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DOI 10.1007/s00441-013-1671-1
REVIEW
Received: 7 May 2013 / Accepted: 27 May 2013 / Published online: 9 July 2013
# Springer-Verlag Berlin Heidelberg 2013
Introduction
Glaucoma is best described as a progressive optic neuropathy
of various origins. A loss of retinal ganglion cells and their
axons is accompanied by loss of visual function ultimately
leading to severe visual impairment and even blindness. At
N. Pfeiffer (*) : J. Lamparter : A. Gericke : F. H. Grus :
E. M. Hoffmann : J. Wahl
Department of Ophthalmology, Johannes Gutenberg-University,
Langenbeckstrasse 1, 55131 Mainz, Germany
e-mail: Norbert.Pfeiffer@unimedizin-mainz.de
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Two groups investigated whether the treatment of individuals with increased IOP but without signs of glaucoma, usually termed ocular hypertension (OHT), would prevent the
onset of POAG. The results were contradictory: Kass and
colleagues (2002) showed that, over an observation period
of 5 years, the rate of individuals progressing from OHT to
glaucoma without treatment was 9.5 %, whereas medical
treatment reduced this to 4.4 % (Ocular Hypertension
Treatment Study, OHTS). On the other hand, the European
Glaucoma Prevention Study (EGPS) failed to show such an
effect in a statistically significant proportion of participants
(Miglior et al. 2007). However, the two studies were substantially different: the EGPS had a randomised and, in addition, a
double-masked design, whereas in contrast, the OHT treatment trial was unmasked. The EGPS involved treatment with
one agent only, namely dorzolamide, whereas the OHTS
allowed multiple treatments. The double-masked EGPS
abolished observer bias. However, such a masked design did
not allow for adaptive treatment to reach a certain IOP target.
This, however, was the case with the OHTS in which medications were added until a certain IOP target had been reached.
Thus, the IOP-lowering effect in the OHTS was much greater
than that in the EGPS. Indeed, the neuroprotective effect of
IOP-lowering therapy seems to be dose-dependent considering the results from the EMGT, EGPS and OHTS thereby
emphasising the role of the lowering of IOP.
In general, surgical therapy leads to greater IOP reductions than medical therapy. Both the Advanced Glaucoma
Intervention Study and the Collaborative Glaucoma
Treatment Study (AGIS and CIGTS) have demonstrated a
larger protective effect for greater IOP reductions and lower
IOPs. Data from the AGIS have also suggested that visual
fields of glaucoma patients tend to remain highly stable if
their IOPs always range under 18 mmHg.
Most interesting are the results from the Low-pressure
Glaucoma Study Group (Krupin et al. 2011). This group
showed, in a series of observations, that the lowering of
IOP did indeed retard the progression of glaucoma, even if
previous untreated IOPs had never been elevated beyond the
range of IOP considered to be the normal. However, NTG is
thought to be a disease entity of its own, as numerous distinct
differences exist between NTG and POAG, including the
more frequent occurrence of optic disc haemorrhages, a high
prevalence of migraine, Raynauds syndrome or systemic
hypotension in NTG.
In summary, the lowering of IOP has been shown either to
prevent or at least to retard the onset of POAG. Moreover,
the lowering of IOP slows the progression of established
open angle glaucoma with either high IOP or even normal
IOP. Furthermore, the effects seem to be dose-dependent
with the lower IOPs offering better protection from the
progression of glaucoma than higher IOPs. Thus, the lowering of IOP may be regarded as neuroprotective in glaucoma.
247
Examples
Parasympathomimetics
Pilocarpine
Carbachol
Adrenaline
Dipivalyl-epinephrine
Carteolol
Timolol
Betaxolol
Metipranolol
Levobetaxolol
Acetazolamide
Sympathomimetics
-Adrenergic receptor antagonists
Doclophenamide
Dorzolamide
Brinzolamide
2-Adrenergic receptor agonists
Prostaglandin analogues
Clonidine
Apraclonidine
Brimonidine
Unoprostone
Latanoprost
Travoprost
Bimatoprost
Tafluprost
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Concluding remarks
Glaucoma appears to be an enigma. When first described, it
was thought to be a disease that was precipited by increased
IOP attributable to various origins inducing the cupping of
the optic disc purely by mechanical stress. However, almost
at the same time, the idea was conceived that glaucoma
might be a primary optic nerve disease that makes it only
more prone to respond to risk factors such as increased IOP.
Indeed, good arguments for both views can still be made.
OHT is about eight times more prevalent than glaucoma.
This is a condition in which IOP is increased above normal
limits but optic nerve damage does not occur or has not
occurred as yet. A mechanism leading to glaucoma independent of IOP is supported by the observation that some patients present with typical optic disc cupping and a typical
loss of visual function on perimetry but have apparently
never had elevated IOP.
Only recently, studies have demonstrated convincingly
that the lowering of ocular pressure seems to be helpful in
all conditions: in patients with elevated IOP and
glaucomatous optic nerve cupping, in patients with such
nerve cupping without elevated IOP and finally also in individuals with elevated IOP. Under IOP-lowering treatment,
patients develop glaucoma less frequently. Thus, the lowering of IOP by means of medication and probably also by
surgical therapy appears to be neuroprotective for the optic
nerve in the human eye.
A multitude of pharmacological substances have been
shown to have neuroprotective properties in various models
including those that concern the optic nerve. Some of them
also lower IOP, which, for example, in the case of the optic
nerve crush injury model, probably does not play a major
250
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