BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page1
GLAUCOMA AND PRESSURES
Understanding Glaucoma:

Basic anatomy
o

Basic physiology
o

Anterior/posterior chamber, angle
Aqueous humor production and drainage
Better understanding of glaucoma pathogenesis and treatment
Anatomy Review: The Angle

Limbal region

Scleral suclus & Scleral spur

Trabecular meshwork  sieve-like tissue

Schlemm canal

Intrascleral “collector” channels

Supracilliary space  potential space b/w CB & sclera

Pars plicata  where the “action” is

Ciliary processes  where aqueous humor is produced

Iris  divides aqueous humor chamber into:
o
Anterior chamber
o
Posterior chamber
Aqueous Humor PRODUCTION:

Ciliary processes of CB

Pigmented epithelium


o
Carbonic anhydrase  target of many glaucoma meds
o
Na/K/Cl symport
Non-pigmented epithelium
o
Na/K-ATPase
o
Carbonic anhydrase
Net secretion of ions
o

(+) stroma
Where ions go, water follows
o
Carbonic anhydrase
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
o
Date: 03/09/2016, 1st hour
Page2
Na/K-ATPase
Aqueous Humor FLOW:

CB processes  posterior chamber  iris and lens  through pupil  anterior chamber

It then exits the eye by two main routes
Aqueous Humor DRAINAGE: 2 main routes
1. TRABECULAR (Traditional)

TM  Schlemm’s Canal  intrascleral collector channels  episcleral veins

Pressure dependent

Accounts for ~80% of aqueous humor outflow
o
Somewhat variable
2. UVEOSCLERAL (Non-traditional)

Aqueous humor flows across iris root  between CB muscle bundles  suprachoroidal space 
venous circulation

Outflow relatively independent of IOP (bulk flow)

Accounts for ~20% of aqueous humor outflow
o

Somewhat variable
Modification of CB muscle (ex. accommodation, pilocarpine, etc) will affect uveoscleral outflow
Outflow Vocabulary:

Resistance  opposition to outflow

Facility  ease of outflow

Increase resistance, reduce outflow

Increase facility, increase outflow (decrease IOP)
Resistance to Outflow:

Progressive increase in resistance with increasing age (this is normal)
o
These normal changes are exaggerated/accelerated in glaucomatous eyes
o
High IOP in glaucoma is not because of too much aqueous produced, but rather poor outflow

Increased resistance is the cause of increased IOP in glaucoma

Major players:
1. Trabecular meshwork
2. Schlemm’s canal
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page3
3. Venous system (episcleral veins)
4. Aqueous humor
TRABECULAR MESHWORK:

Uveal & corneoscleral meshwork
o
Single layer of phagocytic endothelial cells clean up of obstructive debris

o
Loss of endothelial cells with age alters surface trabeculae


Basically maintain patency of TM spaces to allow outflow to continue
Trabecular beams get thicker
Juxtacanalicular meshwork
o
Primary site of outflow resistance

Extracellular matrix with proteoglycans, GAGs, MMPs. Changes in amount/distribution
influence aqueous humor outflow

Sheath-derived plaques accumulate with age and to a greater extent in glaucomatous
eyes  further reduce size of openings through which aqueous can get through
- Top photo is a normal eye
- Bottom photo is an aged or
glaucomatous eye

Increased formation of
plaques

Reducing space through
which aqueous can get through

Reduction in GV
formation and enlargement of
trabecular beams
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page4
SCHLEMM’S CANAL & EPISCLERAL VEINS:

Giant vacuoles along inner wall of Schlemm’s canal
o
Bulk of aqueous humor flow into Schlemm’s canal
o
Pressure dependent (increased IOP, increased GV size & vice versa)
o
Decreased ability to form giant vacuoles with age


Further decrease in glaucomatous eyes
Aqueous humor ultimately drained/absorbed by episcleral veins
o
Increasing episcleral venous pressure will increase resistance to outflow (inhibits outflow)

This can happen by laying on back or increasing thoracic pressure
- Goldmann is the gold standard for
measuring IOP
- Patients with glaucoma, disease,
OHTN absolutely must have
Goldmann tonometry done
- Tonopen  requires anesthetic,
need confidence interval of 95%, less
accurate at higher pressures
- iCare  no anesthetic, pretty fast
and reliable
- NCT  quick and easy, but not very
accurate at higher pressure. Also, the
anxiety it causes some patients
causes artificial increase in IOP
Normal IOP?

Normal IOP can only be defined as that pressure which does not lead to optic nerve damage

There is no specific value to safely generalize to all patients

“Normal” = description of IOP distribution in the population and statistical normal range

“Normal” IOP Stats:
o
Mean IOP of 15.4 mmHg +/- 2.5 SD
o
Thus upper limit of normal is 21 mmHg
o
Always (rare exceptions) measured via Goldmann tonometry in the management of disease
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page5
- There is a subset of patients who
never have pressure over 21, but
they have glaucoma
- There is another subset of patients
who always have pressure over 21,
and do not develop glaucoma
Paradox of IOP:

One group of patients
o

90% of patients with elevated DO NOT go on to develop glaucoma
Another group
o
30-50% of patients with glaucoma DO NOT have IOP over 21 mmHg
Characteristics of IOP:

Increases slightly with age
o

Slightly higher in women
o

This is a normal change not associated with the development of glaucoma
No real significance to this
Symmetrical between eyes:
o
~2-4 mmHg
o
Greater than this can be a sign a disease, or angle pathology
o
Should consider doing gonioscopy on patients with asymmetric IOPs

Need to look at the angle to see if there is something causing the difference between the
two eyes

Diurnal fluctuation
o
Heightened in glaucoma patients
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page6
Factors Affecting IOP:
INCREASE IOP
External pressure on eye (lid, fingers)
DECREASE IOP
Exercise

Poor lid-holding technique

Can provide transient 20% decrease

Need to make sure you are holding lid

Regular aerobic exercise can transiently
against patient’s brow bone (should not be
lower IOP
able to feel anything soft & squishy)
Steroids (topical/oral)
Acute (early stage) uveitis
Increased episcleral venous pressure

Supine position, positional valsalva

Lying down raises IOP (2-4 mmHg) by
Retinal detachment
increasing episcleral venous pressure and
causing an increased resistance to aqueous
outflow
Alcohol & marijuana

Very transiently and unpredictably

No evidence that marijuana is a goof
treatment plan for glaucoma patients

Effects only last 2-3 hours

Patient would have to be high the entire day
- Redistribution of
body fluids
- More fluid behind the
eye  increases
episcleral venous
pressure
- Decreases aqueous
drainage
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar

Date: 03/09/2016, 1st hour
Page7
Interesting tidbit: YOGA
o
Study found that:
o
“There as a uniform 2-fold increase in the IOP during Sirsasana (headstand
position), which was maintained during the posture in all age groups irrespective of
the ocular biometry and ultrasound pachymetry. We did not demonstrate a higher
prevalence of ocular hypertensive’s in this cohort of yoga practitioners, nor did the
risk factors contributing to glaucoma show any correlation with magnitude of IOP
raise during posture”
o
If you have patients who do yoga and they have glaucoma, you may want to advise
against this position

Corneal thickness
o
o
Affects measurement of (Goldmann) IOP

Thicker cornea usually gives higher IOP reading

But there is a lot of variability, so cannot adjust IOP based on pachymetry
Doesn’t cause increase/decrease in pressure, but rather affects measurements
IOP Level & Stability:

IOP fluctuates diurnally  Up to 4 mmHg in normal (i.e. non-glaucomatous) eyes

Diurnal flux is greater in glaucoma patients

Large diurnal IOP fluctuations are a significant risk factor for disease progression

Patients with periodic pressure spikes can lose visual field due to cumulative damaging effects

Example: Sustained IOP of 24 mmHg may not be bad as lots of fluctuations between 12 and 24 mmHg
Clinical Sampling of IOP is sparse

525,600 minutes in a year

~2 minutes of IOP measurements assuming 4 office visits per year
24-Hour Rhythm of Aqueous Humor Flow & Formation:

Hours
Rate (ul/min)
Volume (ul)
% Day’s Total
6AM-12PM
3.0
1087
33%
12PM-10PM
2.7
1602
50%
10PM-6AM
1.2
585
17%
Total 24 hr
2.3
3274
100%
Reduction of aqueous humor production at night, but that is when IOP is theoretically highest
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page8
SLEEP STUDIES  Our understanding of diurnal and nocturnal IOP has been expanded by recent studies
24 Hour IOP: 10+ year data

24 hour IOP measured sitting and supine
o

Measured under ideal conditions in a specially designed sleep laboratory
By far, the highest IOP spike occurred while sleeping (measured supine)
o
Likely from increased episcleral venous pressure in supine positioning
Nocturnal IOP Study:

Patients are set-up in a sleep laboratory which is modeled like an apartment

11pm, lights off, go to bed

Throughout the night, grad students go into room and measure IOPs with as little disruption to patients as
possible

Measured via pneumatonometer (applanation-type), which does require anesthetic
o
Patients were still in supine position during measurement

The above graph is looking at the sleep lab data for healthy, young adults

Comparing IOPs seated vs. supine  can see definite increase due to positional effect

Largest peak around 4-6am

Can also notice that IOP is higher in morning hours than in afternoon, but not the peak (overnight is the
highest)
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar

Date: 03/09/2016, 1st hour
Page9
The above graphs are looking at healthy patients vs. glaucoma patients
o
Both healthy eyes and eyes with glaucomatous changes have higher nocturnal supine IOP than
diurnal sitting IOP
o
Pressures peaking in overnight hours
Overlapping graph
of older glaucoma
patients, older
healthy patients,
and younger
patients
Glaucoma patients
have higher
nighttime spike,
and higher overall
pressures than
normal patients
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page10
So what??

Maybe 2 minutes isn’t enough sampling

Limited clinically
o
Overnight IOP measurements impractical
o
Serial tonometry can help some

Patient comes into clinic in the morning, and you take a reading every 30 minutes for a
few hours

Remains unsolved problem for now…
Future Possibilities:


24-hr IOP Measure via SCL
o
Doesn’t actually measure pressure; measures change in shape of cornea
o
Gives a graphical printout
o
Extrapolating that when cornea changes shape, IOP is changing as well
o
Now FDA approved (3/7/16)

Note that this needs to be updated in the handout we received! **

It is still a long way from being used clinically
iCare One for Home Use:
o
Patient can keep track of IOP at home between visits
o
This allows for more readings throughout the year because
some glaucoma patients will only see you 2-3 time a year
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar

Date: 03/09/2016, 1st hour
Page11
What do we do with this information clinically?
o
Know about it  need to understand fluctuations
o
Medication selection

Do all glaucoma medications work the same in the day as they do at night?
Effects of Treatments on Aqueous Humor Dynamics:
**Need to know these medications very well for clinic!
Class
Mechanism of Action
beta-adrenergic antagonists
Inhibit aqueous humor production (daytime, minimal nocturnal effect)
Prostaglandins
Increase outflow
Carbonic anhydrase inhibitors
Inhibit aqueous humor production
alpha-adrenergic agonists
Inhibit aqueous humor production and increase outflow

The above graph is comparing the effects of timolol vs. latanoprost

Pink = untreated

Orange = Timolol

Green = Latanoprost

Both drugs lower IOP pretty well during daytime hours, but latanoprost has better effect at night than timolol
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page12
This graph shows effects
of brimonodine treated
eyes vs. untreated eyes
At night, brimonodine vs.
untreated is the same
essentially
(Note that the graph may
be labeled incorrectly)
This graph shows add-on
efficacy. ALL patients here
are on letanoprost.
Black = letanoprost only
Red = letanoprost + azopt
Green = letanoprost + timolol
There is little added effect
with timolol, but azopt did
give some additional benefit
compared to letanoprost
alone
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page13
Summary:

IOP fluctuates throughout the day

IOP is usually highest in the overnight hours

A single measurement of IOP during office hours is truly insufficient for glaucoma management

The diagnosis and treatment of glaucoma should include measurement of IOP at various times throughout
the day/night, if possible
o
Ex. patients shouldn’t only come for appointments during lunch hour

Consider the effectiveness of anti-glaucoma medications lowering 24-hour IOP

The optimal way to estimate 24-hour IOP peak to enhance diagnosis and treatment of glaucoma is not
known
Pachymetry:

Obtain 3 readings on central cornea (i.e. CCT)
o

Remember that cornea is thinnest in the center and thickens towards periphery
Enter the average of the 3 readings into NextGen
o
Each reading actually takes 25 individual measurements
Corneal Thickness and IOP Measurement:


Thinner corneas lead to lower Goldmann tonometry readings
o
Maybe ~2-7mm for every 100um change?
o
But highly variable  DON’T “CONVERT” VALUES
Potential Clinical Errors:
o
Patient diagnosed with normal tension glaucoma when truly primary open angle glaucoma (thin
cornea)
o
Patient diagnosed with ocular hypertension when truly normal (thick cornea)

CONVERSION CHARTS DON’T WORK  they can only make a weak, generalized estimation

“Assuming that CCT can be used as a correction factor for GAT is a misinterpretation of the results of
OHTH…that couldn’t be further from the truth. Adjusting IOP based on CCT is attempting to instill a degree
of precision into a flawed measurement. You may actually correct in the wrong direction. The issues related
to the most accurate tonometry need to include the material properties of the cornea.“

IOP and the Cornea:
o
“As we learn more about corneal biomechanics, we realized that there is a lot more to
understanding the cornea than simple pachymetry.”
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page14
Why measure pachymetry?

Primarily use per OHTS study findings:
o
Determine the “RISK” of a patient with OHTN of going on to develop glaucoma
o
Can determine low, average, or high risk
The Ocular Hypertension Treatment Study (OHTS):

First (and only) rock solid evidence that lowering IOP in patients with OHTN (24-32 mmHg) reduces the risk
of developing POAG for some individuals
o

POAG def = repeatable VF defect or ONH change
Prior to this, it was just assumed that all patients with OHTN should be treated
o
All of these patients were treated even if there were no glaucomatous changes
o
Consider the “costs” of treating everyone

Money spent when not necessary

There are potential side effects
 Objective:
o
To determine whether topical hypotensive medication can delay or prevent the onset of POAG in
patients with ocular hypertension and assess the safety of topical hypotensive medication.

Patients and Methods:
o
Five-year longitudinal, multicenter, randomized controlled trial
o
N = 1636 patients
o
IOP ranging from 24 to 32 mmHg in one eye and 21 to 32 mmHg in the other eye

Followed patients with high eye pressures over time

These were patients who didn’t have any indications of glaucomatous damage
o
Patients randomized to observation alone vs. topical medications
o
Target IOP of <= 24 mmHg and at least 20% reduction in IOP from baseline

If a 20% reduction was not under 24 mmHg, continued to lower it until under 24 mmHg

If a 20% reduction was enough to bring the IOP under 24 mmHg, stopped there
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page15
- Plotting time over patients
developing glaucoma
- Red arrow = 5 year mark
Can see that as time went on,
there is a difference between the
groups. Smaller percentage of
patients who developed glaucoma
in the medication treatment group
(vs. observation only group)
Reduce risk of OHTN patient
developing glaucoma at 5 years
by 50% via treatment
Same information as the above
graph, different layout
Should also note that over 5
years, only 10% of patients with
OHTN developed glaucoma. If
you treat everybody with high eye
pressure, you are treating 9/10
patients unnecessarily. This is
where risk assessment comes in;
trying to evaluate who needs to
treatment and who doesn’t.
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar

Date: 03/09/2016, 1st hour
Page16
OHTS and Corneal Thickness:
o
For all IOPs, a thinner cornea increased the risk of developing glaucoma at 5 years
CCT (microns)
IOP
<555
>555-<588
>588
>25.75
36%
13%
6%
>23.75-<23.75
12%
10%
7%
<23.75
17%
9%
2%
o
Shows the risk or rate of progression to glaucoma of patients in the different categories of corneal
thickness and IOPs

o
Thin CCT & high IOP  high chance of developing glaucoma in 5 years
o
Thick CCT & high IOP  much lower risk of developing glaucoma in 5 years
BIG FOUR Risk Factors for OHTS Data:
o
Age  20-40% increase per decade

Ex. patient who is 70 years old has a 20-40% increased risk of developing glaucoma
compared to 60 year old

o
IOP  >26 mmHg
o
Vertical C/D  >0.5
o
CCT  <= 555um
OHTS Results & Conclusions:
o
In patients with elevated IOP, topical ocular hypotensive treatment was effective in delaying the
probability of onset of POAG
o
For patients with a moderate to high risk of developing POAG, IOP-lowering treatment should be
considered. This does not imply that all borderline or elevated IOP patients should receive
treatment.
o

Some predictors of developing POAG were found to be:

Baseline IOP

Age

Vertical cup-to-disc ratio, and lower central corneal thickness
Note that we also need to keep in mind other risk factors not included in this study (family history, high
myopia, diabetes, etc)  these are all things you would also want to take into consideration
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar

Date: 03/09/2016, 1st hour
Page17
OHTS & CCT 3 Outcomes: MEMORIZE THIS!
o
Applies to patients with ocular hypertension
o
Suggests that there is a slight protective value to having a thicker cornea
Thin
<555um
High risk
Average
555-588um
No change in risk
Thick
>588um
Low risk
Case EG:

67 year old male
o


Systemic History:
o
Negative for diabetes/hypertension
o
No medications
Ocular History:
o

Retired school teacher, excellent compliance with follow up care and treatment
Unremarkable
Family history:
o
Positive for glaucoma
o
Important tips for clinic:

It is important to find out WHO has glaucoma (i.e. aunt, mom, dad, sister, etc)

Also make sure that the patient doesn’t mean that someone in there family had cataracts
(these are often confused by patients)

Slit Lamp  normal anterior segment. 4+ VH angles

IOP = 30 mmHg OD; 28 mmHg OS

Gonio  open to CB 360 OU
o
Need to do before being able to make a diagnosis of open angle glaucoma
o
Indications for gonio = narrow VH angle, asymmetrical IOPs (even if both normal), elevated IOPs

CCT = 540um OD, 558 um OS

Optic nerves look healthy

Visual fields look normal (no glaucomatous patterns)

Plug patient’s information into OHTS calculator (see image below)
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page18
o
Ideally you want to use three different IOPs from three different visits
o
Pattern Standard Deviation is from visual field testing
o
This patient’s risk of developing glaucoma in 5 years (based on OHTS) is ~19%

Wouldn’t do this on glaucoma suspect patients who do NOT have high IOPs because that
is not the population used in OHTS

Results & Discussion:
o
These are suggested guidelines only, treat every case individually

Must consider other factors

Ex. 97 year old patient who is sickly whose life expectancy is not much longer

Probably don’t want to add to their medication burden when their IOP is not
going to create blindness for another 3 years

Have a conversation with your patient. Let them know what there risks are, importance of
monitoring and re-assessing. Repeat calculation over time.
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Questions: (things to think about)

Does this patient have OHTN or glaucoma?

Do you want/need additional information?
o

What? What do you think you’ll find?
Does this patient need treatment?
o
When to start?
o
What options for treatment?
o
What is the follow-up time period?
Date: 03/09/2016, 1st hour
Page19
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page20
Value of IOP:

There is no “safe” IOP in glaucoma
o
Continuous monitoring of the visual field and optic nerve head are required of any IOP

Used to identify effectiveness of medications

A marker to be followed over time

30-50% of all undiagnosed glaucoma patients will be seen in a “general” eye exam with an IOP below
21mmHg, by virtue of normal IOP flux above and below 21

Tt is important, but it is JUST one test and one risk factor
Most Prominent & Consistent Risk Factors for Glaucoma:


Ocular Hypertension Treatment Study (OHTS)
o
CCT of less than 555 microns has higher risk
o
IOP  every 1mmHg higher (>22) increased risk by 10%
Early Manifest Glaucoma Triel (EMGT)
o

Advanced Glaucoma Intervention Trial (AGIS)
o

Every 1mmHg of IOP reduction lowers risk of progression by 10%
IOP always under 18mmHg or a mean of 12mmHg has a lower risk of progression
Collaborative Normal-Tension Glaucoma Study
o
30% reduction of IOP reduces risk of progression
Clicker Questions from 1st Hour:
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page21
ANSWER: B
ANSWER: B
ANSWER: D
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page22
ANSWER: C, E, F
ANSWER: B
ANSWER: A & D
BHS263.2 – Ocular Disease II
Notetaker: Ekjot Brar
Date: 03/09/2016, 1st hour
Page23
ANSWER: A
ANSWER: C