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Glaucoma
Is effective treatment a reality?
Peter Bedford, United
Kingdom
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Introduction
The many
inherent difficulties encountered in all domesticated species
in the management of glaucoma range from difficulty in
diagnosis to the prevention of retinal ganglion cell death.
Clinical experience alone dictates the expected poor prognosis
for sight, but recent awareness of the mechanisms almost
certainly involved the ganglionopathy clearly indicates
that adequate neuroprotection might never be achieved. Not
only are possible therapies still conjecture, but the early
occurrence of what is probably a self-propagating process of
neurodegeneration renders effective therapy particulary
difficult in the species we treat. Currently our existing
therapies must fall short of the mark and the practical
difficulties associated with the assessment of outflow
facility, the accurate monitoring of therapy and the
complexity of surgical techniques all combine to confound the
prognosis. Whilst it is logical that angle-closure-glaucomas
can never be treated effectively by carbonic anhydrase
inhibition alone, those glaucomas which do lend themselves to
this kind of therapeutic approachare often diagnosed when
ganglion cell death is already extensive and loss of sight
inevitable. The overriding factor in all glaucoma is the
degeneration of the retinal ganglion cell, thus
neuroprotection through effective ocular hypotension is the
essential requirement of any therapy we utilise.
However, we are often too late in instituting that therapy and
although we may contain associated pain and discomfort, the
process of neuroretinal degeneration currently can neither be
reversed nor stopped. The most we can achieve through the
adequate reduction of intraocular pressure (IOP) is to slow
this process down and retain sight for longer periods.
What do we understand by the term “glaucoma?” It has been
simply defined as the process of ocular tissue destruction
caused by a sustained elevation of the IOP above its normal
physiological limits. It is the specific effect of that
elevated pressure upon the composite parts of the optic nerve
that renders glaucoma an emergency. The existence of “normal
tension” and “low tension” glaucomas in man has blurred
this simple definition for these diagnoses find origin in the
clinical similarities of the optic nerve
degeneration seen both in association with elevated IOP and
other non-pressure related factors such as disc ischaemia or
retinal excitotoxicity. It can even be argued that the rise in
IOP seen in primary open-angle glaucoma in man is effect
rather than cause, with only the effect being assessed and
treated by current therapies. Fortunately, open-angle glaucoma
has limited incidence in the domesticated species, for seldom
are
we in a position to diagnose its early presence and thus
inhibit ganglion cell degeneration early in the process.There
is evidence to indicate that abnormality in ganglion cell
function exists in Beagles, with inherited primary open-angle
glaucoma before the elevation in IOP occurs, and there is
strong temptation to use this evidence to suggest that the IOP
changes themselves are purely a secondary feature to another,
as yet ill-defined, disease process. Only in those glaucomas
in which there is demonstrable primary or induced defect in
aqueous outflow through the iridocorneal angle can we say that
the elevated pressure rise is directly responsible for the
ensuing ganglion cell death. Even so, such knowledge does not
ensure effective therapeutic control. It remains difficult to
define the extent of the ciliary and peripheral anterior
synechiae formation caused by an anterior uveitis whilst
posterior synechiae formation is usually resistant to therapy.
In lens luxation, it is the pupillary block achieved by the
anterior movement of
the lens that causes the collapse of the ciliary cleft and
only early lensectomy will restore adequate aqueous outflow.
In primary angle-closure glaucoma, we describe possible
congenital predisposition and physiological pupillary block as
the probable exciting factors in the acute cessation of
aqueous outflow from the anterior chamber, but such
consideration does not exclude other aetiologies. Again, lack
of aetiological detail renders hypotensive therapy difficult,
and inherent complications to the surgical techniques usually
utilized, render prognosis uncertain. However, it is likely
that all
the glaucomas we see are due to maintenance of a
physiologically incompatible rise in IOP, and it is the
characteristics of that elevated IOP, which have prompted the
consultation, whether they be pain, episcleral congestion,
corneal oedema, globe enlargement, or defective vision. Based
on the clinical picture, we simply record the elevated IOP,
diagnose glaucoma, and set about treatment along the
traditional hypotensive lines, with the knowledge that
effective, long-term reduction in the IOP will approach the
best we can achieve. There is sufficient experimental evidence
to
demonstrate that the process of ganglion cell degeneration,
whether it be necrosis or apoptosis, starts within the first
few hours of the rise in IOP, and that once triggered, this
process cannot be stopped. Thus, currently the prognosis for
sight must always be poor, with the moderating influence of
any hypotensive therapy being variably expressed from one
patient to another.
Mechanism
and Types of Glaucoma
There are several classification
systems used to describe glaucoma in the domesticated species
and considerable discussion concerning the appropriateness of
the terms utilised. “Congenital” dictates a presence at
birth and “primary” refers to inherited glaucoma to which
there may be congenital predisposition. There is confusion
between the terms “narrow angle” and “closed-angle.”
Both refer to the width of the entrance to the ciliary cleft
as assessed by gonioscopy. In primary glaucoma, a congenitally
narrowed angle may predispose to easier closure, but there has
been difficulty in ascertaining if IOP elevates prior to
actual closure. It is likely that both terms are simply
gradations of the same congenital abnormality. Thus, both
terms are used, and their proponents vigorously justify their
usage. It should be noted that the term geoniodysgenesis” is
used commonly to mean narrow angle or pectinate ligament
dysplasia or both. Its use is limited by our gonioscopic
observations, but in essence, this
term should cover other abnormalities of the ciliary cleft
which lie beyond the level of the pectinate ligament.
Glaucoma can complicate other ocular disease processes such as
uveitis, lens luxation, neoplasia and cataract and here the
term secondary is used.Treatment demands both resolution of
the initiating disease and attention to the changes that
induce the rise in pressure.
Pathogensis
In our
patients, all glaucomas are characterised by an elevated IOP,
although the level of elevation may vary. In those glaucomas
in which the elevation is initially low (i.e., open angle
glaucoma, melanocytic glaucoma) and some secondary glaucoma,
retinal ganglion cell and optic nerve damage are slow to
progress. In angle- closure glaucoma the sudden high rise in
IOP often renders the eye blind, undoubtedly primarily due to
a cessation of axoplasmic flow at the level of the lamina
cribrosa.
Retinal ganglion cell degeneration may be necrosis, but the
possibility that it is apoptosis triggered by the rise in IOP
is plausible, and the respective roles of nitric oxide and
glutamate are worthy of discussion.
The following observations are part of the current glaucoma
debate in terms of
pathogenesis and possible therapy. Ischaemia In human studies,
it has been widely accepted that tissue ischaemia has a part
to play in the initiation or progression of the optic disc
damage that occurs in glaucoma. The autoregulation of blood
flow within the disc is an essential mechanism in the
maintenance of nutrition and an elevation in IOP
can interfere with autoregulation. Nitric Oxide The hypothesis
that nitric oxide (NO) is involved in the degeneration of
retinal ganglion cell axons is most appealing for several
reasons. The apparent up-regulation and induction of some
nitric oxide synthase
isoforms (NOS) in astrocytes within the optic nerve head when
there is an elevation
of IOP has been clearly demonstrated and there is clear
evidence of NO toxicity to the axons. NO and endothelin appear
to be involved in the regulation of IOP and in the modulation
of ocular blood flow, with NO also being involved in apoptosis.
Glutamate
Glutamate levels are elevated in the vitreous of primate,
canine, and rabbit glaucoma patients and the retinal ganglion
cell layer is very susceptible to glutamate toxicity.
Excitotoxicity can result in neuronal apoptosis; the mediation
of excitotoxicity is by the stimulation of the N-methyl-D
aspartate (NMDA) type of glutamate receptor. The
overstimulation of the NMDA receptors can lead to increased NO
levels and a complex and potentially vicious circle.
Prevention of NMDA-induced excitotoxicity represents a
potential mechanism for neuroprotection.
Apoptosis
The
possibility that programmed cell death can be triggered by a
pressure induced failure of axoplasmic flow has been long
hypothesised, and was simply based on the failure of trophic
factors to reach the ganglion cell body. However, there are
other aspects to apoptosis that lend themselves to its
possible consideration in glaucoma, including the roles of NO
and glutamate induced excitotoxicity.
Treatment
Success always demands the use of
effective therapy and although several aetiologies are
involved in the glaucoma complex, the absolute determinant in
therapy selection is the amount of primary and/or induced
change within the iridocorneal angle. Medical suppression of
an elevated IOP can be attempted using four types of drugs:
the aqueous formation suppressors; miotics; uveoscleral
outflow enchancers; and the hyperosmotic agents. All four are
used in the treatment of canine glaucoma, the first three
commonly
as emergency treatment and in long term control while the
hyperosmotic agents are invaluable as emergency and
preoperative treatment. A fifth category of drugs, the
neuroprotection agents, is beginning to emerge as an important
possible addition to medical therapy.
A. Aqueous
Formation Suppressors
Carbonic anhydrase inhibitors are used traditionally in the
dog and with
difficulty in the cat. The alternative use of beta-adrenergic
blocking agents is still being evaluated for both species.
i) Carbonic anhydrase inhibitors
Acetazolamide (Diamox; Lederle). An oral dose rate of 50 to 75
mg per kg
should be used and dosage should be two to three times daily.
No ocular side
effects are seen, but acute overdosage or long term therapy
may produce metabolic acidosis, usually indicated initially by
malaise, vomition and diarrhoea.
Dichlorphenamide (Daranide; Merck, Sharpe and Dohme) has
provided a useful
alternative to acetazolamide in that it is accompanied by less
metabolic acidosis. A dose rate of 10 to 12 mg per kg is
preferred two or three times daily for the dog. Potassium
depletion is prevented by supplementing potassium rich food or
by specific medication. Two percent dorzolamide HCl (Trusopt;
Merck) a topical carbonic anhydrase inhibitor and brinzolamide
(Azopt-Alcon) would appear to be as effective and is less
irritating.
(ii) Beta-adrenergic blocking agents. Timolol maleate (Timoptol;
Merck Sharpe and Dohme). Usage in the small animal patient is
not indicated because the low concentration of the commercial
preparation renders it ineffective in the dog and cat.
Concentrations of four percent plus are required to reduce
normal canine IOP by any appreciable degree. Other such agents
used in man are betaxolol HCl, carteolol HCl, levobunolol HCl
and metipranolol. A combination of timolol and dorzolamide is
marketed as Cosopt (Merck, Sharp and Dohme), but experience in
the dog and cat is limited.
(iii) Alpha2-adrenoreceptor agonists. Two such drugs are
currently available. Apraclonidine (Iopidine) reduces aqueous
secretion poorly in dogs but brimonidine tartrate (Alphagan;
Allergan) seems to be more effective.(30) It produces less
allergic response, probably increases uveoscleral outflow and
is also neuroprotective. This drug could prove to be of
considerable value to the veterinarian but long term efficacy
studies are required to assess its potential use in the dog
and cat.
B. Miotics
Miotic drugs are either parasympathomimetics, producing direct
stimulation
(cholinergic) of the iridal musculature (e.g., carbachol and
pilocarpine), or anticholinesterase inhibitors producing
miosis indirectly by the potentiation of acetylcholine
activity (e.g. demacarium bromide).
Pilocarpine is perhaps the miotic most often used in the
treatment of canine glaucoma. It should be remembered that
although the potential to increase
the outflow facility exists, the patient must have retained
some trabecular meshwork function. Adversely, pilocarpine can
sting and it can reactivate and contribute to iritis.
Demacarium bromide has been of particular value in maintaining
long-term miosis in the management of posterior primary lens
luxation, but its commercial production has now ceased.
Latanoprost (Xalatan-Pharmacia and Upjohn) may prove to be of
similar value, although this prostaglandin F2 analogue is used
primarily to improve uveoscleral
outflow. It also produces long acting miosis and in the
absence of a long acting miotic preparation, its use in the
dog with posterior primary lens luxation could prove
invaluable.
C. Uveoscleral Outflow Enhancers
Latanoprost increases the rate of outflow by the uveoscleral
route. It is effective against the peptides that are present
in the extracellular matrix, rendering the muscle more porous.
Brimonidine tartrate also increases uveoscleral outflow but
the mechanism for this activity has not yet been defined.
D. Hyperosmotic Agents
A reduction in IOP can be produced effectively and rapidly by
increasing the osmolality of the plasma within the ciliary
circulation to produce an osmotic pressure gradient across the
blood/aqueous barrier within the ciliary epithelium.
Hyperosmotic agents are valuable as emergency therapy. Their
use preoperatively is an essential adjunct to glaucoma surgery,
for the surgical paracentesis effect is less significant when
the IOP is low, and the resultant reduction in the total blood
volume of the congested globe greatly facilitates the
execution of surgery. Mannitol, glycerol and urea are used
routinely, all three being effective at 1.0 to 1.5 g per kg
body weight.
Neuroprotection and Neuroregeneration
Undoubtedly elevation of the IOP is the most significant
trigger factor for glaucomatous optic neuropathy
and lowering of the IOP to a normal or subnormal level is the
essential factor in treatment. However, observation that the
NOS and glutamate levels are elevated in glaucoma and that
they are involved in retinal ganglion cell necrosis or
apoptosis has raised the possibility of neuroprotective
therapies and even neuroregeneration. Thus NOS inhibitors,
exciting amino acid antagonists, glutamate receptor
antagonists, apoptosis inhibitors and calcium channel blockers
are all involved potentially in the development of future
glaucoma therapies. The calcium channel blockers may reduce
the effect of impaired microcirculation to the optic nerve
head whilst potentially increasing outflow facility at the
level of the trabecular cells.
Surgical
Therapy
The difficulty of achieving
adequate reduction of the IOP in canine glaucoma
by the medical means currently available has prompted the use
of several surgical techniques in this species. A reduction in
aqueous production can be achieved by cyclodestruction
utilising cryosurgery, heat or laser. The amount of ciliary
body damage must be sufficient to ensure that balance is
regained between the resultant impaired aqueous production and
whatever aqueous drainage is possible. The reopening of a
closed ciliary cleft by cyclodialysis involves the breaking
down of collapsed cleft tissue and synechiae to separate the
ciliary body from the underlying sclera, allowing
the anterior chamber to become confluent with the
suprachoroidal space.
The certain failure to control glaucoma is due to the
subsequent closure of the cleft by the rapid formation of
postoperative adhesions.
In the dog, surgical bypass of the collapsed ciliary cleft is
most easily achieved either by iridencleisis or by a
corneoscleral (limbal) trephination technique combined with
peripheral iridectomy. These techniques allow aqueous to pass
directly from the anterior chamber to the subconjunctival
tissues where it is absorbed by the vascular and lymphatic
elements present. Both may prove successful initially but in
the short-term, fibrin may occlude the sclerostomy wound and
long-term control may be denied by
fibrosis of both the sclerostomy and the subconjunctival
tissues.
Shunt (or gonioimplant) surgery offers a realistic approach to
the control of IOP for it counteracts the effects of
subconjunctival fibrosis to some extent. Several types of
shunt exist: those with or without valves. Satisfactory
results may be obtained using a one-piece silastic drainage
implant consisting of an anterior chamber tube and an attached
large surface area strap. The shunt allows aqueous to be
diverted from the anterior
chamber to the large subconjunctival scar sac that develops
around the strap. Further modification of this technique
resulting in smaller gonioimplants and even simpler surgery
will be possible using fibroblast inhibitor drugs. In the
future simple sclerostomy may be all that is necessary to
offer the patient effective long term IOP control.
References
1.
Nickells, R.W. (1996) Retinal ganglion cell death in glaucoma:
the
how, the why and the maybe. J. Glaucoma, 6: 123.
2. Offri, R., Samuelson, D.A., Strubbe, D.T., et al
(1994) Altered retinal
recovery and optic nerve fibre loss in primary open-angle
glaucoma in the Beagle. Exp. Eye Res., 58: 245.
3. Haefliger, I.O., Dettmann, E., Liv, R., et al (1999)
Potential role of nitric oxide and endothelin in the
pathogenesis of glaucoma. Survey of Ophthalmology, 43, S51.
4. Dreyer, E.B., Zurakowski, D., Schumer, R.A., et al
(1996) Elevated glutamate in the vitreous body of humans and
monkeys with glaucoma. Arch. Ophthalmol., 114, 299.
5. Brooks, D.E., Garcia, G.A., Dreyer, E.B., et al
(1997) Vitreous body
glutamate concentrations in dogs with glaucoma. Am.J.Vet.Res.,
58, 864.
6. Swartz, M., Belkin, M., Yoles, E. et al (1996)
Potential treatment modalities for glaucomatous
neuropathy:neuroprotection and neuroregeneration. J. Glaucoma
5, 427.
7. Bedford, P.G.C. (1989) A clinical evaluation of a
one-piece drainage system in the treatment of canine glaucoma.
J. Small. Anim. Pract. 30, 68.
8. Garcia, G.A., Brooks, D.E., Gelatt, K.N., et al
(1998) Evaluation of valved and non-valved gonioimplants in 83
eyes of 65 dogs with glaucoma.
Anim. Eye. Res. 17, 9.
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