not get the IOP low enough yet.
By David L. Epstein, MD, MMM
G
laucoma filtration surgery is over 100 years old,1,2
so I am very enthusiastic about novel surgical
techniques3 directed at the site of abnormal
resistance at or near the inner wall of Schlemm
canal.4 The scientific rationale for Schlemm canal surgery,
however, dates back approximately 50 years to the exquisite
dissection and perfusion studies of W. Morton Grant, MD.4
The field has not progressed as much as one might believe,
and my purpose in this article is to remind Glaucoma
Today’s readers of Grant’s experiments4 and what he actually discovered. Many have misinterpreted his findings, and
there is no clear rationale for some of the proposed surgical
procedures aimed at Schlemm canal. I urge readers to critically examine the rationale for all novel surgical procedures
targeting this site with Grant’s work in mind.
FILTRATION SURGERY
VERSUS SCHLEMM CANAL SURGERY
Filtration surgery totally bypasses the conventional
outflow pathway and basically connects the anterior
chamber to the subconjunctival space (guarded by an
intervening scleral flap), where it is believed that the
pressure is 0 to 1 mm Hg (B.A. Ellingsen, unpublished
data, 1969). The surgeon is fistulizing the inside of the
eye to the outside. If wound healing does not induce
resistance to the subconjunctival flow of fluid (as typically happens gradually over the first several postoperative
weeks), the procedure results in very low pressures and
often hypotony, especially immediately postoperatively.
In contrast, manipulating or operating on Schlemm
canal leaves its outer wall as well as the more distal
structures intact. Significant remaining distal resistance4,5
results in a higher IOP than would bypassing these distal
structures to directly access the subconjunctival space.
WHAT D r . GRANT REALLY FOUND
In what I consider to be one of the greatest single
publications of multiple experimental manipulations of
46 glaucoma today September/October 2013
“There is significant outflow
resistance from the outer wall of
Schlemm canal distally.”
the aqueous outflow system ever published4—and one
that I hand out to all of my fellows and residents—Grant
progressively dissected the trabecular meshwork in
enucleated human eyes such that the depth of dissection
was correlated with perfusion of the same eye to measure outflow facility. He observed no change in outflow
resistance until he penetrated the inner wall of Schlemm
canal. He thus found that approximately 75% of the
resistance to aqueous outflow was either at or just proximal to the inner wall of the canal in both healthy human
eyes and those with open-angle glaucoma (OAG).4 In
other words, in glaucomatous eyes, he eliminated both
normal and abnormal glaucomatous resistance by incising the inner wall of Schlemm canal.
These findings are all well known, but it is important
to recognize that 25% of the normal resistance to outflow was located somewhere between the outer wall
of Schlemm canal and distally. (Furthermore, this distal
resistance was the same in both healthy and glaucomatous eyes, thus providing no evidence—albeit only
in a small number of diseased eyes—of distal outflow
pathway glaucoma.) Residual distal resistance after most
of the new canal surgeries results in a higher IOP than
does a glaucoma filtration operation, where the anterior
chamber is short-circuited and bypassed to the subconjunctival space, which has low resting pressure.
The most significant detail of Grant’s experiments is
often overlooked. He perfused these eyes at elevated
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IOP (approximately 35 mm Hg) in order to accurately
measure outflow resistance (his constant-pressure outflow apparatus required high levels of flow). I remember
awakening in the middle of the night worrying that this
choice of perfusion pressure might have increased resistance by compressing Schlemm canal or the trabecular
meshwork, so my colleagues and I repeated these experiments at a much lower perfusion pressure.5 Fortunately,
Grant’s summary findings and conclusions held true
with one exception. We found that the distal outflow
resistance from Schlemm canal outward represented
an even higher percentage of normal outflow resistance
(approaching 40%) in normal eyes in the same internal
trabeculotomy experiments.5
From Grant’s experiments,4 one can tentatively conclude that all of the glaucomatous outflow resistance
is at or proximal to the inner wall of Schlemm canal
and that normal and glaucomatous eyes therefore have
similar distal outflow pathways and resistance. The
morphological correlate of this distal resistance is really
unknown, because the collector channel vessels appear
to have open lumens. Johannes Rohen (unpublished
data, 1989) has hypothesized that there may be sphincters immediately behind the ostia of the collector channels in the outer wall of Schlemm canal, but the exact
cause of the distal resistance in both normal and glaucomatous eyes remains unclear. By performing excimer
laser dissections from the sclera inward to the outer wall
of Schlemm canal, Schuman has shown that the distal
resistance is very close to the outer wall.6
I would also like to highlight Grant’s exact dissection
technique. He had to incise the inner wall of Schlemm canal
for the total 360º of the angle (all 12 clock hours),4 because
outflow pathway resistance behaves segmentally. There is
minimal circumferential flow in the canal, so a 1- to 2-hour
internal trabeculotomy (incising or disrupting the inner
wall) produces only a proportional amount of the 75%
reduction in resistance. Of note, only six eyes with primary
open-angle glaucoma (POAG) were studied in this way,
and Grant issued a plea for further study. I am aware of perhaps six additional POAG eyes studied by myself or others
that, fortunately, demonstrated findings similar to Grant’s.
Still, there could be some unique (POAG) eyes where the
abnormal resistance derives from another location. The
entire proximal corneal-scleral trabecular meshwork or the
distal outflow pathway beyond the outer wall of Schlemm
canal could be the locus of any added abnormal outflow
resistance in other secondary or even primary glaucomas.
That is, the cause of glaucoma could be increased abnormal
resistance at a site where normally there is no significant
resistance. This certainly may be the case in many secondary
OAGs (eg, exfoliation glaucoma).7
TRABECULECTOMY
Cairns8,9 originally devised the trabeculectomy not to
be a guarded scleral flap filtration operation but rather
to remove the site of Grant’s abnormal glaucomatous
resistance. Based on the details of Dr. Grant’s work
already presented, it is clear that such a localized surgical
procedure would not eliminate resistance when Grant
had to incise 360º of the angle to achieve that effect.4,5
Interestingly, for a while after the procedure’s introduction, there was vigorous debate over whether a trabeculectomy was a filtration operation or not. The cause of
discussion was case examples of low postoperative IOP
without an apparent bleb. The original dissection technique of Cairns,8,9 however, involved the excision of the
scleral spur in order to include the total abnormal trabecular meshwork (and the aqueous humor is believed
to exit primarily from the posterior half of the trabecular
meshwork closest to the scleral spur). I therefore strongly
suspect that many of these blebless cases achieved low
IOPs due to the formation of cyclodialysis clefts.
The history of trabeculectomy might be summarized
as the right operation for the wrong reason.
ELIMINATING PROXIMAL RESISTANCE
The outflow pathway behaves segmentally, because
there is limited circumferential flow in Schlemm canal
(Figure 1). With the canal’s outer wall exposed, why does
the aqueous humor not flow out through the collector
channels (or go around the lumen of Schlemm canal)?
One answer might be that, in a form of Ohm’s law, it
does. Increased flow through a lumen with resistance
(either the collector channel or Schlemm canal’s lumen)
raises pressure in the lumen. This is totally different than
entirely bypassing the conventional outflow pathway
and Schlemm canal in a filtering operation and allowing communication between the anterior chamber and
subconjunctival space, where there is very low pressure.
Alternatively, from the observations of Rohen, one might
just think of the ostia of the collector channels (or the
collapsed, cut ends of Schlemm canal) as functionally
having sphincters.
How many 1-hour effective trabeculotomies, then,
would eliminate all of the proximal resistance? My interest in this question arose when it became feasible to
use YAG goniopuncture10-12 to treat glaucoma. How
many holes in Schlemm canal and with what spacing
could eliminate resistance? My colleagues and I repeated
Grant’s classic experiments using a series of 1-hour
incisional internal trabeculotomies.5 Except for certain
secondary glaucomas, such as juvenile OAG12,13 and glaucoma due to juvenile rheumatoid arthritis,13 YAG laser
therapy to the trabecular meshwork proved ineffective
September/October 2013 glaucoma today 47
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Figure 1. Resistor model of aqueous outflow network.
Reprinted with permission from Yan DB. A Network Model
of the Human Aqueous Outflow System [master’s thesis].
Cambridge, MA: Massachusetts Institute of Technology; 1988.
because the tissue healed,10,11 which we did not understand at the time.
Our data are shown in Figure 2.5 Consistent with
Grant’s findings, whether at low or high pressure, 1 clock
hour of trabeculotomy was notably suboptimal for eliminating the outflow resistance. Despite some differences
with larger extents of trabeculotomy, whether perfused
at high or low pressure, our general impression was that
four equidistant 1-hour trabeculotomies would eliminate
almost all of the proximal resistance at the inner wall of
Schlemm canal. Of course, in a glaucomatous eye (which
we did not study), one might expect to get more bang
for the buck with fewer 1-hour trabeculotomies, because
with each hole made in Schlemm canal, one is bypassing
the extra glaucomatous resistance (Figure 3). The point,
however, is that one would still wind up with a relatively
higher IOP in such eyes, because the remaining distal
resistance should be similar to that of the normal eye.
These considerations are of great practical importance, despite the failure of YAG trabeculopuncture. For
example, both Grant’s4 and Rosenquist’s5 studies would
predict further lowering of IOP postsurgically if more
than one iStent Trabecular Micro-Bypass Stent (Glaukos
Corporation)14,15 were placed in Schlemm canal, especially spaced as far apart as possible. Douglas Johnson’s
group studied this experimentally in cultured human
anterior segments,16 and my interpretation of their data
is that they confirmed this concept. There also seem
to be preliminary data from human surgical experience
indicating that more than one iStent provides additional
IOP lowering.17 These findings are predictable based on
Grant’s experiments.4
Figure 3. Effect of YAG holes on IOP. Reprinted with permission from Yan DB. A Network Model of the Human
Aqueous Outflow System [master’s thesis]. Cambridge, MA:
Massachusetts Institute of Technology; 1988.
HOW DO SCHLEMM CANAL
PROCEDURES WORK?
When analyzing the newest Schlemm canal operations, surgeons need to remember Grant’s scientific
work.4,5 They also need to ask for a specific rationaliza-
tion of the mechanism of efficacy for these procedures
in the context of that research. Just as trabeculectomy
turned out to be the right operation for the wrong reason, if these procedures work, then it may not matter
what the concept is. I would think, however, that one
48 glaucoma today September/October 2013
Figure 2. Percentage of baseline resistance eliminated by
sequential 1-, 4-, and 12-hour internal trabeculotomy at 7
versus 25 mm Hg perfusion pressure. Extent of trabeculotomy at each step indicated by circles at bottom of graph. Error
bars are standard errors. Resistance units are (mm Hg/ (µL/
min)). Reprinted with permission from Rosenquist et al.5
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might be able to devise an optimal novel Schlemm canal
surgical procedure by using Grant’s observations and
principles.
For example, septae connect the outer and inner walls
of the canal. As shown by two different groups, disrupting the outer wall can inadvertently rupture the inner
wall (and therefore eliminate some of the proximal resistance).18,19 As with YAG goniopuncture,10,11,20 the general
problem with internal trabeculotomy procedures is healing over time. I would therefore expect the IOP effects
not to be long-lasting. Also, disrupting the Descemet
window is unlikely to provide the needed circumferential flow in Schlemm canal. Rather, this likely creates a
guarded filter to short-circuit the anterior chamber to
the subconjunctival space, perhaps through an intervening scleral lake.19 Of course, one might wonder whether
the scleral lake would alter the distal resistance as an
inadvertent benefit.
Canaloplasty21 is an intriguing surgical procedure
that involves 360º of manipulation of Schlemm canal,
but the mechanism of action is unclear, especially when
vigorous tightening of the suture is required for maximum efficacy. A full discussion of possible mechanisms
is beyond the scope of this article, but could this procedure be causing breaks in the inner wall of Schlemm
canal?18,19 Could the distention of the trabecular
meshwork as a result of this suture tightening cause a
greater filtration area in the trabecular meshwork with
an effect similar to that of pilocarpine?22 Have surgeons
underappreciated the role of Schlemm canal’s collapse
in glaucoma?23
The subject of the canal’s collapse as a primary or secondary mechanism in glaucoma has been controversial.
Most have thought that, although the canal’s diameter
decreases in POAG,23 the septae—which preferentially
bridge the inner wall of Schlemm canal to its outer wall
near the ostia of the collector channels18,19—might prevent total collapse. Much remains to be explained. As far
as stents in Schlemm canal, there is likely only minimal
circumferential flow beyond the two ends of the stent,
which must also be fashioned not to occlude the ostia of
the collector channels.
I predict that the future may bring about the combination of Schlemm canal surgery with pharmacological
therapy to its inner wall.24 Novel drugs are currently in
human testing25 that are believed to affect the entire circumference of the canal’s inner wall.26
CONCLUSION
The point of this article was to remind readers of
Grant’s seminal findings4 and to stimulate them to think
creatively about how to implement these scientific
observations to develop a better surgical procedure for
glaucoma directed at Schlemm canal. It is important to
remember that these operations may not get the IOP as
low as desired. The main reason, as Grant’s work demonstrated,4,5 is a lack of circumferential flow in Schlemm
canal and the presence of significant distal (ie, outerwall) resistance. n
David L. Epstein, MD, MMM, is the Joseph
A. C. Wadsworth clinical professor of ophthalmology and chairman of the Department
of Ophthalmology at the Duke Eye Center in
Durham, North Carolina. He acknowledged no
financial interest in the product or company mentioned
herein. Dr. Epstein may be reached at (919) 684-5846;
[email protected].
1. Shields MB. Fistulizing techniques. A Study Guide for Glaucoma.1st ed. Baltimore, MD: Williams & Wilkins;
1982:458-459.
2. Elliot RH. A preliminary note on a new operative procedure for the establishment of a filtering cicatrix in the
treatment of glaucoma. Ophthalmoscope. 1909;7:804.
3. Hondur A, Onol M, Hasanreisoglu B. Nonpenetrating glaucoma surgery: meta-analysis of recent results.
J Glaucoma. 2008;17(2):139-146.
4. Grant WM. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol. 1963;69:783-801.
5. Rosenquist RC, Epstein DL, Melamed S, et al. Outflow resistance of enucleated human eyes with two different
perfusion pressures and different extents of trabeculotomy. Curr Eye Res. 1989;8:1233-1240.
6. Schuman JS, Chang W, Wang N, et al. Excimer laser effects on outflow facility and outflow pathway morphology.
IOVS. 1999;40(8):1676-1680.
7. Richardson TM, Epstein DL. Exfoliation glaucoma: a quantitative perfusion and ultrastructural study. Ophthalmology. 1981;88(9):968-980.
8. Cairns JE. Trabeculectomy. Preliminary report of a new method. Am J Ophthalmol. 1968;6t76:673-679.
9. Cairns JE. Trabeculectomy. Trans of the Ophthalmol Societies of the UK. 1968;88:231-233.
10. Melamed S, Pei J, Puliafito CA, Epstein DL. Q-Switched neodymium-YAG laser trabeculopuncture in monkeys.
Arch Ophthalmol. 1985;103(1):129-133.
11. Epstein DL, Melamed S, Puliafito CA, Steinert RF. Neodymium: YAG laser trabeculopuncture in open-angle
glaucoma. Ophthalmology. 1985;92(7):931-937.
12. Melamed S. Latina MA, Epstein DL. Neodymium:YAG laser trabeculopuncture in juvenile open-angle glaucoma.
Ophthalmology. 1987;94(2):163-170.
13. Epstein DL. YAG (and surgical) goniotomy in JOAG. In: Epstein DL, Allingam RR, Schuman JS, eds. Chandler and
Grant’s Glaucoma. Baltimore, MD; Williams & Wilkins; 1996:446-447.
14. Craven ER, Katz LJ, Wells JM, Giamporcaro JE. Cataract surgery with trabecular micro-bypass stent implantation
in patients with mild-to-moderate open-angle glaucoma and cataract: two-year follow-up. J Cataract Refract Surg.
2012;38:1339-1345.
15. Samuelson TW, Katz LJ, Wells JM, et al. Randomized evaluation of the trabecular micro-bypass stent with
phacoemulsification in patients with glaucoma and cataract. Ophthalmology. 2011;118:459-467.
16. Bahler CK, Smedley GT, Zhou J, Johnson DH. Trabecular bypass stents decrease intraocular pressure in cultured
human anterior segments. Am J Ophthalmol. 2004;138(6):988-994.
17. Belovay GW, Naqi A, Chan BJ, et al. Using multiple trabecular micro-bypass stents in cataract patients to treat
open-angle glaucoma. J Cataract Refract Surg. 2012;38:1911-1917.
18. Johnson DH, Johnson M. How does nonpenetrating glaucoma surgery work? J Glaucoma. 2001;10(1):55-67
19. Tamm ER, Carassa RG, Albert DM, et al. Viscocanalostomy in rhesus monkeys. Arch Ophthalmol.
2004;122:1826-1838.
20. Melamed S, Teekhasaenee C, Epstein DL. Role of fibronectin in closure of YAG laser trabeculopuncture. Laser &
Light in Ophthalmol. 1989;2:233-241.
21. Lewis RA, vonWolff K, Tetz M, et al. Canaloplasty: circumferential viscodilation and tensioning of Schlemm
canal using a flexible microcatheter for the treatment of open-angle glaucoma in adults: two-year interim clinical
study results. J Cataract Refract Surg. 2009;35:814-824.
22. Grierson I, Lee WR, Abraham S. Effects of pilocarpine on the morphology of the human outflow apparatus.
Br J Ophthalmol. 1978;62(5):302-313.
23. Allingham RR, de Kater AW, Ethier RC. Schlemm’s canal and primary open angle glaucoma: correlation
between Schlemm’s canal dimensions and outflow facility. Exp Eye Res. 1996;62(1):101-109.
24. Epstein DL, Freddo TF, Bassett-Chu S, et al. Influence of ethacrynic acid on outflow facility in the monkey and
calf eye. IOVS. 1987;28(12):2067-2075.
25. Williams RD, Novack GD, Van Haarlem T, Kopczynski C (on behalf of AR-12286 Phase 2A Study Group). Ocular
hypotensive effect of the rho kinase inhibitor ar-12286 in patients with glaucoma and ocular hypertension. Am J
Ophthalmol. 2011;152:834-841.
26. Rao PV, Deng PF, Kumar J, Epstein DL. Modulation of aqueous humor outflow facility by the rho kinase specific
inhibitor, Y-27632. IOVS. 2001;42(5):1029-1037.
September/October 2013 glaucoma today 49