E.q. Eye Res.
`
`(1984)
`
`39, 807-829
`
`of the Eye to Irritation
`in the Responses
`Species Differences
`and Trauma:
`a Hypothesis
`of Divergence
`in Ocular Defense
`Mechanisms,
`and
`the Choice of Experimental
`Animals
`for
`Eye Research
`
`LASZLO
`
`Z.BITO
`
`Eye Research Division,
`College of Physicians
`
`University,
`Columbia
`of Ophthalmology,
`Department
`and Surgeons, New Yorlc, New York 10032, U.S.A.
`
`(Received 2 April
`
`1984 and accepted 27 July 1984, New York)
`
`identified
`has
`decade,
`last
`the
`especially
`century,
`past
`the
`during
`published
`Information
`structures,
`of ocular
`organization
`in
`the morphological
`not only
`species differences,
`pronounced
`and surgical
`but also
`in the
`functional
`responses
`of the eyes of different
`mammals
`to experimental
`have
`been
`procedures,
`as well as to drugs
`and autacoids.
`For
`the most
`part,
`these differences
`adaptations
`regarded
`as peculiarities
`or weaknesses
`rather
`than
`as fundamental
`evolutionary
`a working
`optimally
`suited
`to
`the environment
`and behavior
`of each species. This paper
`proposes
`hypothesis
`of evolutionary
`divergence
`in ocular
`defense mechanisms,
`based on some of the known
`morphological
`and
`functional
`differences
`among mammals,
`and discusses
`the
`implications
`of these
`differences
`regard
`to
`the choice of appropriate
`animals
`for use as models
`in different
`areas
`of ophthalmic
`research.
`; paracentesis
`; protein
`humor
`; aqueous
`; primates
`; rabbit
`Key words
`; eye
`; mammals
`barrier
`; Schlemm’s
`canal
`; prostaglandins
`; blood-aqueous
`inflammation
`; axon
`refiex
`meshwork;
`episcleral
`venous
`pressure;
`conjunctival
`hyperemia;
`miosis.
`
`; irritation
`; trabecular
`
`with
`
`;
`
`Introduction
`
`processes
`visual
`and central
`electrophysiology
`of retinal
`of our understanding
`Much
`of species,
`including
`from studies on a variety
`in mammals
`has been derived
`primates.
`However,
`the rabbit
`has been used primarily,
`if not exclusively,
`in most other areas
`of ocular
`research,
`including
`studies
`on aqueous
`humor
`homeostasis
`and dynamics,
`and on the effects of potential
`ophthalmic
`drugs. This
`is particularly
`surprising
`in light
`of the generally
`accepted
`view
`that
`this species has an atypically
`labile blood-aqueous
`barrier
`(BAB).
`Indeed,
`it is virtually
`impossible
`to perform
`experimental
`procedures
`on the rabbit
`eye without
`inducing
`a so-called
`ocular
`irritative
`response
`that
`includes,
`in addition
`to BAB breakdown,
`pupillary
`miosis,
`increased
`intraocular
`pressure
`(IOP),
`and anterior
`uveal hyperemia
`(Duke-Elder
`and Duke-Elder,
`1931; Davson and Huber,
`1950; Perkins,
`1957; Sears, 1960; Cole and Unger,
`1973; Eakins,
`1977).
`their
`Some
`investigators
`have attempted
`to minimize
`these effects by shortening
`experiments,
`by reducing
`the trauma
`by cannulation
`of the anterior
`chamber,
`caused
`by pretreating
`rabbits
`with
`drugs presumed
`to protect
`against
`BAB
`breakdown,
`or
`by using
`intravitreal
`rather
`than
`intracameral
`drug
`administration
`(Sears,
`1960;
`Neufeld,
`Jampol
`and Sears, 1972; Bito, Nichols
`and Baroody,
`1982). However,
`an
`
`‘Effects
`entitled
`lecture
`in my plenary
`this paper were presented
`in
`discussed
`the concepts
`Some of
`delivered
`to
`the Vth
`International
`Congress
`of Eye Research
`in
`of prostaglandins:
`a second
`look’,
`Eindhoven,
`The Netherlands,
`3-8 October
`1982. That
`congress
`provided
`my
`last opportunity
`to
`talk
`with David Cole about
`subjects
`of mutual
`interest.
`That and many of our previous
`discussions
`have played
`a significant
`role
`in
`the development
`of some of the concepts
`and hypotheses
`presented
`in
`this paper.
`David
`Cole’s death
`has silenced
`an important
`voice
`in ocular
`research,
`but his thoughts
`and publications
`will continue
`to stimulate
`and guide us.
`
`00144835/84/120807+23
`
`$03.00/O
`
`@ 1984 Academic
`
`Press
`
`Inc.
`
`(London)
`
`Limited
`
`Micro Labs Exhibit 1024
`
`

`

`808
`
`I,. %. 1317’0
`
`levels after
`is yet
`to br
`to varying
`changes
`of most)
`
`protein
`chamber
`in anterior
`increase
`an
`effective means of preventing
`of the
`rabbit
`eye
`chamber
`of the anterior
`paracentesis
`or cannulation
`achieved.
`Since BAB
`breakdown
`and other signs of ocular
`irritation
`occur
`degrees after virtually
`any manipulation
`of the rabbit
`eye, the consequent
`in intraocular
`fluid composition
`and dynamics
`greatly
`affect the interpretation
`experimental
`findings
`on the eye of this species.
`eye has
`for the mammalian
`The acceptance
`of the rabbit
`eye as a suitable model
`constitut’es
`apparently
`been based on the assumption
`that
`its sensitivity
`to irritation
`identical
`to
`only a quantitative
`difference
`in the expression
`of mechanisms
`that are
`those of other
`species.
`If this were
`the case, the extreme
`sensitivity
`of the rabbit
`eye
`might
`even offer an experimental
`advantage
`over
`the use of the much
`less sensitive
`and much more
`costly primate
`eye. However,
`there
`is no experimental
`evidence
`to
`support
`this assumption.
`This paper examines
`the possibility
`that,
`on the contrary.
`to
`there
`are qualitative
`species differences
`in
`the
`responses
`of mammalian
`eyes
`trauma-
`i.e.
`that
`evolutionary
`divergence
`has
`led
`to
`the
`development
`among
`mammals
`of different
`types of eyes that have different morphological
`and physiological
`arrangements
`and
`respond
`differently
`to trauma.
`
`Species
`
`Variations
`
`in
`
`the Responses
`
`of the Eye
`
`to Irritation
`
`topical
`after
`that shortly
`and Bito, 1983) showed
`(Klein
`study
`A recent comparative
`the anterior
`a pronounced
`flare developed
`in
`administration
`of nitrogen
`mustard,
`chamber
`of the
`rabbit
`eye and,
`to a lesser extent,
`in
`that of the guinea
`pig, This
`response was somewhat
`delayed
`and much
`less severe
`in the cat
`than
`in
`the
`rabbit
`eye. A similar
`development
`of flare was not observed
`in
`the eyes of ducks or owl
`monkeys.
`These
`findings
`are presented
`schematically
`in Fig.
`l(a).
`to the eyes
`A marked
`increase
`in IOP also
`followed
`nitrogen
`mustard
`application
`of rabbits,
`guinea
`pigs and cats; a smaller
`increase
`occurred
`in
`the eyes of ducks.
`However,
`no increase
`in IOP was observed within
`24 hr after application
`of the same
`dose of nitrogen mustard
`to the eyes of the owl monkeys
`[Fig.
`l(b)].
`In rabbits,
`the
`IOP
`increase was biphasic:
`two episodes
`of ocular
`hypertension
`were separated
`by a
`brief period
`of normal
`IOP or hypotension
`(Camras and Bito,
`1980a; Klein
`and Bito,
`1983).
`In guinea
`pigs,
`the
`IOP
`increase was also biphasic,
`but
`the
`initial
`increase was
`smaller
`and was not
`followed
`by a period of hypotension.
`Indomethacin
`pretreatment
`minimized
`both phases of the IOP
`rise in guinea pigs and ducks and reduced
`or blocked
`the second, but not
`the first hypertensive
`phase
`in rabbits.
`Indomethacin
`also reduced
`or delayed
`the hypotensive
`phase
`that
`followed
`the
`initial
`pressure
`in cats
`[Fig.
`rise
`1 (b)], and diminished
`the development
`of flare
`in rabbits
`and guinea
`pigs
`[Fig. 1 (a)].
`Although
`topically
`applied
`nitrogen mustard
`did not induce
`flare and had a striking
`lack of hypertensive
`effect on the
`IOP of owl monkeys,
`it produced
`profound
`pupillary
`miosis
`that could not be blocked
`by indomethacin
`pretreatment
`[Fig.
`l(c)]. There was
`also a miotic
`response
`in
`the eyes of rabbits
`and cats, which was more pronounced
`and more effectively
`blocked
`by indomethacin
`in the latter. The same doses of nitrogen
`mustard
`had no measurable miotic
`effect on the eyes of ducks or guinea pigs
`[Fig. 1 (c)].
`Even more
`striking
`species differences
`have been observed
`in
`the
`responses
`of
`vertebrate
`eyes to ionizing
`radiation.
`Exposure
`of the
`rabbit
`eye to as little
`as 250
`rads of X-ray
`caused
`severe BAB
`breakdown
`(Worgul,
`Bito
`and Merriam,
`1977)
`whereas
`doses
`four
`to 40 times greater
`did not produce
`a similar
`effect
`in the eyes of
`guinea
`pigs, cats, monkeys
`or chickens
`(Stetz and Bito,
`1978; Bito and Klein,
`1981).
`
`Micro Labs Exhibit 1024-2
`
`

`

`SPECIES
`
`DIFFERENCES
`
`IN OCULAR
`
`IRRITATIVE
`
`RESPOIL’SES
`
`809
`
`(a)
`
`Robbit
`
`Guinea
`
`pig
`
`cot
`
`Duck
`
`Owl monkey
`
`cl=::-
`
`Lil:
`
`-A:_‘-
`
`-.--
`
`<-:-
`
`INDO
`
`(bl
`
`Robbit
`
`Guinea
`
`pig
`
`cot
`
`Duck
`
`Owl monkey
`
`llJT:->.
`
`_e:lr:
`
`_R,_,,-&...
`
`or
`
`,
`
`oy46.-;4
`
`Time
`
`(hr)
`
`Rabbit
`
`Guinea
`
`pig
`
`cot
`
`Duck
`
`Owl monkey
`
`,NDO
`
`~~;‘-
`
`-.-.
`
`-~~,r
`
`. . . .
`
`-
`
`---------_
`
`L.
`
`representation
`I. Schematic
`FIG.
`after
`topical
`application
`of nitrogen
`(b)
`intraocular
`pressure;
`(c) pupil
`responses
`of animals
`that
`were
`indomethacin.
`(Based
`on previously
`
`responses within
`time course of ocular
`and
`of the extent
`of five vertebrates.
`to the cornea1
`surface
`mustard
`solution
`diameter.
`In each panel,
`the second
`row
`of graphs
`refers
`pretreated
`with
`a combination
`of systemic
`and
`topically
`published
`data: Camras
`and Bito.
`1980a,
`b; Klein
`and Bito,
`
`first 24 hr
`(a) Flare:
`to ocular
`applied
`1983.)
`
`the
`
`prostaglandins
`of the eye to exogenous
`reactions
`in the
`species variations
`Dramatic
`eye is the most sensitive
`of the species studied
`rabbit
`The
`have also been
`reported.
`so far and
`the primate
`eye the least sensitive,
`especially
`to the adverse effects of these
`autacoids
`(Bito,
`1984).
`demonstrate
`These observations
`Furthermore,
`the
`same
`irritants.
`to
`mediated
`by the same mechanism
`
`species
`that eyes of different
`even
`similar
`responses
`and/or
`autacoid(s).
`
`respond
`are not
`
`differently
`necessarily
`
`Species
`
`Variations
`
`in
`
`the Responses
`Aqueous
`Humor
`
`of the Eye
`
`to the Loss of
`
`differently
`respond
`that eyes of different mammals
`is also accumulating
`Evidence
`to the
`loss of aqueous
`humor. Anterior
`chamber
`paracentesis
`causes profound
`BAB
`breakdown
`in
`the
`rabbit,
`as demonstrated
`by the
`formation
`of a plasmoid
`aqueous
`
`Micro Labs Exhibit 1024-3
`
`

`

`of
`
`L. %. B ITO
`810
`of the ciliary
`leakiness
`demonstrable
`and morphologically
`and by physiologically
`breakdown
`processes
`(Kozart,
`1968; Unger, Cole and Hammond,
`1975). The barrier
`is evident
`primarily
`in the iridial
`portions
`of the ciliary processes of the rabbit
`(Wmelser
`and Pei, 1965; Kozart,
`1968), which
`are well developed
`in this species but are virtually
`nonexistent
`in primates
`(Prince,
`1964; Kozart,
`1968; Ohnishi
`and Tanaka,
`1981).
`In contrast,
`paracentesis-induced
`protein
`accumulation
`in the anterior
`chamber
`rhesus monkeys,
`and at least some of that
`in
`the anterior
`chamber
`of cynomolgus
`monkeys,
`occurs by reflux
`through
`Schlemm’s
`canal
`(Raviola,
`1974; Okisaka,
`1976;
`Bartels,
`Pederson,
`Gaasterland
`and Armaly,
`1979),
`a structure
`that
`is highly
`developed
`in primates,
`but which does not exist in the same form
`in rabbits
`(Duke-Elder
`and Wybar,
`1961; Tripathi,
`1974).
`.Although
`the existence
`of such a canalicular
`reflux
`mechanism
`has been questioned
`by some
`investigators,
`its feasibility
`is supported
`by
`numerous
`observations.
`For example,
`Dannheim
`and Barany
`(1968) demonstrated
`reverse
`flow
`through
`the meshwork
`at a rate of 15-18 ~1 min-’
`in some primates
`when
`the
`pressure
`in a reservoir
`connected
`to Schlemm’s
`canal was elevated
`515 mm Hg above
`that of the anterior
`chamber.
`Furthermore,
`when
`IOP
`falls below
`the episcleral
`venous pressure,
`the lumen
`of Schlemm’s
`canal
`is greatly
`expanded
`and
`contains
`red blood
`cells
`(Johnstone
`and Grant,
`1973; Bill,
`1977; Moses, 1979).
`Although
`Raviola
`(1974, 1977) concluded
`that
`the ciliary
`processes are unaffected
`by paracentesis
`in rhesus monkeys,
`others
`(Okisaka,
`1976; Bartels
`et al., 1979) have
`reported
`that, after paracentesis
`in primates,
`plasma
`proteins
`enter
`the ocular
`fluids
`not only by reflux
`through
`Schlemm’s
`canal, but
`through
`the ciliary processes as well.
`However,
`in contrast
`to the diffuse morphological
`changes
`that occur
`in the
`iridial
`ciliary processes of the rabbit
`eye after paracentesis,
`which
`suggest autacoid-mediated
`BAB breakdown
`(Laties, Neufeld, Vegge and Sears, 1976),
`the morphological
`changes
`in the ciliary
`processes of rhesus eyes after paracentesis
`have been described
`as being
`consistent
`with mechanical
`trauma
`associated
`with
`rapid decompression
`of the globe
`(Pederson, MacLellan
`and Gaasterland,
`1978). Like
`reflux ofplasma
`through
`Schlemm’s
`canal, such decompression-induced
`breakdown
`of the ciliary
`processes could occur
`nature
`only after substantial
`amounts
`of aqueous
`humor
`had been
`lost.
`and
`The stability
`of the primate
`BAB
`is indeed
`impressive.
`For example, Ohnishi
`Tanaka
`(1981) apparently
`had
`to perform
`paracentesis
`on the eyes of rhesus monkeys
`four
`times
`in order
`to induce demonstrable
`damage
`to the ciliary processes. Even
`then,
`the most affected
`region
`of the ciliary
`body showed
`only selective
`breakdown
`of tight
`junctions,
`and the total damage
`appeared
`to be less than
`that observed
`in rabbits
`after
`a single
`paracentesis.
`The existence
`of such species differences
`in ocular
`defense
`mechanisms
`is further
`supported
`by the observation
`that pretreatment
`with doses of
`cyclooxygenase
`inhibitors,
`which
`reduced
`the development
`of flare
`in rabbits,
`failed
`to do so in rhesus monkeys
`(Kass, Neufeld
`and Sears, 1975). Therefore,
`the highly
`developed
`BAB
`breakdown
`mechanism
`of the
`rabbit
`eye appears
`to be nonexistent
`or vestigial
`in primates.
`eye
`the human
`expect
`we would
`grounds,
`and morphological
`On both phylogenetic
`with
`regard
`to its BAB
`stability
`primates
`to be similar
`to the eyes of other anthropoid
`is supported
`by several
`observations.
`and
`responses
`to
`trauma.
`This
`conclusion
`the protein
`concentration
`in the human
`Kronfeld,
`Lin and Luo
`(1941)
`reported
`that
`aqueous
`humor
`did not
`increase
`after sham paracentesis
`(the bulbar
`conjunctiva
`was
`grasped with
`forceps and
`the cornea was punctured)
`or even after 75 y0 of the aqueous
`volume was withdrawn
`and re-injected
`within
`10 sec. These observations
`indicate
`that
`prophylactic,
`or even decompression-induced
`BAB
`breakdown
`is not characteristic
`of
`
`in
`
`Micro Labs Exhibit 1024-4
`
`

`

`SPECIES
`
`DIFFERENCES
`
`IN OCULAR
`
`IRRITATIVE
`
`RESPONSES
`
`811
`
`the human
`conclusion
`chamber
`breakdown.
`will enter
`re-injection
`after
`the
`experiments
`concluded
`responses
`
`Raviola’s
`with
`consistent
`are
`findings
`these
`contrary,
`the
`eye. On
`in
`the anterior
`protein
`entry
`that,
`in primates,
`paracentesis-induced
`rather
`than as a result
`of BAB
`occurs by reflux
`through
`Schlemm’s
`canal
`considerable
`amounts
`of protein
`Clearly,
`once the BAB
`has broken
`down,
`the anterior
`chamber,
`even after normal
`IOP has been re-established
`by the
`of aqueous
`humor.
`In contrast,
`canalicular
`reflux will
`cease immediately
`IOP
`equals
`or exceeds
`the episcleral
`venous
`pressure.
`Based
`on
`their
`with
`laser
`irradiation
`of the
`iris, Unger, Brown
`and Edwards
`(1977) also
`that
`the human
`eye does not exhibit
`the pronounced
`and sudden
`irritative
`that are characteristic
`of the
`rabbit
`eye.
`
`The Apparent
`
`and Disadvantages
`Advantages
`Breakdown
`Mechanism
`
`of a Prophylactic
`
`BAB
`
`responses.
`irritation-induced
`that
`has shown
`decades
`recent
`during
`Research
`eye by complex mechanisms
`rabbit
`are mediated
`in the
`BAB
`breakdown,
`including
`1954; Perkins,
`1957; Cole,
`neuronal
`processes
`and autacoids
`(Maurice,
`involving
`1961a; Cole and Unger,
`1973; Unger, Cole and Bass, 1977; Eakins,
`1977; Camras
`and
`Bito,
`1980a, b). The
`development
`of
`these
`sophisticated
`mechanisms
`cannot
`be
`regarded
`either
`as accidental
`or as the
`result
`of structural
`weakness.
`Therefore,
`we
`must
`consider
`the possibility
`that
`the selective
`influences
`of certain
`habitats
`and
`behavioral
`adaptations
`have
`led,
`in some species,
`to
`the development
`of specific
`mechanisms
`for BAB
`breakdown
`while,
`in other
`species,
`different
`habitats
`and
`behavioral
`adaptations
`have
`led
`to
`the development
`of a more
`stable BAB
`and
`different mechanisms
`for protein
`entry
`into
`the anterior
`chamber.
`To support
`this
`hypothesis,
`it must be shown
`that a mechanism
`that
`facilitates
`BAB
`breakdown
`is
`advantageous
`to some species but disadvantageous
`to others.
`the
`entry
`The most pronounced
`effect of acute BAB
`breakdown
`is protein
`into
`introduction
`aqueous
`humor. One clear advantage
`of such protein
`entry
`is the
`the aqueous humor
`of a clotting mechanism
`which,
`in the event of cornea1 perforation,
`can minimize
`the
`loss of aqueous
`humor
`and
`facilitate
`re-formation
`of the anterior
`as
`chamber.
`Delivery
`of plasma
`proteins
`into
`the anterior
`chamber must be regarded
`part of a primary
`defense mechanism,
`since neither
`the cornea nor
`the aqueous
`humor
`has a continuously
`available
`clotting mechanism.
`It can be expected,
`therefore,
`that
`selection
`for mechanisms
`that
`facilitate
`the prophylactic
`breakdown
`of the BAB
`has
`occurred
`in species which,
`because
`of their morphological,
`behavioral,
`and environ-
`mental
`adaptations,
`are
`the most vulnerable
`to cornea1 perforation.
`is
`that
`system
`Some species, particularly
`grazing mammals,
`have evolved
`a visual
`1956). Such
`well
`suited
`for monitoring
`their
`environment
`for predators
`(Prince,
`monitoring
`requires
`a nearly
`spherical
`visual
`field, which
`can only be achieved
`by
`laterally
`placed,
`somewhat
`protruding,
`and hence,
`relatively
`unprotected
`globes.
`Clearly,
`a deep-seated
`orbit
`or a prominent
`brow
`ridge would
`block an animal’s
`view
`of predators
`approaching
`from
`the side or from overhead.
`of ocular
`and high degree
`Rabbits,
`with
`their
`shallow
`orbits,
`protruding
`globes,
`lateralization
`(Fig. 2) represent
`an extreme
`example
`of the monitoring
`type of eye
`(Prince,
`1956). The
`fact
`that
`rabbits
`typically
`inhabit
`an underbrush
`environment,
`makes
`their
`eyes especially
`vulnerable
`to mechanical
`trauma.
`However,
`the
`lack of
`external
`ocular
`defenses
`in rabbits
`appears
`to be fully compensated
`for by a highly
`developed
`and exceptionally
`sensitive
`intraocular
`defense mechanism.
`This conclusion
`
`into
`
`Micro Labs Exhibit 1024-5
`
`

`

`\
`
`- Rabbit
`
`k’
`
`Fro. 2. Species differences
`to accidental
`the globe
`of
`the exposure
`in
`angle of the visual
`axes of the eyes. The corresponding
`figures
`indicate
`provided
`for
`the globe by
`the bony
`orbit
`in different
`species
`(skulls
`Baaed on Prince (1956)
`See text
`for details.
`and
`other
`sources.
`
`trauma.
`the
`relative
`are not drawn
`
`The graph
`extent
`to
`the
`
`the
`depicts
`of protection
`same
`scale).
`
`or even
`of the cornea,
`irritation
`the
`that
`fact
`the well established
`by
`is supported
`which may not be an uncommon
`region,
`of nerves
`in
`the periocular
`stimulation
`for rabbits
`in the wild,
`is sufficient
`to produce miosis and BAB breakdown
`occurrence
`in this species
`(Maurice,
`1954; Perkins,
`1957).
`in visual acuity caused
`is the reduction
`An obvious disadvantage
`of BAB breakdown
`the anterior
`chamber
`in
`by the scattering
`of light
`by the elevated
`protein
`content
`visual acuity
`is normally
`(Hogan,
`Kimura
`and Thygeson,
`1959). However,
`because
`low
`in rabbits
`and other hunted
`species
`that have a monitoring
`type of visual system
`(Prince.
`1956; Duke-Elder,
`1958), occasional
`flare constitutes
`little or no evolutionary
`disadvantage
`for such
`species. On
`the whole,
`a sophisticated
`system
`of BAB
`than as a disadvantage
`breakdown
`may be regarded
`as an asset rather
`for rabbits
`and
`similarly
`adapted
`species.
`type
`depend on a searching
`primates,
`especially
`On the other hand, many mammals,
`and stereopsis
`are considered
`of visual system
`for their survival.
`Indeed,
`binocularity
`to be major aspects of primate
`adaptation
`(Walls,
`1963; Le Gras Clark,
`1971). Because
`it must
`interfere
`with normal
`binocularity
`and stereopsis,
`acute unilateral
`reduction
`in visual acuity must pose a special problem
`in most primates,
`undoubtedly
`hindering
`feeding
`in insectivorous
`primates
`(Cartmitl,
`1972) and having even graver consequences
`
`Micro Labs Exhibit 1024-6
`
`

`

`kjPE(‘IES
`
`DIFFERENCES
`
`IN OCULAR
`
`IRRITATIVE
`
`RESPONSES
`
`813
`
`when
`especially
`depth perception,
`loss of normal
`acute
`latter,
`In the
`ones.
`in arboreal
`would
`troops
`or by predators,
`by antagonistic
`being
`chased
`through
`a forest canopy
`any
`locomotion.
`Furthermore,
`decrease
`the chances of escape by hindering
`optimal
`loss of visual
`function
`would
`also
`increase
`the
`risk of injury
`or death
`in arboreal
`primates
`by increasing
`the chances of falling
`out of trees due
`to misjudgment
`of the
`position
`and/or
`size of branches
`that may or may not be suitable
`for arboreal
`locomotion.
`of cornea1
`the absence
`in
`breakdown
`BAB
`facilitate
`that
`Thus, mechanisms
`require
`high visual acuity
`that
`in species
`penetration
`must have been selected against
`in these species have
`led
`and stereopsis
`for their
`survival.
`Instead,
`selection
`processes
`including
`globes
`that are
`to the evolution
`of well developed
`external
`ocular
`defenses,
`deep-seated
`within
`bony orbits beneath
`prominent
`brow
`ridges
`(Fig. 2). Although
`these
`features
`guard
`against
`damage
`to the cornea,
`they must
`limit
`the visual
`field. This
`handicap
`is typically
`overcome
`in such species by socio-behavioral
`adaptations
`that
`allow
`collective
`surveillance
`of the environment
`by each extended
`family
`or social
`group.
`Mechanisms
`eye can be perforated.
`the cornea of even the best protected
`However,
`must
`therefore
`exist
`in all eyes, including
`the searching
`type of eyes of primates,
`for
`the rapid
`delivery
`of clotting
`factors
`into
`the anterior
`chamber.
`Although,
`as noted,
`a prophylactic
`BAB
`breakdown
`mechanism
`is apparently
`lacking
`or
`is not well
`developed
`in primates,
`protein
`entry can be achieved
`in these species by plasma
`reflux
`through
`Schlemm’s
`canal
`(Raviola.
`1974). However,
`such reflux
`can occur only after
`the
`IOP
`has
`fallen
`below
`the episcleral
`venous
`pressure
`(Bill,
`1980).
`Thus,
`the
`canalicular
`reflux mechanism
`should
`not be regarded
`as deleterious
`by itself.
`since
`rapid
`decompression
`of the globe and
`the
`resultant
`marked
`reduction
`of IOP can be
`expected
`to occur
`in nature
`only after cornea1 perforation
`or other major ocular
`t,rauma
`has already
`compromised
`visual acuity.
`chamber may be just one
`in the anterior
`It should be noted
`that prevention
`of flare
`defense mechanisms.
`The ciliary epithelia
`advantage
`of t,he primate
`type of intraocular
`(the plural
`is used advisedly,
`since
`this
`tissue should
`be regarded
`as being
`comprised
`of two separate
`epithelial
`layers) play
`important
`roles
`in keeping
`potentially
`harmful
`substances
`out of the eye and
`in removing
`such substances
`from
`the intraocular
`fluids.
`In
`fact.
`the
`riliary
`processes,
`together
`with
`retinal
`capillaries
`and
`the choroidal
`epithelium
`- generally,
`but
`incorrectly
`called
`the
`retinal
`pigment
`epithelium
`- have
`a critical
`function
`in the maintenance
`of the normal
`chemical milieu
`of the retina
`(Bito
`and DeRousseau,
`1980). Thus, breakdown
`of the BAB
`of t’he posterior
`chamber may
`also interfere
`with
`retinal
`function
`by altering
`the concentrations
`of solutes normally
`present
`in the
`intraocular
`fluids and allowing
`the entry of substances
`that are normalla
`of
`kept out’ of the eyes (Bito,
`1974).
`In contrast,
`the canalicular
`reflux mechanism
`primates
`delivers
`blood-borne
`substances
`directly
`into
`the anterior
`chamber,
`whence
`their diffusion
`toward
`the retina
`is minimized,
`and probably
`prevented
`by the iris and
`the
`lens.
`
`Presently
`
`Available
`
`Evidence
`
`in Support
`
`of the Hypothesis
`
`defense
`the ocular
`in
`divergence
`of evolutionary
`the hypothesis
`for
`Support
`among
`correlation
`of a positive
`on documentation
`of mammals
`depends
`mechanisms
`on visual acuity and BAB
`stability
`and a negative
`these species between
`dependence
`correlation
`between
`cornea1 vulnerability
`and BAB
`stability.
`The
`literature
`provides
`
`Micro Labs Exhibit 1024-7
`
`

`

`81-l
`
`I
`
`1
`
`
`
`7. 1
`
`Ii
`
`II’0
`
`that
`specks
`in those vertebrate
`of t’he BAB
`stability
`The relative
`such documentation.
`can be
`ranked
`as follows:
`rabbits
`< guinea
`pigs 6 cats < owl
`have been
`studied
`monkeys
`< rhesus monkeys
`< ducks < chickens
`(Stetz
`and Bito.
`197X; Klein
`and
`Bito,
`1983). This
`relationship
`generally
`corresponds
`to
`the
`ranking
`of vertebrates
`(Prince,
`1956: Duke-Elder,
`1958; Walls, 1963) according
`to their visual acuity and/or
`their dependence
`on visual
`function
`: grazing mammals
`< large carnivores
`< arboreal
`primates
`d birds of prey.
`the
`with
`species should also correlate
`The
`relative
`stability
`of the BAB of different
`is a measure
`of the degree of lateral
`angle between
`their
`visual axes, since
`this angle
`placement
`of the globes
`and
`is, therefore,
`indicative
`of cornea1
`vulnerability.
`The
`rabbit
`has by far
`the greatest
`ocular
`lateralization
`of all mammals
`studied
`to date.
`with an angle of almost
`180’ between
`its visual axes (Prihce,
`1956). Furthermore,
`this
`species has an unusually
`shallow
`orbit, which
`cannot effectively
`protect
`the globe. The
`angles between
`the visual axes of other mammals
`are much smaller,
`ranging
`from 140’
`in some grazing mammals
`to O”, the ultimate
`in binocularity
`and ocular
`protection.
`in man and most other primates
`(Fig. 2). According
`to the data collected
`by Prince
`(1956),
`this angle decreases
`in a distinct
`order:
`rabbits
`> goats > cattle > horses >
`pigs > dogs > cats > humans,
`and
`the skulls of these species have
`increasingly
`well
`developed
`and protective
`orbits
`(see also Fig. 2). Data on the relative
`stability
`of the
`BAB
`of all
`these species
`is not yet available;
`hence, exact correlations
`and possible
`exceptions
`are yet
`to be established.
`However,
`the extreme
`lateralization
`and
`vulnerability
`of the rabbit
`eye as compared
`to eyes of other mammals
`is consistent
`with
`the
`extreme
`sensitivity
`and
`sophistication
`of
`the
`internal
`ocular
`defense
`mechanisms
`of this species.
`
`The Possible Role of the Primate Type of Chamber Angle in Ocular
`Defense Mechanisms
`
`of
`in the complexity
`among mammals
`to be unique
`reputed
`are generally
`Primates
`are
`their chamber
`angle and aqueous humor
`outflow mechanism.
`Anthropoid
`primates
`the only species known
`to have
`true Schlemm’s
`canals, as well as highly
`developed
`trabecular
`meshworks
`and scleral
`spurs, and
`to exhibit
`a sophisticated
`functional
`relationship
`between
`their
`ciliary muscles
`and
`their
`conventional
`and uveoscleral
`outflow mechanisms
`(Barany,
`1967; Rohen,
`Lutjen
`and Barany,
`1967: Tripathi,
`1974:
`Bill, 1975). The
`IOP and
`the rate of aqueous
`humor
`turnover
`relative
`to the aqueous
`humor
`volume
`are, however,
`remarkably
`similar
`in the eyes of all mammals
`studied.
`even
`in such diverse
`species as rabbits
`and primates
`(Cole, 1974a). Thus, differences
`in
`the
`rate of outflow,
`or
`in
`the
`required
`resistance
`to outflow,
`cannot
`explain
`the
`pronounced
`species differences
`in
`the
`functional
`morphology
`and complexity
`of the
`chamber
`angle. We must,
`therefore,
`consider
`the possibility
`that
`these differences
`in
`the chamber
`angle are, at least
`in part,
`the consequence
`of evolutionary
`divergence
`in ocular
`defense mechanisms.
`the
`that characterizes
`structures
`of sinusoid
`The dead-end
`system of small segments
`1974).
`1964; Tripathi,
`(Prince,
`the
`rabbit
`chamber
`angle of some species,
`including
`into
`the
`reflux of plasma proteins
`effective
`does not appear
`to be capable
`of providing
`anterior
`chamber.
`Such small segments would
`be filled with
`red blood
`cells after
`just
`a few microliters
`of plasma
`had
`filtered
`through,
`hindering
`further
`passage of plasma
`proteins
`into
`the
`trabecular
`meshwork.
`On
`the other
`hand,
`the
`complex,
`well
`developed
`Schlemm’s
`canal, which
`covers 360” of the cornea-scleral
`junction
`the
`
`in
`
`Micro Labs Exhibit 1024-8
`
`

`

`SPECIES
`
`DIFFERENCES
`
`IN OCULAR
`
`IRRITATIVE
`
`RESPOR’SES
`
`815
`
`the expected
`of
`representation
`3. Schematic
`FIG.
`venous
`pressure
`in the superior-temporal
`episcleral
`globe as a result
`of perilimbal
`hyperemia.
`Episcleral
`anastomosis,
`AVA. Arrows
`indicate
`the direction
`
`pattern
`flow
`blood
`is higher
`quadrant
`vein, EV; anterior
`of blood,
`and/or
`
`canal when
`Schlemm’s
`within
`regions
`of the
`in other
`than
`that
`ciliary
`artery,
`AV; arterio-venous
`aqueous
`humor
`flow.
`
`of
`
`in
`such
`during
`
`the circumferential
`by allowing
`reflux mechanism
`an effective
`eye, can provide
`primate
`some of the plasma
`has been
`1979) even when
`or segmental
`flow of blood
`(Moses,
`Schlemm’s
`canal
`is expected
`to
`flow
`through
`filtered
`off (Fig. 3). Continuous
`blood
`pressure
`becomes
`higher
`over one segment
`of
`occur whenever
`the episcleral
`venous
`the globe
`than over others,
`such as during
`trauma-induced
`conjunctival
`hyperemia.
`If, at the same
`time,
`the
`IOP drops below
`episcleral
`venous pressure
`as a result
`cornea1 penetration,
`such blood
`flow
`through
`Schlemm’s
`canal will allow
`the continuous
`reflux of plasma
`through
`the trabecular
`meshwork,
`with only a minimal
`concentration
`of red blood
`cells within
`this canal.
`type
`features of the primate
`that all the unique
`It should
`not be assumed,
`however,
`In primates,
`the selection
`of chamber
`angle are related
`only
`to this reflux mechanism.
`process
`that
`has
`led
`to dependence
`on high
`visual
`acuity
`has also
`led
`to
`the
`development
`of an effective accommodative
`mechanism.
`Contraction
`of the ciliary
`muscle,
`required
`for accommodation,
`decreases uveo-scleral
`outflow
`by decreasing
`the
`extracellular
`spaces between
`the muscle bundles
`(Bill, 1975). Extreme
`accommodation
`is also associated
`with
`large
`reduction
`in the depth
`of the anterior
`chamber
`(Bito,
`a
`DeRousseau,
`Kaufman
`and Bito,
`1982), which
`presumably
`affects
`fluid distribution
`within
`the eye. Thus,
`selection
`for highly
`developed
`accommodative
`mechanisms
`primates
`is likely
`to have necessitated
`selection
`for anatomical
`arrangements,
`as well-developed
`scleral
`spur,
`to allow
`increased
`conventional
`outflow
`accommodation.
`The periodic
`ciliary muscles
`
`structural
`during
`
`provided
`‘shake-up’
`or
`distortion
`each accommodative
`effort may,
`in
`
`by contraction
`fact, contribute
`
`of the
`to
`the
`
`Micro Labs Exhibit 1024-9
`
`

`

`816
`
`I,. Z. 13iTU
`
`The possibilit?-
`meshwork.
`trabecular
`primate-type
`of a complex,
`functioning
`effective
`at’ least
`in som(’
`effort decreases,
`and
`force of accommodative
`frequency
`that
`the
`the onset
`of presbyopia
`must’ 1~
`the years or decades
`after
`during
`individuals,
`and should be investigated,
`since the preceding
`considerations
`suggest
`that
`considered
`lack of such periodic
`‘shake-up’
`of the
`trabecular
`meshwork
`may contribute
`to
`the
`development
`of glaucoma
`in
`long-term
`presbyopic
`eyes. Although
`there
`is some
`evidence
`that presbyopia
`per se is not a result of the
`inability
`of the ciliary muscles
`to contract,
`age-related
`changes
`are certainly
`apparent
`in
`this muscle
`after,
`if not
`before
`the onset of presbyopia
`(Stieve.
`1949: Swegmark,
`1969; E. Lutjen-Drecoll.
`personal
`communication).
`tissues
`on these
`imposed
`requirements
`of the physiological
`Only a full understanding
`under
`normal
`and emergency
`conditions,
`as well as the species variations
`in
`these
`requirements,
`will allow
`us to understand
`the complex
`functional
`morphology
`of the
`outflow
`system and
`the effects of normal
`and pathological
`aging on these structures
`and
`functions.
`A better
`understanding
`of
`the morphological
`organization
`of
`the
`primate
`chamber
`angle may, however,
`be obtained
`by viewing
`this structure
`not
`merely
`as a passive one-way
`system serving
`the single
`function
`of aqueous
`outflow,
`but as a complex
`system which,
`among
`other
`possible
`functions,
`can
`fac