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
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.
MECHANISMS AND TYPES
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.
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
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
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 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.
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.
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
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
effects are seen, but acute overdosage or long term therapy may produce
metabolic acidosis, usually indicated initially by malaise, vomition and
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
(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.
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
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
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.
The difficulty of achieving adequate reduction of the IOP in canine
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,
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
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.
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how, the why and the maybe. J. Glaucoma, 6: 123.
2. Offri, R., Samuelson, D.A., Strubbe, D.T., et al (1994) Altered
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
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Anim. Eye. Res. 17, 9.
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