Correlation Between Intraocular pressure(IOP)and Intracranial pressure(ICP) inDog

Alireza Sheikhi M.D
Under super vision of
EhsanAli Aliby M.D and
M.Mehdizadeh,M.D
 Neuroscience Research Center
Department of Neurosurgery
Poostchi Eye Research Center
Department of Ophthalmology
Shiraz university of medical sciences

 1-1: optic nerve
 Optic nerve is the second pair of the cranial nerves in
the human and overall it is considered as the parts of
central nervous system.
 It is surrounded by all three meningial layers. In the
other word , optic nerve is a part of brain which is
extending into the periphery and it covers as it in the
brain tissue. (1, 2)
 Overall the optic nerve has four anatomical parts: the
intraocular, intra orbital, intra canalicular, and intra
cranial sections. (2)

 1-2: Intra ocular pressure
 Intra ocular pressure (IOP) is the pressure of fluid inside the
eyes. (3, 4) the fluid is produced by aqueous humor and
drainage from trabeclar meshwork which is located in the
anterior chamber angle. The pressure is also influenced by
thickness and rigidity of corneal.
 Tonometer is an acceptable method for measurement of IOP.
Normal IOP is defined between 10 mmHg up to 20 mmHg.
(Average of 15.5) (3, 4)
 With considering of direct connection of optic nerve and brain
tissue, it is acceptable to think about the possible correlation
between intraocular pressures in the globe and intra cranial
pressure in the brain.

 1-3: Intra Cranial Pressure
 Intracranial pressure (ICP) is the fluid pressure
inside the skull and on the brain tissue. The
pressure is mainly controlled by balance in the
production and absorption of fluid. CSF produced
by choroid plexus and the brain float in it.
 (5) ICP is normally varied between 7-20 mmHg in
the supine position and became negative in the
vertical position. (6,7)

 There is several mechanism of increasing in ICP,
mass effects of tumors or abscess can directly
cause increasing in ICP. Increase in CSF production
in meningitis, idiopathic intracranial hypertension
is the other cause. (6)
 Headache, nausea and vomiting are most important
symptoms in increasing in ICP. Altered level of
consciousness and papilledema are the signs that
detected in physical examination. An edemas optic
nerve is a helpful sign that shows the ICP elevation.
(7, 8)


 1-4: Lamina cribrosa
 Lamina cribrosa works as a junction between intra
cranial and intra ocular compartments. It is a Mesh-
like structure. This structure formed by several layers
which is containing of collagen fibers.
 The optic nerve fibers exit the eye ball through this
sclera hole in the posterior part of the globe. It is
helps to maintain the pressure gradient among the
eye tissues and surrounding parts. By increase in the
intraocular pressure this component bulges outward,
this bulging and pressure effect on the optic nerve is
considered as an important pathology in glaucoma
and other disease with increasing IOP. (9)

 1_5:CSF pressure may be equivalent to IOP in
its influence on laminar pressure gradient
and optic disk surface movement.
 The correlation of IOP and ICP was based
partly to both anatomical and physiological
connection between intracranial fossa in one
hand and orbit in the other hand, considering
with the compression of posterior globe by
neuro imaging in some patients with
increased ICP.

 1_6:The direct connection of optic nerve and the
brain tissue suggests that there should be a possible
correlation between IOP in the globe and ICP in the
brain, lamina cribrosa works as a junction between
these two compartments and it may play an unknown
role in this relation.
 In the other word, both CSF pressure and IOP
influence the laminar pressure gradient in and
consequently on the optic disk surface movement.
The influence of CSF pressure affects the axonal
transport, which is known to be important in
glaucoma process.


 1_7:Based on the detection of posterior
compression of the globe in some patients with
increased ICP in neuro imaging studies, the
balance between the CSF pressure around the
optic nerve and the IOP in the globe may change
the position of the lamina cribrosa.
 So papilledema may be the results of imbalance
between ICP and IOP that leads to bowing of the
lamina cribrosa toward the less pressured
chamber, i.e. the vitreous cavity. (10)


 1_8:Posterior bowing of the lamina cribrosa known as
cupping in the glaucoma patients may be another
presentation of this imbalance.
 Accordingly, it was supposed that this compression of
posterior of glob may lead to a transient event that may
resemble as a temporary increase in IOP. The increase of
IOP would accordingly return to base line by any means
since IOP was controlled by numerous factors.
 The correlation between IOP and ICP still remains un-
clarified and there are controversies of presence of any
correlation between IOP and ICP. In this study we try to
investigate the effect of iatrogenic reduction of Intraocular
Pressure on Intracranial Pressure in dogs as animal
models.

Shiraz university of medical sciences

 1_1)Berdahl JP et al study in 2008
 Berdahl JP et al in 2008 via a case control study
tried to compare cerebrospinal fluid (CSF)
pressure in patients with primary open-angle
glaucoma (POAG) and with that in
nonglaucomatous patients.
 In this study between 1996 to 2007 Thirty-one
thousand, seven hundred and eighty-six subjects
were underwent lumbar puncture (LP)..

 The mean CSF pressure was 13.0+/-4.2 mmHg
in nonglaucomatc patients and 9.2+/-2.9 mmHg
in POAG patients (P<0.00005). The CSF pressure
was lower in POAG patients.
 Linear regression analysis showed that cup-to-
disc ratio was correlated independently with IOP
(P<0.001), CSF pressure (P<0.001), and the
Trans laminar pressure difference (P<0.001).
 On the other hand Multivariate analysis showed
that larger cup-to-disc ratio (P<0.001) was
associated with lower CSF pressure.

 Accordingly in his study the researchers
demonstrated that CSF pressure is
significantly lower in POAG patients in
compare with that in nonglaucomatous
controls.
 Their results support the notion that CSF
pressure may play an important contributory
role in the pathogenesis of POAG. (11)

 2_1)Dickerman RD et al study in 1998
 In the study of Dickerman RD et al in 1998 the
researchers tried to investigated that does Intra-
ocular pressure changes during maximal isometric
contraction reflect intra-cranial pressure or retinal
venous pressure or not.
 This study was started with review of the articles
which was evaluated the recent publications. The
researchers mentioned that the recent studies have
suggested IOP may be an indirect assessment of ICP.

 Both IOP and ICP have similar physiologic pressure
ranges and both have similar responses to changes in
intra-abdominal, intra-thoracic and aortic pressure.
 The researchers said that there are many reports that
showed the intracranial hemorrhage, subarachnoid
hemorrhage, retinal hemorrhage and retinal
detachment are associated with weight lifting but
there are no human study which examined the IOP
changes during heavy exercises and weight lifting.
 So they tried to investigate the IOP changes during
maximal isometric contraction.

 In this study Intra-ocular pressure was measured
by noncontact tonometry at rest and during
maximal isometric contraction.
 All subjects IOP were within normal ranges
(mean 13 +/- 2.8 mmHg) at rest but it was
significantly (p < 0.0001) elevated in each
subject during maximal contraction (mean 28
+/- 9.3 mmHg).
 Linear regression analysis showed a significant
linear relationship (r = 0.62, p < 0.0001) in the
net change of IOP from rest to maximal
contraction for each subject.

 Their study demonstrates that IOP elevates to
pathophysiologic levels during resistance
exercise. The increased pressures generated
by power athletes during weightlifting may
leads to elevations in ICP which obstruct
venous outflow leading to hemorrhage and
elevations in IOP. (12).

 Sajjadi SA et al study in 2006
 In the study which was done on 2006 in Tehran
university sajjadi et al evaluated the correlation
between ICP and IOP. Their study was performed on
77 patients. The patients who had any history of
glaucoma, using drugs which affected IOP and
abnormal ocular finding were excluded from the
study.
 ICP of the other patients was measured by LP and
IOP was measured by two scales of Schiotz tonometer
in both eyes and the mean was calculated. Finally
they found a significant correlation between IOP and
ICP. (13)

 Sheeran P et al study in 2000
 In the study which was performed at 2000 by
Sheeran P et al they demonstrated that
although there is a significant correlation
between intraocular pressure and intracranial
pressure in neurosurgical patients, change in
intraocular pressure is a poor predictor of
change in intracranial pressure. (14)

Han Y, et al study in 2008
 On the other hand Han Y, et al in 2008 showed there
isn’t any correlation between intraocular pressure and
intracranial pressure.
 They reviewed the medical records of all patients
who underwent lumbar puncture between 1991 and
2007 in the neuro-ophthalmology clinic of the
University of California San Francisco. Data for IOP
and ICP were available for 55 patients. But they didn’t
find any correlation between IOP and ICP (Pearson
correlation coefficient, r = 0.07; p = 0.59) and
accordingly mentioned that IOP measurement is not a
useful substitute for ICP measurement. (15)

 1_The mentioned studies had several
limitations for example some of these studies
was performed only patients with both
glaucoma and neurological problem
necessitate lumber puncture that may affect
the results of study by some unexpected
biases.

 2_Nowadays, the subject of any correlation
between IOP and ICP remains as a
sophisticated puzzle to be resolved.
 Since there is no animal model study in the
literature, as a first experience in the world,
the present study was designed to evaluate
any relation of IOP and ICP under controlled
experimental condition by inducing iatrogenic
reduction of IOP in normal eyes and healthy
animals and measurement of ICP in response

 1-1;Fifteen matured healthy out-bred dogs (
mean: 10 kg) provided from laboratory animal
center related to shiraz university of medical
sciences , were enrolled. The study was approved
in the university ethic committee and all
procedures were performed in accordance to
ARVO statement for the use of animals.

 In the supine position all the dogs underwent
general anesthesia using Nesdonal (Sandoz,
Gmbh , Kundl, Austria )

 1-2:The mean IOP was recorded by double
measurements in both eyes and considered as a
primary IOP. The animals were allocated to three
groups. Group 1 received Timolol ( Timolol sina
darou) one drop each 12 hours, As topical anti
glaucoma medication only in the right eye.
 Group 2, received latanoprost (Xalatan , Farmacin ,
Belgium) ; one drop once a day. And group 3
underwent Trabeculectomy in the right eye to reduce
IOP. The IOP was determine using tonopen (Roichert
TONO-PEN XL Applanation) for both eyes except for
group 3 where the mean pressure was recorded by
double measurement of IOP in the right eye . (Table
3-1)

 1_3:To measure the ICP, the hairs were
clipped in the back of the head and the neck
area of the dogs. For cerebromedullary
approach, the land mark for midline position
( the occipital protuberance) was marked and
the neck of the animal was positioned in
hands and flexed up to optimal position for
palpation of the space .

 1_4:A 22 gauge needle was inserted in
midline near the cranial borders of the wing
of atlas. (C1)When a slight loss of resistance
was determined the needle was inserted
further. A 3 way tube was connected to the
needle and when a flow of CSF was observed
in the tube, the CSF pressure was measured
against a water column.

Table 3-1: type of intervention in each group
Groups Type of intervention in
right eye
Group 1 Timolol drop 0.5% twice a
day
Group 2 Latanoprest(xalatan )drop
daily
Group 3 Trabeculectomy operation

1_6:Trabeculectomy
 Trabeculectomy was performed using Watson’s
modification of the Cairns technique (16) first, a
limbus-based conjuctival flap was prepared, the
sclera was exposed and a rectangular 3*4 mm
sclera flap was made. Then a 1 mm sclerosomy
was made followed by peripheral iridectomy and
finally the conjunctiva was closed with a
continuous 10-0 nylon suture.

 1_7:In the same manner, after 2 and 4 weeks
of drug administration or surgical procedure,
the IOP was measured with tonopen in the
right eye. The procedure was similarly carried
out four weeks later.

 1_8:To show the correlation between IOP and
ICP, all results were sorted while ignoring the
methods of reduction of IOP and also the
time of measurements.
 All the dogs underwent a same method of
anesthesia, and measurement of IOP and ICP
was the same in all groups so bias effect of
these materials will be at least.

 1_9:An analysis of variables with repeated measure
design was used to determine changes in parameters
over time (day 0, 14, and 28). An independent t-test
was used to determine possible differences in various
parameters in IOP and ICP on day 0, 14, and 28.
 Pearson correlation coefficient was used to
determine the strength of the relationship existing
among various parameters. On the other hand we
used General linear model to evaluate ghanges in
each group separately.
 The data were analyzed, using the statistical package
for social science series (SPSS 15.0) and p≤ 0.05 was
considered as significant.

 1_1:There were 15 skeletally mature healthy dogs
enrolled in this study .All dogs were remained
lived till end of study .The overall mean age was
2.1years± 0.28 (range: 1.5-2.5 years) with a
mean weight of 17.5 ± 1.18 kg (16-19 kg).
 The mean primary IOP was 20.40± 4.70 and that
of ICP was 7.46± 2.09. As is shown in table 4-1
dogs randomly allocated in 3 groups were
matched in terms of weight, age, and also in
both primary IOP and ICP. (Table 4-1)

Groups Age Weight Primary IOP Primary ICP
Group A 2-2.5
2.2± 0.27
16-19
17±1.41
15-27
22.80±4.71
5-9
6.6±1.81
Group B 1.5-2
1.90±0.22
16-19
17.8±1.09
15-27
21.8±4.65
5-10
7.6±2.07
Group C 2-2.5
2.20±0.27
16-19
17.7±1.09
14-20
16.6±2.40
5-10
8.2±2.48
P value 3.65 1.01 4.76 1.90
Table4-1: primary
measurements of the
parameters

 1_3:According to drug administration and
trabeculectomy to changes IOP and
subsequently evaluate changes in ICP
multiple liner repeated measurement was
performed that showed statistically
considerable deference in IOP after drug
administration for 2 weeks and even after 4
weeks indicative of effective application of
drugs and confirmed the study to full fill our
idea (Table 4-2, figure 4-1).

Groups
IOP
Primary IOP IOP after 2
weeks of drug
administration
IOP after 4
weeks of drug
administration
P value
Group A 15-27
22.80±4.71
10-19
16.2 ±3.70
10-18
14.8±3.27
0.003
Group B 15-27
21.8±4.65
10-18
14.2±3.89
9-14
11.4±2.40
0.00
Group C 14-20
16.6±2.40
3-6
4.4±1.14
3-5
4±0.70
0.00
Table 4-2: secondary
measurements of the
parameters

0
5
10
15
20
25
30
Intera Ocular Pressure
Intera Cranial Pressure
Prior to drug adminstration
or surgery
2 weeks after to drug
adminstration or surgery

0
5
10
15
20
25
30
Intera Cranial Pressure
Prior to drug adminstration
or surgery

0
2
4
6
8
10
12
14
16
18
20
0 5 10 15 20 25 30
InteraCranialPressure

 1_5:In this regard the correlation of primary
IOP and primary ICP was not statistically
significant ( 17.50 vs. 20.40; P Value:
0.95 ); however after 2 weeks these
measures become considerable ( 11.06
vs. 11.73 ; P value : 0.02 ) . Subsequently;
after 4 weeks again results were infavor of
considerable negative correlation of IOP and
ICP ( 10.06 vs. 11.83 ; P value: 0.02 ).

 1_6:On the other hand ; as we encounter with
statistically considerable correlation between
IOP and ICP in order to be able to make a
model for the relation we joined all the
results of IOP and ICP ignoring methods of
induced IOP changes and also time of
measurement in order to IOP in 45 samples .

 1_7:Therefore , according to Pearson
correlation analysis there was considerable
negative correlation between IOP ( v= -0.67 ;
P value =0.00 )(fig. 4-5) .As was shown in
table 3 , felting a multiple regression model
to the data , where ICP was the dependent
variable and IOP was the continuous predictor
variable and generated the model to show
correlation as follows:


 1_8:(^ICPi) =15.66 - 0.337 IOP, ( R2 =0.448 )
and according to the table 4 the regression
analysis acceptable statistically.

 Table 4-4: Measures was indicated that the regression analysis
acceptable statistically.
Model Un
standardiz
ed
coefficients
Standardiz
ed
coefficients
t Significant
Constant
IOP
B Std.Error Beta 242.034 34.939
15.066 0.890 -0.670 16.930 0.00
-0.337 0.057 -0.670 -5.911 0.00

icpiop
30
20
10
0
preiop
preicp
2 wk iop
2 wk icp
4 wk iop
4 wk icp

 1_1:According to what mentioned in the
introduction and review of the articles it
seems that the compression of posterior of
glob may led to a transient event which can
temporary causes increased in the IOP.
 In contrast IOP may have some effects in the
ICP. As the best of our knowledge IOP can
controlled by many factors in this study we
tried to investigate this relation and also the
effect of decreasing in the IOP on ICP.

 1_2:The relation of ICP and IOP is a subject of
controversy till now. Sajjadi and colleagues
claimed that there was a strong positive
correlation between IOP and ICP (r= 0.955)
and introduced IOP measurement as a reliable
non invasive procedure for evaluation of ICP
in patients with neurosurgical problems.

 1_3:The mechanism painted out by Saladin et al
for direct correlation of IOP and ICP was
attributed to the anatomical and physiological
connection between intracranial fosse and orbit
by detection of the compression of posterior
globe by neuro imaging in some patients with
increased ICP ; however , as was mentioned this
rising of IOP if actually happened was only a
transient event with rapid reversal to baseline
since there was no increasing of IOP was
observed in response to increase of ICP in other
studies.

 1_4:One of them was the study was designed by
Han Y, et al 2008 on records of 55 patients
underwent concomitant measurement IOP and
ICP between 1991 and 2007 in the neuro-
ophthalmology clinic at the University of
California San Francisco.
 Their results were indicative of no correlation
between IOP and ICP (Pearson correlation
coefficient, r = 0.07; p = 0.59)and they implied
that IOP measurement is not a useful substitute
for ICP measurement.

 1_5:As a promising new finding was Berdahl et al
study which was the new detection of low CSF
pressure in patients with open angle glaucoma
and they suggested that low CSF Pressure may
work in concert with IOP to produce an
unacceptably high Tran laminar pressure
gradient (a pressure difference across the lamina
cribrosa), .
 they introduced this event as a disrupting
pathway for retinal ganglion cell axoplasmic flow,
ultimately leading to retinal ganglion cell
apoptosis and visual loss in patients with
glaucoma.

 1_6:Since then many letters are published
giving variable arguments on the results of
this study and to finding a way for
interpretation of their results.
 One of the pitfall points pertained to that
study was the selection of patients with
neurological problem which may have
confounding effect and can be considered as
an obstacle to generalize the results to all
conditions.

 1_7:The present study was the first animal model
study to show the pattern of correlation of ICP in
response to iatrogenic reduction of IOP in healthy
mature dogs. The superiority of this study to
others is the selection of normal eyes to be
enabled to measure purely the effect of IOP on
ICP.
 Since IOP can be changed in stressful conditions
even in animals and also to measure both IOP
and ICP in all subjected in a similar stable
condition all dogs were received general
anesthesia and measurements began in a
moments after intubations .

 1_8:We refused to use Ketamin as a known
drug to affect IOP and ICP.
 Instead we use pento barbital and we
consumed that since we measured all
parameters in all dogs in the same condition
with the same medication any possible
confounding effect of anesthesia would be
eliminated.

 1_9:Also, two different drugs with different
mechanisms for reduction of IOP as well as
surgical procedure with another alternate
mechanism for lowering IOP was used to
overcome other possible biases in this study.
 Our results were confirmed the subject
reported by Berdahl et al in a way that IOP
was correlated with ICP with a statistically
significant negative standardize coefficient i.e
about – 0.67 , pv =0.00

 1_10:Also the regression formula estimated
this relation to be ^ICPi = 15.06 – 0.337 IOP
(R² =0.448).The question to be addressed in
this subject is the mechanism this relation
could be interpreted as was expected by
Berdahl et al study.

 1_11:There might be some unknown
receptors in the lamina crirosa that function
as detectors of any changes in both IOP and
ICP. Their attempts will be toward
measurements of the sum of IOP and ICP to
be constant.

 1_12:Therefore, any reduction or elevation in
pressure of IOP or ICP would result in the
inverse changes of the counterpart to hold
this summation unchanged.
 In the other words, in a case of glaucoma,
while the receptors detected high IOP , they
work toward reduction of IOP but because of
the presence of malfunction and pathology
behind glaucoma process , they could reduce
only in ICP.

 1_13:Conversely, in the patients with low IOP,
their activation would result in an increase in
ICP. The same mechanism will work toward
any reduction in IOP as shown in this study.

 1_14:In conclusion, there was a negative
linear correlation between IOP and ICP when
the multiple regression formula was applied
to make a model.
 As reduction of IOP in a single eye
considerably affected ICP, it is reasonable
that changes in IOP in both eyes may have
more effects on ICP.

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Correlation Between Intraocular pressure(IOP)and Intracranial pressure(ICP) inDog

Correlation Between Intraocular pressure(IOP)and Intracranial pressure(ICP) inDog

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