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The Mechanism of Glaucomatous Damage to the Optic Nerve
Primary Vascular Dysregulation Figure 3: Pathogenetic Concept Including Both
PVD syndrome is characterised by an inborn tendency to respond
Mechanical and Ischaemic Factors
differently to a variety of stimuli such as feeling cold or emotional or
physical stress. The symptoms may already be present in childhood,
NTG HTG
but become clearly manifest during puberty and mitigate as
Vascular
subjects get older, in particular during menopause. The syndrome is
dysregulation
BP IOP IOP
observed more often in females than in males, in slim rather than in
obese people, in professionals rather than in blue-collar workers
Disturbed Unstable Activation of
autoregulation OBF astrocytes
and in Asians rather than in Caucasians. The leading symptom in
PVD is cold extremities.
Sleep apnoea Reperfusion NOS-2
In addition, their feeling of thirst is also reduced. These subjects
normally drink enough only because they know that they have to
0
.-
2
NO
.-
drink, rather than because they feel thirsty. They also have a
prolonged sleep-onset time, which is due to the fact that there is a
ONOO
-
ET-1 MMPs
strong connection between feet temperature and sleep-onset time.
PVD subjects also have an altered drug sensitivity. This is at least
partially due to altered gene expression of the ABC transport
Apoptosis Tissue remodelling
proteins. PVD subjects often have low blood pressure when they
are young, particularly at night. Moreover, the ET level in their
NTG = normal-tension glaucoma; HTG = high-tension glaucoma; BP = blood pressure;
–
OBF = ocular blood flow; NOS = nitric oxide synthase; ONOO = peroxynitrite;
circulating blood is increased, and the sensitivity to ET is blood- 8
ET = endothelin; MMP = matrix metalloproteinases. Source: Flammer and Mozaffarieh, 2006.
pressure-dependent. PVD patients more often show splinter
haemorrhages, reversible diffuse visual field defects and clinical In parallel, recurrent mild reperfusion leads to the production of
signs of activated astrocytes in the retina. In terms of circulation, the superoxide anion (O
.-
2
) in the mitochondria, which is copiously
their retinal vessels show a higher spatial irregularity and are stiffer, located in the axons of the ONH. In this situation, the superoxide
and vasodilation to flickering light is reduced. The autoregulation anion (O
.-
2
) can readily combine with NO to produce the highly
(adaption to changes in perfusion pressure) of OBF is disturbed. This damaging peroxynitrite (ONOO
-
), which in turn, induces apoptosis.
8
is the major link to glaucoma. PVD subjects have a higher risk of Blood flow and, consequently, oxygen supply is unstable if IOP
various eye diseases but particularly for glaucoma.
7
fluctuates at a relatively high level or if autoregulation is disturbed.
In turn, autoregulation is disturbed in cases of PVD syndrome.
Primary Vascular Dysregulation PVD can also lead to low blood pressure and thereby further
and Autoregulation contributes to GON.
There is increasing evidence that GON is related more to an unstable
OBF than to a constant blood-flow reduction. OBF is unstable if either Conclusions
IOP fluctuates on a high level (sometimes exceeding the autoregulation The pathogenetic mechanisms that lead to GON are only partially
capacity) or autoregulation itself is disturbed. For decades, defective known. Obviously, a number of factors and mechanisms are involved.
autoregulation of OBF in glaucoma patients has been postulated, but These factors are most likely inter-related, as in a ‘complex network’.
only recently could this be demonstrated. The main cause of disturbed Therefore, it not a question of whether glaucomatous damage is more
autoregulation is a PVD syndrome. The involvement of PVD explains likely due to one or the other factor (e.g. pressure versus vascular
why systemic hypotension in these subjects (but less so in others) is a factors), but rather a question of how these and other factors interact
risk factor for GON, why females suffer from NTG more often than in a patient. The elucidation of these factors in the future will
males (females suffer more often from PVD) and why NTG occurs more hopefully lead to the development of new treatment strategies. n
often in the Japanese than in Caucasians (Japanese suffer more often
from PVD), but also why NTG patients and females have splinter
Josef Flammer is Chair of Ophthalmology and Dean
haemorrhages more often.
of the Faculty of Medicine at the University of Basel.
The main milestones of his scientific career include:
Pathogenetic Concept
the development of visual field indices and the
design of the Octopus program G1; the recognition
The above-described facts led to the following pathogenetic concept:
of the role of NO and endothelin; the link between
both mechanical and ischaemic stress activate the glial cells, leading vascular dysregulation syndrome and glaucoma;
to an altered microenvironment, particularly in and around the ONH
and the role of reperfusion and oxidative stress in
glaucoma. Dr Flammer has published over 500
(see Figure 3). This includes increased production of MMPs, which are
scientific articles, edited nine books and written a monograph on glaucoma,
involved in tissue remodelling. In addition, the activation of astrocytes which has been translated into 20 languages. He has received several awards,
leads to increased NO production. Although it has a short half-life, NO
including the Chibret, Alcon, Montgomery, MacKenzie and Vogt. He has been the
invited guest of many glaucoma societies and the honorary guest of the meeting
is small and liposoluble and can, therefore, readily diffuse to
of Nobel Prize laureates.
neighbouring cells such as the axons of the ONH.
1. Flammer J, et al., Prog Retin Eye Res, 2002;21:359–93. 4. Mozaffarieh M, et al., Mol Vis, 2008;14:224–33. care-providers, a quick reference, 3rd English ed, Bern: Hogrefe &
2. Flammer J, Mozaffarieh M, Can J Ophthalmol, 2008;43:317–21. 5. Flammer J, et al., J Glaucoma, 1999;8:212–19. Huber Publ., 2006.
3. Grieshaber MC, Flammer J, Surv Ophthalmol, 2007;(Suppl. 2) 6. Flammer J, et al., Prog Retin Eye Res, 2001;20:319–49. 8. Flammer J, Mozaffarieh M, Surv Ophthalmol, 2007;(Suppl. 2):
52:S115–S121. 7. Flammer J, Glaucoma: A guide for patients, an introduction for S162–S173.
EUROPEAN OPHTHALMIC REVIEW 35
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