This document discusses ocular blood flow in glaucoma. It provides details on the arterial blood supply and venous drainage of the eye. It describes how glaucoma may be related to low ocular perfusion pressure and abnormalities in ocular blood flow autoregulation. Several studies linking low ocular perfusion pressure to glaucoma risk are summarized. Possible mechanisms like atherosclerosis, vasospasm and endothelial dysfunction that could contribute to impaired ocular blood flow in glaucoma are also outlined.

1. OCULAR BLOOD FLOW IN
GLAUCOMA
Dr Kumar Amruth
Dr Nikhil R P

2.  Glaucoma is a family of multifactorial optic neuropathies characterized by loss
of RGCs leading to ONH damage and distinctive visual field defects.
 Pathogeneis of glaucoma is unknown, it is well established that the main risk
factor for glaucoma is elevated IOP
 Several studies implicated vascular risk factors in the pathogenesis of
glaucoma of which blood pressure (BP) and Low Ocular perfusion
pressure(OPP) being most studied (1)
 Both systemic hypertension and hypotension are risk factors for development
and progression of glaucoma (1)
1) A Popa C, et al., Ocular perfusion pressure and ocular blood flow in glaucoma. Current Opinion in Pharmacology 2013, 13:36-42

3. Arterial blood supply:
Common carotid artery-
Internal carotid artery
External carotid artery

4. Arterial blood supply:
Internal carotid artery:
It supplies the structures within the cranium
, including the eye and related structures.
External carotid artery:
It supplies the superficial areas of the head
and neck, and also small portion of ocular
adnexa.
Eyelids supplied by both internal and external
artery.

5. Branches of ophthalmic artery:
• Central retinal artery.
• Lacrimal artery (terminates into zygomatic branches)
• Supra – orbital artery.
• Posteriorciliary artery
-long posterior ciliary arteries ( 2 arteries)
- short posterior ciliary arteries (10 to 20 arteries )
• Muscular arteries
• Ethmoidal arteries
• Anterior ciliary arteries
• Palpabral arteries
• Dorsonasal artery
• Supratrochlear artery

6. Circle of Zinn
 Circular anastomosis between short
posterior ciliary arteries when they are
piercing the sclera
 Gives branches to choriod, optic nerve
head and pial network
 Cilio-retinal artery – helps to maintain
vision in case of CRA occlusion

7. Blood supply of Optic Nerve:
Intraocular part/ optic nerve head
Surface nerve
fiber layer and
Prelaminar part
•
•
•
Cilioretinal artery
Peripapillary choroidal vessels
Vessels from zinn and heller
Lamina cribrosa
region
• Short Posterior Ciliary Arteries
•
•
Central retinal artery
Pial vesselsRetrolaminar

8. Venous drainage of Eye
 No valves
 Tortuous & freely anastomose with one another
Veins
 Superior ophthalmic vein
 Inferior ophthalmic vein
 Middle ophthalmic vein
 Medial ophthalmic vein
 Vortex veins
 Angular Vein
 Cavernous Sinus

9. Venous drainage :
part
cerebral &
Intracranial
• Pial plexus
which ends
in anterior
basal vein
Orbital part
• Peripheral
pial plexus
• Central
retinal vein
Optic nerve
head
• Central
retinal vein

10. Ocular blood Flow
 Blood flow is laminar. The pressure and shearing stresses in the fluid vary smoothly from point
to point.
 The mean retinal circulation time has been determined to be 4.7+/-1.1 s (2)
 The retinal blood flow and blood volume in healthy adult have been estimated to be about
170ml/100g/min and 14ml/100g (2)
 Choroid receives about 65- 85 %
 Iris and ciliary body receives about 10-35%
 Retina receives about 5 or less than 5 % of total ocular blood flow (3)
 The oxygen utilisation from choroid is less (about 3 %) as compared to retina (38%) (2)
 As the IOP is raised , the blood flow ceases in the following order – anterior uvea , choroid and
retina (4)
2) Hickam J et . Al., A study of retinal venous blood oxygen saturation in human subjects by photographic means . Circulation
27: 375
3) Henkind P et al., Ocular circulation in records RE, ed: Physiology of the human eye and visual system, Harper Row
1979,p98-155
4) Masket et al., Vascular perfusion pressure gradients in the eye . Invest Ophthal 12: 198

12. Colour Doppler imaging
 It is a method of detecting changes in the frequency of sound reflected from
flowing blood, allowing estimation of flow velocity.
 The technology of duplex scanning allows simultaneous B-mode imaging and
pulse wave Doppler facility
 To relate the systolic and diastolic velocities to each other, a ratio, the resistive
index (Pourcelot’s index), is used. This ratio is angle independent and is
regarded as a good method to quantify the vascular resistance of the
circulation.
 Ocular perfusion pressure (OPP) in the sitting position is defined by the
equation: OPP=2/3 (MAP-IOP), where MAP= mean arterial pressure
 This equation shows that in normotensive patients increased IOP leads to decreased
ocular perfusion.

13. Ophthalmic artery imaged as over the optic nerve.
Note the tall wave forms at the bottom, indicating high flow

14. Central retinal artery imaged in the substance of optic nerve.
Note the short wave forms at the bottom, indicating low flow

15. Posterior ciliary arteries (PCA) imaged as they pierce the ocular wall around the
optic nerve head. CRA is in the substance of Optic nerve.

16. Perfusion pressure
 Perfusion pressure is defined as the difference in the pressure between the
arteries entering the tissue and veins leaving it.
 In the eye, PP refers to the mean arterial pressure(MAP) minus the intraocular
pressure (IOP)
 Therefore, a fall in the MAP or a rise in IOP should lower the Perfusion
pressure and thus lowering ocular blood flow
 However with the progressive increase in IOP, there in no decrease in retinal
blood flow upto a certain level because of autoregulation
 Bill A et al., and their collegues concluded that for a given BP, the OPP in the
supine position is actually higher than in erect position because the height
difference between the heart and eye is eliminated
Bill A Et al., Circulation in the eye. In: Renkin EM- handbook of physiology pp1001-1034

17.  Mean arterial BP (MAP) was calculated as DBP + ⅓(SBP − DBP).
 Mean ocular perfusion pressure (MOPP) was defined as ⅔(MAP −
IOP),
 Systolic perfusion pressure (SPP) as SBP − IOP,
 Diastolic perfusion pressure (DPP) as DBP − IOP.
 In a study done by Y Zheng et al., in the year 2010, they showed that
MOPP and DPP were significantly associated with OAG risk in Asian
Malay persons, consistent with the findings from population-based
studies in white, black, and Hispanic populations. They concluded that
low DBP, low MOPP, and low DPP are statistically significant and
independent risk factors for OAG

18. Example - How the BP will affect OPP
1. When BP 140/90 IOP – 14 mmhg
MAP = 90+ 1/3( 140-90)= 90+20 = 110
OPP = 110-14 = 96  Normal Autoregulation
2. When BP 80/ 60 , IOP- 20
MAP= 60 + 1/3( 80-60)= 60+ 7= 67
OPP = 67- 20 = 47  Altered Autoregulation

19. LOW OPP –
A Risk factor for
glaucoma

20. Prevalence, incidence and progression studies
investigating Ocular perfusion pressure and
glaucoma
1) Baltimore eye survey Tielsch et al. (1995)
DOPP < 30 mmHg had a 69 increased risk of developing POAG compared to
individuals with DOPP > 56 mmHg
2) Blue mountains eye study (Mitchell et al. 2004)
Higher SOPP (for each 10 mmHg) had a 10% increase in OAG prevalence (OR =
1.09; p = 0.05)
3)The Beijing eye study(Xu et al. 2009)
No association between OPP and OAG risk

21. 4) The Singapore Malay eye study (Zheng et al. 2010)
Lower MOPP and DOPP were associated with increased prevalence of POAG For
each ↓ 10 mmHg in MOPP and DOPP – OR = 1.22
5) Barbados eye study (Leske et al. 2008)
Lower OPP was associated with increased risk of OAG
6) Los angeles latino eye study (Memarzadeh et al. 2010)
Lower MOPP; DOPP and SOPP and higher SOPP were associated with increased
prevalence of OAG
7) The rotterdam study (Ramdas et al. 2011)
No independent significant effect of MOPP on OAG

22. Auto regulation
 It is that property of a vascular bed ( vasoconstriction or dilation ) which
permits constant or nearly constant blood flow over a wide range of perfusion
pressure. The retinal vessels exhibit such a phenomenon
 Vascular waterfall mechanism explains that the pressure perfusing the retinal
vascular bed is dependent upon the mean arterial pressure and IOP.
 In retina and ONH – myogenic and metabolic mechanisms
 In the choroid – Parasympathetic, sympathetic, intrinsic neurons play a role in
autoregulation

23.  In glaucoma abnormal autoregulation of ocular blood flow was observed in a
large variety of studies.
 The reason for abnormal autoregularities in glaucoma patients is not fully
understood but increased variability of OPP and nocturnal dipping of BP have
indeed been identified as risk factors.
 Alteration in autoregulation in glaucoma may also arise from primary vascular
dysregulation
 Various underlying medical conditions have been proposed which may
contribute to ocular vascular regulatory dysfunction including atherosclerosis,
vasospasm and endothelial dysfunction

27. Atherosclerosis
 Atherosclerosis is a chronic, progressive disease affecting many vascular beds
including the ocular circulation
 Rotterdam eye study found neither atherosclerosis nor serum C-reactive
protein (a marker of inflammation associated with atherosclerosis) to be
important risk factors for the development of OAG (de Voogd et al 2006).
 Although a relationship between certain atherosclerotic risk factors and OAG
has been reported, the direct influence of atherosclerosis on the progression of
glaucoma is undetermined.

28. Vasospasm
 Vasospasm is characterized as a sharp, exaggerated, and often persistent
contraction of a blood vessel, resulting in reduction in luminal diameter and
respective blood flow. This vasoconstriction or insufficient dilatation of the
microcirculation may lead to inadequate blood flow to the surrounding tissue
and consequent ischemia (Mchedlishvili 1981).
 Vasospasm can create an environment of blood flow dysregulation which
increases the vulnerability of the ONH to vascular challenges, leading to
perfusion instability, ischemic changes, axonal loss, and changes of the ONH.
 It has been shown that blood pressure variations away from normal physiologic
nocturnal dips are correlated with vasospasm, OAG, and NTG (Werne et al
2008).
 In summary, vasospasm is associated with multiple disease states including
OAG with NTG patients and women appearing to be the most at risk for
vasospastic contributions to disease processes

29. Endothelial dysfunction
 It is known that NO activity contributes to ocular autoregulation and can
protect the endothelium and nerve fiber layer against pathologic stressors
implicated in glaucoma, ischemia, and diabetes
 A number of studies have investigated the role of ET-1 in glaucoma. ET-1 has
been shown to decrease blood flow to the anterior optic nerve when directly
applied to this region (Orgul et al 1996)
 In summary endothelial dysfunction is likely related to glaucoma, but the exact
role of mediators such as NO, NOS, ET-1, and ETA/ETB in OAG
pathophysiology has yet to be fully appreciated. Endothelial dysfunction may
therefore be primary or secondary to vascular diseases including
atherosclerosis and vasospasm in its contribution to OAG pathology.

30. Blood pressure changes and blood flow
 Fluctuations in IOP, blood pressure, ocular perfusion pressure, and thus blood flow
are implicated in OAG. A patient with vasospastic syndrome may not be able to
compensate for elevations of IOP and/or blood pressure dips, while a healthy patient
can autoregulate to maintain consistent ocular perfusion.
 Choi and colleagues (2007) investigated 24-hour IOP, blood pressure, and perfusion
pressure changes associated with clinically relevant visual field outcomes. The study
determined that both anatomic (retinal nerve fiber layer thickness) and functional
(visual field) outcome variables were significantly worse in glaucoma patients with
wider circadian perfusion pressure fluctuations
 In the Thessaloniki Eye Study, patients without glaucoma having a diastolic blood
pressure of 90 mm Hg with antihypertensive treatment was associated with increased
cupping and decreased rim area of the optic disk (Topouzis et al 2006).

31. Nocturnal Hypertension
 Systemic blood pressure lowers or dips physiologically at night
 Graham et al., and Hayreh SS et al., concluded that in some glaucomatous patients , the
level of dipping is exaggerated compared to non- glaucoma subjects , with the potential
of hypoperfusion of the optic nerve head contributing to glaucomatous optic
neuropathy.
 Study done by Choi et al., and collegues showed that fluctuations in mean OPP were
associated with nocturnal dipping and that the level of fluctuation was related to the
level of visual field damage at diagnosis
Choii J et al., Effect of nocturnal blood pressure reduction on circardian fluctuation of mean OPP Visc Sci 47: 831-836

32. Therapeutic implications
 Modalities or substances which improve ocular blood flow would have a
definitive role in halting glaucoma progression independent of their effect on
IOP
 • Aspirin – by stabilizing microcirculatory flow aspirin improves optic nerve
head perfusion.
 • Ginkgo biloba – by increasing ocular blood flow and platelet activating factor
inhibitory activity it has been demonstrated to improve ocular blood flow. This
drug is now being extensively studied for improving vascular perfusion in
glaucomatous eyes.
 • Calcium channel blockers also act by improving ocular perfusion.

33.  Unoprostone with a antiendothelin-1 effect, betaxolol with its calcium-channel
blocker action, and carbonic anhydrase inhibitors all have been documented to
increase the retinal circulation. All these drugs are touted as neuroprotective
due to their effect on optic nerve head circulation.
 NMDA receptor antagonist Memantine which blocks the toxic effects of
glutamate without significant effects on normal cellular function.
 Neurotrophins agents increase retinal ganglion cell survival and are capable
of being produced by retinal cells
 Systemic Blood pressure: Drop in nocturnal systemic blood pressure is to be
avoided while treating coexisting hypertension in glaucoma patients, since it is
particularly deleterious for the optic nerve head.
 Trabeculectomy has been documented to improve ocular hemodynamics along
with IOP control

34. Conclusion
 Glaucoma is a heterogenous disease comprising multiple etiologies. Alterations in
ocular blood flow have become interestingly implicated in open angle glaucoma
disease pathology.
 One of the reasons why our understanding of the relation between OPP and glaucoma
is still limited, lies in the difficulties to measure retinal and ONH BF [5, 6].
 Doppler optical coherence tomography may become a technique capable of measuring
BF in a valid and reproducible way.
 Continuing research is needed to discern the significance of the vascular factors
responsible for glaucoma.
5) Sugiyama T, Araie M, Riva CE, Schmetterer L, Orgul S: Use of laser speckle flowgraphy in ocular blood flow research. Acta
Ophthalmol 2010, 88:723-729.
6)Riva CE, Geiser M, Petrig BL: Ocular blood flow assessment using continuous laser Doppler flowmetry. Acta Ophthalmol
2010, 88:622-629.