New Developments in
Glaucoma Diagnosis and Care
Robert P. Wooldridge, O.D.
Eye Foundation of Utah
201 East 5900 South, Suite 201
Salt Lake City, Utah 84107
E-mail: rpwod@aol.com
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New Developments in Glaucoma Diagnosis and Care
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Disclosure
Speakers bureau for:
Alcon, Allergan, Heidelberg Engineering, Inspire, Konan Carl Zeiss Meditec,
Oculus, Optovue, RPS, VSP
Consultant for RPS
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Ranae March 13
63 yo WF glaucoma suspect
H/o extreme drop in BP x 2 secondary to meds in prep. for angiogram
S/P bypass (6)
+HTN
Lotension, Zocor, ASA
FH: neg for glaucoma
Ranae
20/25, 20/20
TA R: 18, L: 19
Gonio: slit-closed 360 O.U.
+ bombe
CCT R 503 L 491
Discs, VF as seen
Ranae June 17
R: 15, L: 19
Now use Betoptic O.U.
CCT R 503 L 491
Cause? Effect?
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The Questions
Do we have an accurate, valid means of measuring blood flow to the optic
nerve?
That is clinically useful?
Does blood flow to the optic nerve matter in glaucoma?
Can we affect blood flow to the optic nerve?
Do we have any evidence that doing so improves the prognosis in glaucoma?
What Do We Know?
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What Do We Not Know?
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The First Charge
There is no accurate, repeatable, verifiable method of measuring blood flow to
the optic nerve head.
The instruments purported to do so do not agree.
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We have no means of measuring blood flow to the nerve in a clinically useful
fashion
Optic Nerve Blood Flow in Glaucoma
“Because of its variable arterial origins, small vessel caliber and multilaminate
architecture, the microvascular circulation of the optic nerve head is very
complex and hard to evaluate with our current technology.”
Color Doppler Ultrasound Imaging:
“ This is a highly variable technique and requires a capable ultrasonographer
with a good knowledge of the anatomy of the globe, a steady hand, a good eye
for waveforms, and a good ear for the sounds of the velocities to obtain an
acceptable co-efficient of reproducibility.”
Optic Nerve Blood Flow in Glaucoma
Heidelberg Retinal Flowmeter (HRF)
“A limited depth (of scan) makes the vasculature within the lamina inaccessible.
Also, the measurements may vary depending on the characteristics of the
imaged tissues and the level where the measurements are made…at the level of
the retina or at the bottom of the excavation.”
“Each of the presently available blood flow measurement techniques requires
better validation. Sources of variability should be accounted for and minimized.”
Optic Nerve Blood Flow in Glaucoma
“There is no reliable method to measure accurately the blood flow in the optic
nerve head.”
World Glaucoma Association Consensus Reports
Structure and function in the management of glaucoma
Glaucoma surgery: open angle glaucoma
Angle closure glaucoma
Intraocular pressure
Glaucoma screening
Ocular blood flow in glaucoma
WGA Consensus on Blood Flow
Ft. Lauderdale on May 2, 2009
Goals:
To obtain consensus on the relationship between ocular blood flow and
glaucoma
To establish a foundation for OBF research of glaucoma and the best practice for
its testing in clinical practice.
Consensus statements and comments based on published literature and expert
opinion
Clinical Measurement of Ocular Blood Flow Consensus Points
Color Doppler Imaging (CDI)…measures blood flow velocity and calculates
resistive index in the retrobulbar vessels
Comment: CDI does not measure flow
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The measurements with one CDI instrument are not necessarily compatible with
those of another
Scanning Laser Doppler
Scanning Laser Doppler flowmetry measures velocity, volume and flow limited to
the retinal microcirculation and the optic nerve head
Comment: There is a lack of standardization for analysis, and flow is limited to
arbitrary units of measure.
Comment: the depth of the measurements is not known and may not be
comparable among subjects.
Ocular Pulse Amplitude
The relationship between OPA and total blood flow to the eye and, specifically, to
the optic nerve is uncertain
Significance is controversial
“OPA should not be used as a surrogate for ocular blood flow measurement”
Pulsatile Ocular Blood Flow Analyzer
Advantages: relatively inexpensive, simple to operate, data acquired
immediately, requires no special training,..and is minimally invasive for the
patient.
Disadvantages: Measures IOP rather than blood flow, and the rate of venous
blood flow is not known
Pulsatile Ocular Blood Flow Analyzer
POBF values are influenced by age, gender, BP, pulse and axial length
Decreases significantly with age
“The wide range of normal values and the low discriminating power ofPOBF
between normal and glaucomatous limits the clinical use of the device.”
“POBF was found not to be an adequate measure of total ocular blood flow.”
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Consensus Point
At the present time, there is no single method for measuring all aspects of ocular
blood flow and its regulation in glaucoma.
The Question
Do we have an accurate, valid means of measuring blood flow to the optic
nerve?
That is clinically useful?
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Does blood flow to the optic nerve matter in glaucoma?
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The Second Charge
Blood supply to the nerve plays no significant role in the risk of glaucoma
developing or in the natural progression of the disease.
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The Evidence Against Blood Supply as a Risk Factor for Development of
Glaucoma
Ocular Hypertension Treatment Study (OHTS)
What are the risk factors for the development of glaucoma?
Study design
1636 Patients: 40 - 80 yo
IOP 24 - 32 in one eye, and
IOP 21 - 32 in fellow eye
Normal VF and nerves
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Univariate and Multivariate
Older age
Higher IOP
Greater pattern standard deviation
Thinner central corneal thickness
Larger vertical C/D ratio
Factors NOT Predictive (U and M)
Migraine
Cerebral vascular accident
High OR low blood pressure
Use of oral
Beta blockers
Calcium channel blockers
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Diabetes
Found to be protective in both univariate and multivariate analyses
Later reassessed and found to be neither protective nor a risk factor
OHTS Validated by EGPS
OHTS prediction model applied to European Glaucoma Prevention Study control
patients
Risk of developing glaucoma
OHTS: 9.3% EGPS: 16.8%
Same risk factors identified
Age, IOP, CCT,C/D and PSD VF
Diabetes did NOT decrease or increase risk in EGPS
The Evidence Against Blood Supply as a Risk Factor for Progression of Glaucoma
Early Manifest Glaucoma Trial
To assess factors for progression of glaucoma
Study design
255 patients with mild glaucoma
½ treated
½ followed without treatment
Treatment group
ALT plus Betoptic 0.5% bid
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5
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Control group
No treatment
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Progression (median FU 6 yrs.)
Control group:
62%
Treatment group: 45%
Risk Factors at Baseline
Higher baseline IOP
Exfoliation
Both eyes eligible (bilateral disease)
Worse mean deviation on VF
Older age
Baseline Factors-No Added Risk
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High blood pressure
Cardiovascular disease
Migraine or Raynaud’s Disease
Smoker (current or prior)
Glaucoma family history
Sex
Central Corneal Thickness! (CCT)
Refractive error
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What About Normal Tension Glaucoma??
Optic Nerve Blood Flow in Glaucoma
“There is little direct evidence of vasospasm in the optic nerve head itself in NTG.
The evidence is based on the findings of vasospastic response of the fingernail
vascular bed to cold or other vasospastic disorders in these patients.”
Collaborative NTG Study
Risk factors for progression of VF abnormalities in NTG
160 subjects
Traits that make a person more likely to have NTG.
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Older age
Female gender
H/O Migraine
(Japanese)
Higher IOP (but still normal)
17-22
Traits That Affect the Rate of Progression if Untreated
Female gender
Migraine
Disk hemorrhage at baseline
Racial Heritage
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Asians longer survival time 2527 days
Whites medium
1985 days
Blacks shortest
1282 days
Too few black patients to be statistically significant
Age is NOT a factor in rate of progression
Vascular Risk Factors Evaluated
Blood pressure
Pulse rate
Cardiac arrhythmia
Major cardiovascular crisis
Hypotension
Shock
Blood transfusuion
Major surgery
Vascular Risk Factors Evaluated
Cardiovascular disease
HTN
Angina
Myocardial infarction
Diabetes mellitus
Peripheral vascular disease
Migraine
Raynaud phenomenon
Anemia
Tendency for low blood pressure
Family history of DM and stroke
Results
“HTN, H/O major surgery, FH of Stroke or DM occurred in a substantial
percentage of patients but failed to show up as factors influencing the rate of
deterioration.”
Migraine and disc hemorrhage were the only factors shown to affect the course
of NTG
Are these factors evidence of too little blood flow or too much?? (vasodilation?)
Risk Factors That Did Not
Affect Risk of Progression
Cardiovascular disease
HTN
Angina
Myocardial infarction
Diabetes mellitus
Peripheral vascular disease
Raynaud phenomenon
Anemia
Tendency for low blood pressure
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Family history of DM and stroke
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The Evidence For Blood Supply as a Risk Factor for Development of Glaucoma
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Systolic BP and Glaucoma
IOP is positively (but weakly)correlated with BP
For every 10mm change in SBP, there is a 0.5mm change in IOP
Association between BP and the development of glaucoma is weak
Barbados Eye Study
Low SBP was a risk factor for incidence of OAG
EMGT: Low SBP was a predictor for progression
Consensus Points
Blood Pressure is positively correlated with IOP.
It is unclear whether the level of BP is a risk factor for having or progressing
OAG in an individual patient.
Lower OPP is a risk factor for primary OAG.
OBF parameters measured with various methods are impaired in OAG, especially
in NTG
Consensus Points, cont.
Vascular dysregulation may contribute to the pathogenesis of glaucoma, more
likely in people with lower IOP.
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Conclusion
“The relationship among BP, IOP and development of OAG is complex and
requires further investigation.”
A New Way to Assess OBF:
Ocular Perfusion Pressure
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Ocular Perfusion Pressure: Terminology
OPP – Ocular Perfusion Pressure
SPP – Systolic Perfusion Pressure
DPP – Diastolic Perfusion Pressure
MPP – Mean Perfusion Pressure
Ocular Perfusion Pressure and Glaucoma
SPP = SBP – IOP
DPP = DBP – IOP
MPP = 2/3 mean arterial pressure – IOP
Arterial Pressure = DBP + 1/3(SBP – DBP)
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OPP: Baltimore Eye Survey
Cross sectional study of African Americans and Caucasians in Baltimore, MD
Lower OPP strongly associated with prevalence of POAG
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Sixfold excess of POAG in subjects with lowest category of OPP
OPP: The Egna-Neumarkt Study
Population-based cross-sectional study of Caucasians in Northern Italy
Lower DPP associated with marked, progressive increase in frequency of POAG
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OPP: The Egna-Neumarkt Study
OPP: Barbados 9-year
Same cohort study of African-Caribbeans residing in Barbados, West Indies
9-year risk of developing glaucoma increased dramatically at lower
SPP (RR 2.0, CI 1.1 – 3.5)
DPP (RR 2.1, CI 1.2 – 3.9)
MPP (RR 2.6, CI 1.4 – 4.6)
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POAG Risk Factors 9-year BES
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OPP: Proyecto VER
Cross-sectional study of Hispanics in Nogales and Tucson, AZ
Found lower DPP associated with increased risk of POAG
Subjects with DPP
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OPP: Proyecto VER
OPP in EMGT
Randomized clinical trial comparing no treatment to treatment for initially
diagnosed glaucoma (entire cohort followed for progression)
In patients with higher baseline IOP:
h/o CVD increased risk (HR 2.75, CI 1.44-5.26)
Lower SPP increased risk (HR 1.55, CI 1.02-2.35)
In patients with lower baseline IOP:
Higher systolic BP decreased risk (HR .44, CI .2-.97
Lavon 2/11
36yo WF referred as glaucoma suspect
MH: no illnesses; no migraines
VA 20/15 OU
Ta: R 26 L 25
CCT: R 595 L 608
DCT: R 28 L 23
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Lavon 3/11
Ta: R 27 L 27
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BP: 109/66
DOPP: 66-27=39
Plan:
Advised of ORB of Rx v. no Rx, asymptomatic nature of early glaucoma and need
for careful FU
Will follow without Rx for now
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Can we affect blood flow to the optic nerve?
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The Third Charge
We can do nothing to selectively improve blood supply to the nerve without
possibly affecting blood supply to other tissues of the body and placing them at
risk for ischemia.
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The Fourth Charge
There are no therapeutic agents that improve the natural course of glaucoma by
increasing blood supply to the optic nerve.
Vasodilators
“The magic pills”
Despite being available for many years…
Despite the high prevalence of glaucoma…
Despite the huge potential profitability of any vasodilating agent if proven to be
effective in the management of glaucoma…
There are no agents proven to be effective in selectively increasing blood supply
to the optic nerve or approved by the FDA for the treatment of glaucoma
Optic Nerve Blood Flow in Glaucoma
“A number of studies have found no significant benefits from the use of calcium
antagonists in glaucoma.”
“Calcium antagonists can cause nocturnal hypotension, which, in addition to
other systemic side effects, adversely effects the blood flow in the optic nerve
head.”
“In view of these considerations, there seems to be little scientific basis for use
of calcum channel blockers in glaucoma treatment.”
Impact of Ocular Medications
on OBF
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Clinical Control of OPP
Lower IOP improves OPP
Higher systemic BP improves OPP but don’t necessarily want to raise BP
Stroke #3 cause of death in US behind CVD and CA!
Avoid drugs that lower systemic BP beyond patient’s desired systemic control
Avoid nocturnal hypotension
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Nocturnal Hypotension and OPP
Low BP at night, coupled with high IOP in supine position, compromise OPP
Using systemic BP meds in the AM to minimize nocturnal hypotension makes
sense
Using IOP lowering drugs that lower IOP while sleeping makes sense
Avoiding IOP meds that LOWER systemic BP at night (beta blockers, alpha
agonists) makes sense
Travoprost Reduces and
Sustains Habitual IOP-lowering
Nocturnal and Diurnal Habitual IOP
Brinzolamide, Timolol added to Latanoprost
Brimonidine Habitual Position
OPP and Glaucoma Medications
Cross over study of effect of different classes of IOP lowering meds on DPP
PGA and CAI significantly increased DPP at all time points
Beta-blocker significantly increased DPP from 4AM to 4PM but had no effect at
other times
Alpha agonist significantly reduced DPP at multiple time points, primarily due to
significant decrease in systemic BP
OPP and Glaucoma Medications
Nocturnal and Diurnal Habitual IOP
Travoprost Reduces and
Sustains Habitual IOP-lowering
Clinical Relevance of OBF Measurements Including Effects of General Medications
or Specific Glaucoma Treatment
Ocular medications and OBF
Pilocarpine: no significant effect.1
Phenylephrine: produced vasoconstriction in retrobulbar arterioles around the
ONH.2
Brimonidine:
no change in retinal capillary flow.3
Increase in OBF in POAG4 and NTG.5
No change in OPA.6
Ocular Medications and OBF
Brimonidine:
no change in retinal capillary flow.3
Increase in OBF in POAG4 and NTG.5
No change in OPA.6
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Beta Blockers
Patients using topical beta blockers had:
Lower minimum nocturnal heart rate
Lower minimum nocturnal DBP
Greater percentage drop in nocturnal DBP
Beta-blockers:
Timolol:
Controversial
Most studies report no significant or rather unfavorable results.1
Betaxolol:
Reports vary: beneficial or not significant
More favorable than Timolol
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Prostaglandin Analogues
Latanoprost, Bimatoprost and Travoprost
Generally show beneficial effects on retrobulbar hemodynamics
Carbonic Anhydrase Inhibitors
Dorzolamide, Brinzolamide:
Reports mixed but more showed positive effects on OBF
Others showed no significant effect
Consensus Point
Certain drugs, even when formulated in an eye drop, may have an impact on
ocular blood flow and its regulation.
Comment: The impact of eye drop related changes in OBF on the development
and progress of glaucoma is unknown.
Some data support increased blood flow and the enhancement of OBF regulation
with CAI’s. These appear to exceed what one would expect from their ocular
hypotensive effect alone.
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Role of Systemic Medications?
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Some systemic medications may have an impact on OBF and its regulation.
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Comment: The impact of systemic medications altering OBF on the development
and progression of glaucoma is unknown.
Classes of systemic medications that have been reported to increase OBF include
Calcium channel blockers
Angiotension converting enzyme inhibitors
Angiotension-receptor inhibitors
Carbonic anhydrase inhibitors
Phosphodiesterase-5 inhibitors
Larry 1999
46 yo WM referred as glaucoma suspect
MH: no illnesses FH: mother has glaucoma
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VA 20/15 OU
IOP R 42 L 46
SLE normal OU
ON, VF as seen
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Your Plan?
1. Xalatan qhs OD
2. Xalatan qhs OU
3. Timolol bid OU
4. Trusopt bid OU
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Feb. 15, 1999
IOP R 21 L 38
Gonioscopy Grade IV OU
Now use Xalatan OU
1999-2002
Managed with Xalatan, Alphagan and/or Betoptic
Some problems with irritation, pterygium
IOP’s running 19-26 OU
11/15/2002
On Xalatan OU
CCT R 597 L 581
IOP R 21 L 20
VF normal OU
2/17/03
Using Xalatan OU
IOP R 37 L 37
Plan:
Continue Xalatan OD
D/C Xalatan OS
2/21/03
IOP R 23 L 38
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2/21/03
IOP R 19 L 22
Resume Xalatan OU
Discussed ORB of gtt, SLT, trabeculectomy
3/3/03
IOP R 19 L 22
SLT OS done today
6/17/03
IOP R 26 L 19
+ response to SLT; schedule SLT OD
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2003-2006
IOP running 15-17 OU on Xalatan, after SLT OU
VF, nerves stable
9/06/06
IOP R 16 L 17
11/27/06
Still on Xalatan OU
IOP R 27 L 27
HRT as seen
ON photos stable OU
But…
New disc hemorrhage OS
What is Your Plan?
1. Continue Xalatan OU
2. SLT OU
3. Switch to Travatan OU
4. Add Azopt bid OD
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Rob’s Plan
1. Switch to Travatan OU
2. Add Azopt OD bid
3. Schedule SLT OS
7/10/2007
SLT OS performed 12/15/06
Back on Xalatan OU
IOP R 21 L 22
VF normal OU
2009
S/P SLT OU 2003
Currently taking Xalatan, Combigan OU
VA 20/20 OU
IOP
June 29 R 16 L 14
July 30 R 12 L 13
ON,VF as seen
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Larry 2009
IOP running R 12-17 L 13-14
On Xalatan and Combigan
VF getting worse OD
Now what?
Other Health Issues?
No sleep apnea
No migraines
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What else should we check??
BP
June 29: 102/56 P 48
July 30: 121/74 P 51
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What is Your Plan?
1. Add Cosopt
2. Add Azopt
3. More SLT
4. Refer to someone you don’t like
Clinical Control of OPP
Lower IOP improves OPP
Higher systemic BP improves OPP but don’t necessarily want to raise BP
Stroke #3 cause of death in US behind CVD and CA!
Avoid drugs that lower systemic BP beyond patient’s desired systemic control
Avoid nocturnal hypotension
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Nocturnal Hypotension and OPP
Low BP at night, coupled with high IOP in supine position, compromise OPP
Using systemic BP meds in the AM to minimize nocturnal hypotension makes
sense
Using IOP lowering drugs that lower IOP while sleeping makes sense
Avoiding IOP meds that LOWER systemic BP at night (beta blockers, alpha
agonists) makes sense
Take Home Points
The role of blood supply as a risk factor in glaucoma is poorly understood and
remains controversial
Be aware of vascular health issues in our glaucoma patients
Blood pressure
Sleep apnea
dyslipidemia
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Take Home Points
Encourage good lifestyle habits
Diet
Exercise
Avoid headstands with yoga
Stop smoking
Refer for appropriate evaluation and management of possible risk factors
Blood pressure: avoid nocturnal hypotension
Sleep apnea
Vasospasm
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