9 Role of Ocular Blood Flow in the

Pathogenesis of Glaucoma
ALI S HAFEZ and MARK R LESK

Summary Findings of Ocular Blood

A great body of evidence suggests that abnormal ocular blood Flow Studies in Glaucoma
flow contributes to the pathophysiology of open-angle glaucoma.
Large clinical studies have linked low ocular perfusion pressure to
and their Interpretation
the prevalence, incidence, and progression of glaucoma. Reduced
Investigations using epidemiological, histological and non-
blood flow has been reported in the retina, optic nerve, choroid
and retrobulbar vasculature in glaucoma, as well as systemically. invasive clinical techniques point to defective ocular blood
Putative mechanisms include vasospasm or vascular dysregula- flow as an important risk factor in glaucoma.27–33 Among
tion, defective autoregulation, low or fluctuating blood pressure, the vascular theories, hypoperfusion of the ONH was
atherosclerosis, and autoimmune or rheological mechanisms, reported to be associated with atherosclerosis, vasospasm
which reduce the eye’s ability to adapt to abnormal or changing and vascular changes related to movement of the lamina
IOP and blood pressure. There is evidence that different mecha- cribrosa. Other proposed mechanisms involve abnormal
nisms may play a role in different patients. scleral and lamina cribrosa structure,25,28–32 abnormal
cerebrospinal fluid pressure33 and autoimmune
mechanisms.34
Findings of ocular blood flow studies in glaucoma are
difficult to interpret for various reasons:35 authors use dif-
Although the clinical picture of glaucoma is well described, ferent techniques and therefore measure different aspects
the exact mechanism leading to this specific type of damage of ocular circulation; they include glaucoma patients at
to the optic nerve head (ONH) is not yet clear. It is generally different stages, e.g. early versus late; different types of
accepted that the mechanism of damage in glaucoma is glaucoma are studied without necessarily differentiating
almost certainly multifactorial.1 But while elevated IOP them, e.g. normal-tension glaucoma (NTG), high-tension
remains the risk factor most commonly associated with glaucoma (HTG), myopic glaucoma, or senile sclerotic glau-
glaucomatous optic neuropathy (GON), numerous other coma; some studies include provocation tests while others
variables involved in the development and progression of do not. Consequently, the interpretation of the available
glaucoma have been identified.2–7 Vascular risk factors in data is difficult as blood flow reduction may, at least partly,
particular have been extensively studied.8,9 These include be secondary to a reduced demand. Furthermore, blood
systemic blood pressure alterations,10–12 diabetes,13,14 flow alterations have been described in various parts of the
reduced ocular blood flow (OBF),15–18 and vasospasm.19–24 ocular circulation and it remains unclear how circulatory
Conventionally, two theories have been presented for the disorders in parts of the eye other than the anterior optic
pathogenesis of glaucoma, pressure and vascular: nerve may affect survival of axons and retinal ganglion
cells. Finally, systemic status of study patients regarding
1. Pressure theory, introduced by Muller, supposes that
factors such as diurnal systemic blood pressure, the pres-
GON is a direct consequence of elevated IOP, damaging
ence of vascular dysregulation and plasma levels of vasoac-
the lamina cribrosa and neural axons,25 whereas the:
tive agents such as endothelin is usually not evaluated.
2. Vascular theory, suggested by von Jaeger, considers GON
as a consequence of insufficient blood supply to the ONH In general, studies have reported slower ocular blood flow
due to either elevated IOP or to other risk factors reduc- velocities in glaucoma patients compared to normals. Blood
ing OBF.26 flow velocities have been found to be lower in the retina,
ONH and choroid as well as in the retro-ocular vessels and
Both theories have been vigorously studied and defended in the peripheral circulation. Normal-tension glaucoma
by various research groups for over a century. patients were shown to have lower blood flow velocities
Both experimental as well as clinical studies have proven than those with high-tension glaucoma. The fact that the
the role of IOP and the benefits of IOP-lowering therapy in reduction of OBF has often been observed to precede the
glaucoma. Yet therapeutic IOP reduction does not always damage and that blood flow can also be abnormal in other
stop progression of the disease. The existence of NTG on parts of the body of glaucoma patients, suggests that the
one hand and OHT on the other indicates that other factors hemodynamic alterations may at least partially be primary.35
might be involved in the pathogenesis of GON either directly Also, given the probable variability in the vascular mecha-
or by rendering the eye more sensitive to the influence nisms, the observed variability in blood flow reduction is to
of IOP. be expected.

88
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 9 • Role of Ocular Blood Flow in the Pathogenesis of Glaucoma 89

Studies have also shown that glaucoma patients demon- glaucoma progression with factors such as vasospasm48
strate abnormal ocular and systemic vascular reactivity and nocturnal hypotension,12,49 these epidemiological data
compared to normal subjects, as discussed below. Such have been critical to our understanding of the importance
observations could well point to an underlying vascular of perfusion in glaucoma (see Table 9-1).
mechanism for glaucomatous optic neuropathy:

VISIBLE OCULAR VASCULAR CHANGES Potential Mechanisms of Ocular

IN GLAUCOMA Blood Flow Reduction in
A number of ocular signs point indirectly to the fact that Glaucoma Patients
at least in some glaucoma patients, blood flow plays an
important role (Fig. 9-1). Changes in conjunctival capillar- Theoretically, there are three components to ocular blood
ies (e.g. perilimbal aneurysms), localized constriction of flow reduction in glaucoma patients: (i) increased local
peripapillary retinal arteries,36 increased prevalence of disc resistance to flow; (ii) decreased ocular perfusion pressure
hemorrhages,37 preservation of nerve fibers around retinal (OPP); (iii) increased blood viscosity.
vessels38 and the possible significance of cilioretinal arter- Several indications point to the role of both increased
ies39 have all been described in glaucoma patients. Studies local resistance to flow and decreased ocular perfusion pres-
have also shown that glaucoma patients are twice as likely sure in glaucoma:
to have crescent-shaped RPE and/or choroidal atrophic
changes at the disc margin which might be attributed to
LOCAL RESISTANCE TO FLOW
ischemia.40
Increased resistance to flow is manifested as a reduced vas-
EPIDEMIOLOGICAL EVIDENCE LINKING OCULAR cular diameter and is affected by either structural changes
PERFUSION AND GLAUCOMA
Epidemiologic links have been reported between ocular per- Table 9-1 Clinical Vascular Findings in POAG/NTG
fusion pressure (OPP [defined below]) and the prevalence of OCULAR
glaucoma [Baltimore Eye Survey,10 Rotterdam Eye Study,41 Neuroretinal Rim Flame Hemmorhages
Egna-Neumarkt Eye Study,42 Barbados Eye Study,43 Proyecto Local Constriction of Peripapillary Retinal Arteries
VER44]. In the Baltimore Eye Survey, there was a six-fold risk Peripapillary Chorioretinal Atrophy
of glaucoma for those with the lowest OPP (Fig. 9-2). Low Ocular Perfusion Pressure
Recently a large prospective population-based study found Reduced perfusion of the ocular vasculature
a strong link between both low systemic blood pressure and
SYSTEMIC
low OPP and the development of OAG.45 Low OPP was asso-
Low Blood Pressure
ciated with a 2.6-fold relative risk of developing glaucoma
over 9 years of follow-up. The Early Manifest Glaucoma Nocturnal Hypotension
Trial found that OAG patients with low systolic OPP had an Cold hands and Feet
almost 50% higher risk of progression.46 Consequently, low Migraine
OPP has been strongly linked to the prevalence, incidence, Cardiovascular disease
and progression of OAG.47 Together with studies linking
30

25
Ocular Vascular Findings in
Prevalence of POAG (%)

Glaucoma 20

15

• Optic disc hemorrhages

10
• Localized constriction
of retinal arteries (arrow, 5
lower image)
• beta peripapillary 0
atrophy (arrow, upper 20 30 40 50 60 70 80 90 100
image) Diastolic Perfusion Pressure (mmHg)
Figure 9-2 Systemic vascular findings in glaucoma showing correla-
tion between glaucoma and OPP. There is an epidemiologic link
between ocular perfusion pressure and glaucoma. The risk of glau-
coma is sixfold for those with the lowest ocular perfusion pressure.
Figure 9-1 Ocular vascular findings in glaucoma including disc hem- (Redrawn from Tielsch JM, Katz J, Sommer A, et al. Hypertension, perfusion
orrhages, localized constriction of peripapillary arteries and peripapil- pressure and primary open-angle glaucoma. A population-based assess-
lary atrophy. (Courtesy of MR Lesk, MD.) ment. Arch Ophthalmol 1995; 113:216–21.)

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90 SECTION 2 • Pathogenesis

such as anatomic variations in the vessels, vasculitis, or in NTG as well as their molecular basis, suggesting that a
mechanical obstruction of the lumen (via thrombosis or systemic defect contributes to the susceptibility of the optic
arteriosclerosis) or functional changes such as defective nerve to glaucomatous optic nerve damage.
autoregulation of blood flow. Reduced vascular diameter Optic nerve blood flow was also reported to be influenced
can also be due to reversible spasm of the smooth muscle by ocular perfusion pressure. Reduced ocular perfusion
cells in the vessel wall. A vascular dysregulation caused pressure might be due to increased IOP or decreased sys-
by an endothelial dysfunction is often implicated in temic blood pressure. In primates, ONH blood flow is less
glaucoma.26,50 well autoregulated in response to elevations in IOP if the
blood pressure is lower than if the blood pressure is higher.58
Because autoregulatory myogenic responses of the ocular
OCULAR PERFUSION PRESSURE
blood vessels may be less influenced by IOP than by blood
OPP equals mean arterial blood pressure minus venous pressure it is possible that OPP reductions caused by ele-
pressure in a specific vascular bed. Normally venous pres- vated IOP might have a greater impact on perfusion than
sure is slightly higher than IOP and for practical purposes those caused by low BP.59 While the importance of IOP as a
IOP is a good indicator of the venous pressure. Therefore, risk factor in glaucoma is well established, substantial evi-
OPP can be considered as the difference between mean arte- dence for the role of low blood pressure is emerging. NTG
rial blood pressure and IOP (where mean arterial blood patients were reported to have a clearly increased preva-
pressure = diastolic blood pressure + 13 [systolic blood pres- lence of systemic hypotension.
sure – diastolic blood pressure]).
During the past four decades an increasing amount of
NOCTURNAL HYPOTENSION
evidence has supported the theory that defective perfusion
of the ONH plays a crucial role in the pathogenesis of glau- Lower systemic blood pressure, both systolic60 and diasto-
comatous optic neuropathy. lic,11 was also found, particularly during the night, in
Studies by Hayreh51–53 have shown a close association patients with progressive glaucoma compared to stable
between glaucomatous optic neuropathy and systemic vas- patients12,49 (Fig. 9-3). The supine position is associated
cular disorders such as hypertension, hypercholestero- with approximately a 15 mmHg hydrostatic increase in
lemia, cardiovascular diseases, and diabetes. Hayreh54 OPP, but this increase might not be adequate to protect all
hypothesized that seretonin released from carotid, ophthal- patients.47 The association between glaucomatous damage
mic and posterior cerebral arteries in atherosclerotic and low blood pressure has been confirmed by several
patients produces transient vasospasms of the ONH and authors.61–65 In addition, fluctuation of nocturnal blood
thus contributes to the development and progression of pressure has been associated with the presence of NTG and
glaucomatous optic neuropathy and in particular NTG. In the severity of visual field loss.63,66,67 Clinicians should also
their analysis of optic nerve blood flow abnormalities in
glaucoma, Flammer and Orgul35 considered arteriosclerosis
as a less important factor for the increased local resistance
to blood flow that contributes to defective optic nerve per-
fusion. Although experimental studies by Hayreh et al.55
indicated that arteriosclerosis might increase the sensitivity Stable glaucoma Progressing glaucoma
to IOP elevations and although some arteriosclerotic 140
patients were shown to present with a sclerotic type of glau-
coma,54 Flammer and Orgul35 believed there was currently 130
very little evidence linking glaucomatous optic neuropathy
to arteriosclerosis or its risk factors (gender, obesity, hyper- 120
cholesterolemia, smoking, diabetes, hypertension, carotid
Blood pressure (mmHg)

stenosis). They attributed increased local resistance to blood 110

flow to a functional rather than a structural change, namely
to an abnormal or defective autoregulation of blood flow, or 100
vascular dysregulation.
Autoregulation refers to the capacity of an organ or 90
tissue to regulate its blood supply in accordance to its func-
80
tional or metabolic needs. With intact autoregulation,
changes in ocular perfusion pressure or metabolic demands 70
are associated with local constriction or dilatation of the
terminal arterioles which causes vascular resistance to 60
increase or decrease, thereby maintaining a constant supply 0 8 10 12 14 16 18 20 22 24 2 4 6
of oxygen and nutrients. Conversely, abnormal autoregula- Time (24 hour)
tion could be expressed not only as an excessive arterial
Figure 9-3 Nocturnal hypertension in progressive visual field loss.
constriction (vasospasm) but also as an inadequate arterial Lower levels of blood pressure were found, particularly during the
dilatation.26,56 Observations by Drance and coworkers24 night, in patients with progressive glaucoma (arrow) compared to
have confirmed an increased prevalence of vasospasm in stable patients. (Redrawn from Graham SL, Drance SM, Wijsman K, et al.
patients with NTG. Henry et al.57 presented evidence for Ambulatory blood pressure monitoring in glaucoma. The nocturnal dip.
abnormalities in peripheral (limb) vascular autoregulation Ophthalmology 1995; 102:61–9.)

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 9 • Role of Ocular Blood Flow in the Pathogenesis of Glaucoma 91

be vigilant for sleep apnea as a possible concomitant risk IMPAIRED OPTIC NERVE HEAD, RETINAL AND
factor to nocturnal hypotension in glaucoma.68 Conse- CHOROIDAL BLOOD FLOW IN GLAUCOMA
quently, there is little doubt that low blood pressure is an
essential risk factor for OAG, as is increased IOP. Some of the main evidence implicating blood flow deficits
Increased systemic blood pressure on the other hand was in glaucoma is derived from fluorescein angiography.8,9,73–75
reported to shift the autoregulatory plateau to a higher level These studies have shown delayed retinal circulation as well
compared to normals. This adaptation improves the per- as impaired perfusion of the ONH, peripapillary retina, and
son’s tolerance to hypertension but at the same time makes choroid in glaucoma patients. The severity of perfusion
the individual less tolerant to low systemic blood pressure defects progresses with the severity of glaucoma and the
and more susceptible to an immediate and permanent defects correlate well with visual field loss and nerve fiber
damage from ischemia. Consequently, patients with chronic layer dropout.74,75 Techniques using color Doppler
hypertension are considered to be at greater risk for cerebral imaging76–79 and pulsatile ocular blood flow80–83 have dem-
or coronary ischemia as well as for GON when subjected to onstrated that both retrobulbar blood flow and bulk choroi-
reduced ocular perfusion pressure.11 In the Thessaloniki Eye dal blood flow are reduced in glaucoma patients in contrast
Study,69 a diastolic blood pressure below 90 mmHg due to to normal subjects. Using single-point laser Doppler flow­
antihypertensive treatment was associated with cupping, metry, several authors reported decreased blood flow in the
whereas the same blood pressure was not associated with ONH of OAG when compared to control subjects84 and to
cupping if the patients did not have antihypertensive treat- glaucoma suspects.85
ment. In general, epidemiologic studies suggest that sys- Scanning laser Doppler flowmetry (SLDF) was also used
temic hypertension is protective against glaucoma in for several comparisons between flow measurements in
younger patients (presumably through improved OPP) but OAG patients and normal subjects. Michelson and associ-
deleterious in older patients (presumably through athero- ates86 reported that both neuroretinal rim blood flow and
sclerosis or loss of autoregulation).10 Clinicians need to be peripapillary retinal blood flow were significantly decreased
aware of the potential risk of exaggerated nocturnal hypo- in OAG patients compared to age-matched controls. Neu-
tension in patients with treated systemic hypertension and roretinal rim blood flow was less by 71% while peripapillary
advanced glaucoma, although evidence is not available to retinal flow was less by 49%. Findl and associates18 reported
support specific therapeutic guidelines.47 reduced blood flow in both the disc cup (–46%) and the
Finally, the contribution of hypercoagulability states to neuroretinal rim (–18%) in patients with OAG when com-
GON has been investigated by several authors. Drance pared to control subjects. Nicolela et al.87 reported a signifi-
et al.1 found a relative hyperviscosity in NTG patients cant decrease in blood flow in the lamina cribrosa in OAG
though this was not confirmed by subsequent publica- patients compared to control subjects, whereas no change
tions.69,70 O’Brien et al.71 reported activation of coagulation was noted in the neuroretinal rim.
cascades and fibrinolysis pathways in untreated OAG SLDF has also been used to compare ONH and retinal
compared with controls. Hamard et al.70 using a laser perfusion between OAG patients and ocular hypertensives.
Doppler velocimeter found decreased blood flow in NTG Kerr and associates88 reported reduced blood flow in the
and also increased red cell aggregability. In a 7-year pro- lamina cribrosa and the temporal neuroretinal rim of the
spective study the Canadian Glaucoma Study found a 3.8- ONH of glaucoma patients in comparison to ocular hyper-
fold risk of progression in treated OAG patients having tensives. Using full-field perfusion image analysis, Hafez
elevated anticardiolipin antibodies.72 It can be concluded et al.89 reported a significantly lower ONH blood flow in
that although as yet there is no consistent evidence as to OAG patients when compared to OHT patients and normal
the presence of an abnormal rheology in NTG and OAG, the volunteers with no significant differences in ONH blood
presence of abnormalities should be considered for each flow found between ocular hypertensives and normals.
patient. Choroidal blood flow might also contribute to glaucoma
damage because of its pulsatility. Recently evidence was
presented that there is pulsatile deformation of rim tissue
Current Evidence of Abnormal synchronous with the cardiac cycle, and that this deforma-
Ocular Blood Flow in Glaucoma tion is greater in glaucoma patients compared to normal
subjects.90 It is not known if this putative stretching is a
Evidence that defective perfusion of the ONH plays an source of axonal damage.
important role in the pathogenesis of glaucomatous optic
neuropathy has been accumulating over the past four IMPROVEMENTS IN OCULAR BLOOD FLOW
decades. Studies have reported strong associations between
FOLLOWING THERAPEUTIC IOP REDUCTION
GON and systemic blood pressure alterations, diabetes,
cardiovascular and cerbrovascular disorders, vasospastic Ocular perfusion has been evaluated in OAG and OHT patients
responses, age, hypercoagulability states and increased following therapeutic IOP reduction using topical antiglau-
local resistance to flow. coma medications. The ability of such medications to alter
Recent technical advances have made possible the quan- ocular perfusion has been reported by different authors,
tification of blood flow in different intraocular tissues as well using different methods to assess ocular blood flow.91–96
as of retrobulbar and peripheral blood flow. The following Investigators have also reported improved ocular perfusion
section reviews briefly the current evidence of the role of following sustained IOP reduction in glaucoma patients
defective perfusion of the ONH, retina and choroid as well as following surgery. Color Doppler imaging demonstrated
the various factors involved in the pathogenesis of GON. significant improvements in retrobulbar hemodynamics

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92 SECTION 2 • Pathogenesis

following trabeculectomy in patients with glaucoma.97 Pul- implying a close link between mechanical and hemody-
satile ocular blood flow measurements similarly demon- namic factors in the ONH. In contrast, ophthalmic artery
strated a significant increase (29%) in ocular blood flow flow velocities were found to be unaffected by such changes.
following reduction of IOP post-trabeculectomy.98
Changes in ONH and retinal blood flow were also exam- DEFECTIVE AUTOREGULATION OF THE OPTIC
ined in OAG using SLDF.99 The study was performed in a
NERVE HEAD BLOOD FLOW IN GLAUCOMA
true clinical context, on patients that required therapeutic
IOP reductions and using ocular hypertensives as a control As previously mentioned, autoregulation maintains a rela-
group. Following a similar percentage of therapeutic IOP tively constant blood flow in spite of changes in ocular per-
reduction, rim blood flow did not change in the OHT group fusion pressure (OPP) which in turn depends on systemic
while in the OAG group it demonstrated a statistically sig- blood pressure and IOP. In the absence of autoregulation,
nificant increase of 67% (Fig. 9-4). The reported changes there is an inverse relationship between IOP and OPP. The
provide evidence in favor of defective autoregulation of the higher the IOP the lower the OPP and, in the absence of
ONH blood flow in glaucoma patients. The study also dem- autoregulation, the lower the consequent blood flow to the
onstrates the close relationship between neuroretinal rim ONH. On the other hand, reduction of IOP would be
blood flow and IOP in glaucoma patients. A similar close expected to improve ocular perfusion pressure and conse-
relationship has also been explored between neuroretinal quently could increase ONH blood flow.
rim blood flow and the mechanical properties of the eye.100 Changes in OPP occur routinely in daily life as mediated
by stress and exercise-induced elevations in systemic
BLOOD FLOW RESPONSES TO AN INDUCED blood pressure, by nocturnal reductions in systemic blood
pressure and by diurnal variations in IOP.10 Under normal
CHANGE IN IOP USING SUCTION CUP
conditions if such changes in OPP occur within the physi-
The ability of the eye to adjust to a sudden increase in IOP ological range, local constriction or dilatation in the termi-
was thoroughly investigated both in experimental animals nal retinal arterioles causes vascular resistance to increase
as well as in humans. Blood flow responses to an induced or decrease, thereby maintaining constant blood flow and
change in IOP using a suction cup have also been studied nutrient supply to the tissues.51
in animal models and in man using laser Doppler flowme- The existence of intact autoregulation in the normal
try,101 color Doppler imaging,102 and SLDF.103 In general, ONH has been demonstrated in a large number of
suction-induced IOP elevations reduced retrobulbar, retinal experimental104–108 as well as clinical109–111 studies. Autoreg-
and ONH perfusion parameters in normal and glaucoma- ulation has been reported to operate only within a critical
tous eyes. Such hemodynamic changes were reversed fol- range of ocular perfusion pressure and becomes ineffective
lowing normalization of the IOP. when the ocular perfusion pressure goes below or above this
Induced changes using suction cup have also been used critical range. This range of ocular perfusion pressure has
to demonstrate the highly dependent relation between both been investigated in different species using various
central retinal artery and short posterior ciliary arteries methodologies.104–106,112 In healthy monkeys, Geijer and
hemodynamics and acute changes in IOP.102 Acute incre- Bill104 reported ONH autoregulation to be normal at an
mental elevation of IOP in healthy humans resulted in a ocular perfusion pressure of >30 mmHg. Ernest112 reported
progressive drop in both central retinal artery blood flow similar findings with perfusion pressures >50 mmHg.
velocities and short posterior ciliary arteries velocities, Breakdown of autoregulation was reported to take place at
an ocular perfusion pressure of <30 mmHg by Sperber and
Bill,106 of <25 mmHg by Sossi and Andersen105 and at
30–35 mmHg by Hayreh and coworkers.55
Substantial evidence in the literature suggests that glau-
Pre-IOP reduction Post-IOP reduction comatous optic neuropathy (GON) may be due to an even-
tual breakdown in ONH autoregulation. Ernest112 speculated
300
that GON may be due to a breakdown in the autoregulatory
250 mechanism that normally keeps the blood flow at levels
adequate for tissue requirements. He further speculated
200 that such an autoregulatory mechanism may be damaged
Rim flow (au)

by systemic diseases. Sossi and Anderson105 similarly specu-

150 lated that GON might be due to defective autoregulation
acquired with age. Pillunat et al.113 and Hafez et al.99 pre-
100 sented evidence of defective ONH autoregulation in NTG
and OAG respectively, whereas Grunwald et al.114 reported
50
evidence suggestive of abnormal autoregulation of macular
0
blood flow in OAG. Riva et al.115 reported an increase in
OAG OHT optic nerve head blood flow, as measured by laser Doppler
Figure 9-4 SLDF measurements of ONH blood flow in OAG and OHT
flowmetry of 39.0% in normals versus only 17.5% in ocular
groups before and after therapeutic IOP reduction. (From Hafez AS, hypertensives and 10.4% in early glaucoma patients when
Bizzarro RLG, Rivard M, Lesk MR. Changes in optic nerve head blood flow the fundus was stimulated with a 15-Hz monochromatic
after therapeutic intraocular pressure reduction in glaucoma patients and green light flicker. Flicker stimulation was reported to
ocular hypertensives. Ophthalmology 2003; 110(1):201–10.) increase metabolic demands and consequently induce an

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 9 • Role of Ocular Blood Flow in the Pathogenesis of Glaucoma 93

increase in blood flow via vasodilatation mediated by nitric ophthalmic arteries of NTG patients compared to those of
oxide release. healthy subjects and the resistivity index was found to be
It has been generally assumed that the choroid does not higher. When PCO2 was increased controls remained
possess the capacity to autoregulate. Recent studies pro- unchanged, whereas end-diastolic velocity increased in
vided evidence that the choroid has some autoregulatory NTG. Similar findings were reported by Hosking et al..131
capacity in response to changes in ocular perfusion pres- These studies suggest the presence of a relative vasocon-
sure in healthy subjects. In OAG patients, such autoregula- striction in some orbital vessels of glaucoma patients, which
tion was considerably impaired while in OHT patients the might be the result of vasospasm, and which is partially
autoregulation was found to be normal, increased or slightly reversed by hypercapnia.
decreased.116
A putative molecular role in vascular dysregulation ROLE OF VASOSPASM AND MIGRAINES IN THE
has been attributed to many molecules50,117 including
DEVELOPMENT AND PROGRESSION OF GLAUCOMA
endothelin-1118–122 and nitric oxide.123,124
A high prevalence of peripheral vasospasticity has been
EFFECT OF INHALED CARBON DIOXIDE ON reported in glaucoma patients. This vasospasticity has been
consistently linked to abnormal ocular blood flow. Phelps
RETROBULBAR CIRCULATION IN GLAUCOMA
and Corbett in 1985132 were the first to suggest the possible
Earlier studies on the response of retinal circulation to role of vasospastic phenomena in the development and pro-
changes in arterial oxygen and carbon dioxide were limited gression of glaucomatous optic neuropathy. They found
to measurements of vessel diameter. The studies reported that 47% of their patients with normal-tension glaucoma
that hyperoxia decreased retinal vessel diameter whereas also suffered from migraine. Gasser and Flammer in 198719
hypoxemia increased it.125 Later Riva et al.,126 using laser described ocular vasospasm in which patients with unex-
Doppler velocimetry, measured changes in retinal blood plained scotomas had abnormal capillaroscopic response to
velocity in normal subjects following induced hyperoxia. cold in the nailfold of the fingers. The scotomas were aggra-
After 5 minutes of oxygen breathing, blood velocity was vated by the immersion of a hand in cold water. They
reduced by 53%, vessel diameter by 12% and calculated flux assumed that patients with tendency to vasospasm exhibit
by 60%. Similar results were reported by other investiga- ocular vascular reactions similar to those that occur in the
tors.127,128 Studies using blue-field entoptic stimulation also capillaries of the fingers. In 1988, Guthauser et al.22 dem-
found decreased velocities of perimacular leukocytes asso- onstrated a statistically significant relationship between
ciated with hyperoxia and increased velocities with hypox- patient’s history of cold hands and the outcome of both the
emia.129 Increased velocities were also reported by Sponsel visual field cold water test and the nailfold capillaroscopic
et al.,130 using the same technique with mixtures of 95% test. The visual field results were also found to correlate
oxygen and 5% carbon dioxide. significantly with the capillaroscopic results.
Induced gas perturbations were also used to test the Strong associations have been established between NTG
hypothesis that glaucoma patients show pre-existing and and migrainous headaches. Drance et al.,24 using Doppler
reversible vasoconstriction of retrobulbar vasculature and blood-flow measurements in the finger and a cold test as
thus differ from normals in their response to vasoactive shown in Figure 9-5, showed that in non-glaucomatous
stimuli. In a study by Harris et al.,77 CDI was performed on subjects, 26% without migraine had a positive vasospastic
the eyes of NTG patients and control subjects, before and response while 64% with classic migraine showed such a
after breathing carbon dioxide (CO2). Baseline values for response. Of the patients with low-tension glaucoma, 65%
end-diastolic velocities were found to be lower in the showed a positive vasospastic response. These findings were

Figure 9-5 Top: Tracing of peripheral blood flow in a

vasospastic patient showing a low baseline flow at room
temperature and a marked decrease in flow after immer-
sion of the hand in cold water (4°C) with a delayed recov-
ery to baseline. Bottom: Tracing of peripheral blood flow
in a non-vasospastic patient showing a normal baseline
flow at room temperature and a rapid decrease after
immersion of the hand in cold water (4°C) with a rapid
recovery to baseline. (Courtesy of MR Lesk, MD, AS Hafez,
MD and D Descovich, MD.)

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94 SECTION 2 • Pathogenesis

20 20

15 15
MD (dB)

MD (dB)
10 10

5 5

0 0

14 16 18 20 22 24 26 28 30 32 34 36 38 40 14 16 18 20 22 24 26 28 30 32 34 36 38 40
IOP (mmHg) IOP (mmHg)
Figure 9-6 Correlations between IOP and visual field mean defect MD in two distinct OAG populations; vasospastic (left) and atherosclerotic (right).
(Redrawn from Schulzer M, Drance SM, Carter CJ, et al. Biostatistical evidence for two distinct chronic open-angle glaucoma populations. Br J Ophthalmol
1990; 74:196–200.)

later supported by results from the Collaborative Normal normal-pressure glaucoma than in high-pressure glau-
Tension Glaucoma Study48 that demonstrated a 2.58-fold coma and in progressive than in non-progressive eyes. In
increased risk of progression in glaucoma patients suffering studies applying provocation tests, differences between OAG
from migraines. patients and normal subjects were more pronounced under
Studies also suggested a possible role for calcium channel provocation.
blockers in patients with progressive NTG and an underly- Current evidence also suggests that abnormalities in
ing vasospastic disorder. Kitazawa et al.133 demonstrated ocular blood flow can be explained partly by low ocular
improvement in visual fields following treatment by nifed- perfusion pressure, and partly by vasospasm and abnormal
ipine for 6 months, whereas Netland et al.134 looked retro- autoregulation of blood flow, which can manifest as an
spectively at NTG patients on calcium channel blockers inability to adapt to increased or fluctuating IOP and/or to
and found that they were less likely to progress. Pillunat decreased or fluctuating systemic blood pressure.
et al.135 reported that NTG patients showed increased
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