Endothelial Blebs: Part VIII Corneal Endothelium

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Part VIII Corneal Endothelium

28 CHAPTER

Endothelial blebs

Prior to 1977, it was thought that contact lenses could only research commenced into understanding the endothelial
affect the cornea by direct mechanical influence or oxygen response to lens wear.
deprivation. Because the endothelium is located on the pos-
terior surface of the cornea and is known to obtain all of its
required oxygen from that dissolved in the aqueous humor,1 Prevalence
this tissue layer was thought to be immune from the effects
of contact lenses. The prevalence of endothelial blebs is thought to be essen-
The first clue that contact lenses could alter the corneal tially 100% among contact lens wearers.2 That is, blebs can
endothelium came from Zantos and Holden,2 who noted be observed in all patients within 10 minutes of lens inser-
that the endothelial mosaic undergoes a dramatic alteration tion. There is a large variation in the intensity of the response
in appearance within minutes of inserting a contact lens. between patients.2,6,7 Asian subjects have a significantly
Specifically, they reported observing a number of black, higher degree of endothelial bleb formation than the non-
non-reflecting areas in the endothelial mosaic – which they Asian population for closed eye lens wear.8
called blebs – and an apparent increase in the separation
between cells. These changes can be observed under high
magnification (×40) using the slit lamp biomicroscope Signs and symptoms
(Figure 28.1).
The black, non-reflecting areas observed in the endothelial
mosaic correspond with the position of individual cells or
groups of cells. The initial impression one gains is that cells
have ‘fallen off’ the posterior surface of the cornea, leaving
behind gaps or black holes.2 In corneas displaying a marked
blebbing response, it also appears as if all endothelial cells
throughout the field of view have become more separated
and the endothelial surface takes on a more textured and
three-dimensional appearance.2
The ‘bleb response’ displays a characteristic time course
(Figure 28.2). Blebs can be observed within 10 minutes of
lens insertion. The number of blebs peaks in 20 to 30
minutes, then subsides to a low level after about 45 to 60
minutes. A low-level bleb response can be observed
throughout the remainder of the wearing period.2
Hydrogel lenses cause a greater bleb response than well-
fitting rigid lenses. Lenses of greater average thickness
induce a greater response than thinner lenses. However, the
design and fit of hydrogel lenses have little effect on the
Figure 28.1 Contact lens-induced blebs (arrow) in the endothelial mosaic bleb response.6 Ohya et al.7 observed that blebs are confined
observed in specular reflection with the slit lamp biomicroscope. (Courtesy to the central regions of the cornea beneath rigid lenses, but
of Arthur Ho, Brien Holden Vision Institute.) occur throughout the cornea with soft lenses; that is, blebs
are seen in all corneal areas covered by contact lenses.
The contact lens fraternity remained sceptical for some Williams and Holden9 observed two additional endothe-
time, and it was not until (a) the appearance of blebs was lial phenomena in patients wearing soft lenses on an
verified independently3; and (b) reports of contact lens- extended wear basis. First, there appears to be an increase
induced endothelial polymegethism were published by in the number of blebs in the late evening, prior to going to
Schoessler and Woloschak4,5 in the early 1980s, that serious sleep. Second, the overall magnitude of the bleb response
© 2012 Elsevier Ltd
Endothelial blebs

10
*
Rigid (Dk/t = 16)
0.8 8 Soft (Dk/t = 15)
(% area of endothelium affected)

Area of blebs (%)


No lens (control)
Endothelial bleb response

6
0.6
*
Lens 4 *
0.4 on *
Lens off 2 *
* *
0.2 0
0 5 10 15 20 25 30 35 40 45 50 55
A Time (minutes)
0
0 30 60 90
10
Time (min) Rigid (Dk/t = 49)
8 Soft (Dk/t = 49)
No lens (control)

Area of blebs (%)


Figure 28.2 Time course of appearance and resolution of contact
lens-induced endothelial blebs. 6
**
4
can be seen to decrease over the initial 8 days of extended
wear. Furthermore, Bruce and Brennan10 noted that the
2
overall bleb response was reduced by approximately 50%
after 4 months of soft lens extended wear compared with
0
baseline values. These observations suggest that some form 0 5 10 15 20 25 30 35 40 45 50 55
of short-term9 and long-term9,10 adaptation of the endothe-
B
b) Time (minutes)
lium is taking place.
Brennan et al.11 evaluated the corneal endothelial bleb
response to wear of silicone hydrogel lenses (Acuvue 10
Oaysis, Acuvue Advance and Focus Night & Day) and a
Rigid (Dk/t = 181)
conventional hydrogel lens (SofLens 38) in eyes of East 8 Soft (Dk/t = 175)
Asian subjects. SofLens 38 produced a mean percentage area No lens (control)
Area of blebs (%)

of blebs of 8.0% under closed eye conditions, which was


6
significantly different to that produced by Acuvue Oaysis
(1.6%). Both Acuvue Advance and Focus Night & Day pro-
duced a mean percentage bleb area of 0.4% under open eye 4
conditions. Acuvue Oaysis and Focus Night & Day pro-
duced statistically similar mean percentage bleb areas of 2
1.7% and 2.0%, respectively, under closed eye conditions.
The authors concluded that the similarity of the bleb 0
responses induced by the silicone hydrogel lenses under 0 5 10 15 20 25 30 35 40 45 50 55
the tested wearing conditions is consistent with the proposi- C Time (minutes)
tion that increases in Dk/t above a certain level will produce
minimal change in corneal physiologic conditions com- Figure 28.3 Mean percentage area of the blebs over time following 20
pared with that when no lens is worn. minutes of closed eye lens wear (or no lens wear) for (A) low, (B) medium
Inagaki et al.12 compared the time course of endothelial and (C) high Dk/t lenses. Asterisks represent significant difference from
bleb formation and disappearance between contact lenses control eye (p < 0.05). (Adapted from Inagaki Y, Akahori A, Sugimoto K, et al.
of low Dk/t (rigid 16, soft 15), medium Dk/t (rigid 49, soft Comparison of corneal endothelial bleb formation and disappearance
processes between rigid gas-permeable and soft contact lenses in three
49) and high Dk/t (rigid 181, soft 175). Twenty subjects kept
classes of Dk/l. Eye Contact Lens 2003;29:234–7.)
their eyes closed for 20 minutes after putting on each test
lens. Starting just after eye opening, the eyes were exam- Despite their stunning clinical appearance, blebs are
ined for blebs every 5 minutes by specular microscopy, and asymptomatic and thought to be of little clinical significance.
the percentage area of the blebs was calculated. For control They are, however, of great interest to physiologists who are
purposes, the same eyes were also examined without endeavouring to understand the workings of the cornea.
contact lens wear. The percentage areas of the blebs just
after eye opening and during a 55 minute ‘recovery’ period
are shown in Figures 28.3A, B and C for low, medium and Pathology
high Dk/t lenses, respectively. No difference was observed
between rigid and soft lenses of similar Dk/t values in the
medium and high Dk/t categories. However, for low Dk
Electron microscopy
materials, rigid lenses appear to have a lower impact on the Histological studies of the endothelial bleb response were
corneal endothelium than do soft lenses. conducted by Vannas et al.13 using (a) corneas from eyes
279
Chapter 28 Part VIII: Corneal Endothelium

that were enucleated (because of melanomas); and (b) (×680).14,15 Kaufman et al.14 observed the corneas of three
corneas of beating-heart, brain-death cadavers. The patients wearing high water content hydrogel contact
‘blebbed’ endothelium displayed oedema of the nuclear lenses for the first time. In one patient, endothelial changes
area of cells, intracellular fluid vacuoles and fluid spaces consisting of irregularly shaped, round or oval, dark
between cells. Thus, endothelial blebs appear to be the regions were observed within the endothelial mosaic. These
result of a local oedema phenomenon, whereby the poste- changes were most evident 20 minutes after lens insertion,
rior surface of the ‘blebbed’ endothelial cell is bulged and by 30 minutes the changes were fewer and less promi-
towards the aqueous. The endothelial cell bulges in the nent. Kaufman et al.14 suggested that their results con-
posterior direction because this represents the path of least firmed the ‘localized oedema’ theory of endothelial bleb
resistance; that is, the posterior stromal surface (Descemet’s formation.
membrane) provides much greater resistance to endothelial Efron et al.15 obtained images from each eye of 15 normal
cell swelling than the aqueous humor. subjects (age range 19–36 years; mean 26 ± 6 years) before
and after 20 minutes’ wear of a +5.50 D 58% water content
hydrogel lens in one eye. The extent of the bleb response
Slit lamp biomicroscopy was determined using the grading scales shown in Appen-
A simple optical model can be constructed to explain the dix A of this book (see ‘Observation and grading’); the
appearance of blebs as seen with the slit lamp biomicro- images were also assessed qualitatively. After 20 minutes
scope (Figure 28.4). When the endothelium is viewed using of lens wear, the mean bleb response in the lens-wearing
specular reflection, light rays reflect from the tissue plane eye was grade 1.0 (range 0.0 to 3.2). Two subjects did not
corresponding to the interface between the posterior surface display blebs. No blebs were observed in the non-lens-
of the endothelium and the aqueous humor. This interface wearing eyes. Individual blebbed cells comprised of a
acts as the reflective surface because it represents a signifi- bright central spot, surrounded by a darker annulus, were
cant change in tissue refractive index. The light rays that observed in the endothelium of most subjects.
are reflected from this interface give rise to an observed In one subject, the endothelium was imaged at baseline
image of an essentially flat (or slightly undulating) mosaic and over a time sequence of 5, 10, 15 and 20 minutes of
of largely hexagonal endothelial cells. lens wear (Figure 28.5). The time sequence reveals the
initial appearance of a dark border around some cells,
which broadens into a thick, dark annulus after 15 to 20
minutes of lens wear (Figure 28.6).

A B

Stroma

Endothelium ‘Blebbed’ cell

Figure 28.4 Optical theory explaining the appearance of contact C D


lens-induced endothelial blebs when viewed in specular reflection with the
slit lamp biomicroscope.

Light rays which strike ‘blebbed’ endothelial cells will be Figure 28.5 (A–E) Confocal
deflected away from the observation path, leaving a cor- microscope images of the
responding area of darkness. Thus, an endothelial bleb is development of endothelial blebs
simply an individual endothelial cell (or group of adjacent E over a 20-minute time period.
cells) that has become swollen and bulged in the direction (Courtesy of Haliza Mutalib.)
of the aqueous humor, giving rise to the compelling optical
illusion that the cell (or cells) has disappeared.
An optical model is used to illustrate the appearance of
endothelial blebs using confocal microscopy (Figure 28.6).
Confocal microscopy This model employs normal light reflection because light
The confocal microscope has been used to observe the rays pass to and from the endothelium through the confocal
endothelial bleb response at very high magnification microscope objective lens via a pathway of light directly
280
Endothelial blebs

the prevailing theory that blebs represent swelling of


individual endothelial cells in the posterior (aqueous)
direction.

Aetiology
The aetiology of endothelial blebs has been explained by
Holden et al.16 These authors attempted to induce blebs
using a variety of stimulus conditions, and concluded that
one physiological factor common to all successful attempts
to form blebs was a local acidic pH change at the
endothelium.
Two separate factors induce an acidic shift in the cornea
during contact lens wear: (a) an increase in carbonic acid
due to retardation of carbon dioxide efflux (hypercapnia)17
by a contact lens; and (b) increased levels of lactic acid as a
result of lens-induced oxygen deprivation (hypoxia)17 and
Figure 28.6 Enlargement of a confocal microscope image of blebs (arrows), the consequent increase in anaerobic metabolism (Figure
each showing a bright centre surrounded by a thick dark annulus. The 28.8). When silicone elastomer contact lenses are worn,
surrounding unaffected endothelium reflects brightly. (Courtesy of Haliza such metabolic changes do not take place because of the
Mutalib.) extremely high oxygen permeability of such lenses.

towards and away from the cornea, perpendicular to its


surface (Figure 28.7). This is different from specular micros-
copy using the slit lamp biomicroscope, whereby angular Contact lens
light reflection is employed to observe the endothelium
(see Figure 28.4). H2O + CO2 =
Lactic acid carbonic acid
HCO3–
HCO3–
HCO3–
HCO3–

HCO3–

HCO3–

HCO3–

‘Blebbed cell’ Acute acidic pH shift ‘Blebbed cell’


at endothelium

Figure 28.8 Aetiology of contact lens-induced endothelial blebs.

Endothelial blebs are not observed in the contralateral


eye when induced by lens wear in the ipsilateral eye,18 and
they are observed in graft corneas,19 thus precluding the
‘Blebbed cell’ Normal cell
possibility of central neural control of this phenomenon.
Also, contact lens-induced endothelial blebs are unaffected
Figure 28.7 Optical theory explaining the appearance of contact
by prostaglandin-inhibitor drugs, precluding an inflamma-
lens-induced endothelial blebs when viewed in normal reflection with the tory basis for the response.20
confocal microscope. Bonanno and Polse21 have confirmed by direct measure-
ment that contact lens-induced hypoxia and hypercapnia
result in an acidic shift in the cornea and these authors
The model illustrates a single ‘blebbed’ cell flanked on noted that the extent of acidosis that they measured is
either side by a normal ‘non-blebbed’ cell. It can be seen in the range where endothelial function may be affected.
from the confocal model that light is normally reflected Furthermore, the time course of the appearance of blebs
from the flat surface ‘non-blebbed’ cells and the apex of the following lens insertion, and resolution following lens
blebbed endothelial cell, all of which will appear bright. removal, is consistent with the time course of corneal pH
The sloping sides of the blebbed cell reflect light away change as measured by Bonnano and Polse.21
from the objective and thus appear dark. This model The cornea becomes hypoxic and hypercapnic during
therefore explains the confocal appearance of a blebbed sleep so it would be expected that the consequent acidic
cell as having a dark annulus surrounding a bright central changes would induce blebs. Various authors6,22 have
spot (Figure 28.5). These observations are consistent with indeed confirmed that there is a diurnal variation in the
281
Chapter 28 Part VIII: Corneal Endothelium

endothelial bleb response, whereby more blebs can be automated specular endothelial microscopes are available
observed immediately upon awakening following sleep. for viewing the endothelium;23 these instruments offer
The question arises as to the precise mechanism by which higher magnification and superior resolution compared
acidosis causes endothelial cells to swell. All cells in the with slit lamp observation. As discussed previously, the
human body function optimally when surrounded by confocal microscope provides an even higher level of mag-
extracellular fluid that is maintained within an acceptable nification that allows detailed examination of individual
range of pH, temperature, tonicity, ion balance etc. Car- cells. Endothelial specular microscopes7,8 and confocal
bonic acid and lactic acid may alter the physiological status microscopes14,15 are invaluable as research tools when it is
of the environment surrounding the endothelial cells by necessary to quantify endothelial changes and understand
shifting pH in the acidic direction. This may induce changes the pathology of this phenomenon; however, a general
in membrane permeability and/or membrane pump activ- appraisal of the endothelial bleb response can still be
ity, resulting in a net movement of water into endothelial obtained satisfactorily with a good quality, high magnifica-
cells. The resultant cellular oedema is observed as tion slit lamp.2
‘blebbing’. The extent of endothelial bleb formation can be graded
using the grading scale for this response provided in
Appendix A; however, the usual connotation that is associ-
ated with contact lens grading scales concerning the urgency
Observation and grading for clinical action (see Chapter 29) does not apply here
because contact lens-induced endothelial blebs are thought
The corneal endothelium can be viewed by specular reflec- to be innocuous, irrespective of the level of severity of bleb-
tion using a slit lamp biomicroscope at ×40 magnification. bing. The 0 to 4 scale of the bleb response shown in Appen-
In order to observe the endothelium using this technique, dix A can be considered as being approximately linear.
the angle between the illumination and observation systems High magnification slit lamp photographs of endothelial
must be symmetrical about a plane extending normally blebbing of grades 0 (normal), 2 (slight) and 4 (severe) are
from the cornea, and will typically be between 75° and 90°. shown in Figure 28.9.
The endothelial mosaic can be seen adjacent to a bright
reflex from the corneal surface (Figure 28.1). Using this
technique, only the mid-peripheral nasal or temporal endo- Management
thelium are viewed; this does not pose a problem because
changes in these regions are representative of changes Whilst the phenomenon of endothelial blebs is of immense
elsewhere in the cornea.9 interest from a physiological standpoint, there are no
Although individual endothelial cells can only just be readily apparent clinical ramifications. The bleb response
resolved at ×40 magnification, blebs have a stark appear- occurs to a greater or lesser degree in most patients, and
ance and are easily recognizable. A variety of sophisticated displays a characteristic time course. It is not known

A B C

Figure 28.9 High magnification slit lamp photographs of contact lens-induced endothelial blebs: (A) grade 0 (Courtesy of Steve Zantos, Brien Holden Vision
Institute); (B) grade 2 (Courtesy of Lewis Williams, Brien Holden Vision Institute); and (C) Grade 4. (Courtesy of Brien Holden, Brien Holden Vision Institute.)
282
Endothelial blebs

whether a propensity for the endothelium of a patient to


exhibit blebbing is a positive or negative attribute.
Williams6 surmises that the severity of an endothelial
bleb response is reduced in patients displaying increased
levels of endothelial polymegethism, which could partially
explain the apparent long-term adaptation of the bleb
response. Specifically, a low-level bleb response has been
interpreted as an indication that the endothelium has lost
its capacity to respond to changes in its immediate environ-
ment; that is, the endothelium has become ‘exhausted’.
Theoretically, the bleb response can be used as a relative
measure of the combined impact of contact lens-induced
hypoxia and hypercapnia on the cornea of a given patient.
That is to say, in a given patient, a lens with lower average
oxygen transmissibility will induce a more severe bleb
response.6 This concept has been explored experimentally.7,8
Ohya et al.7 observed the time course, frequency, and loca-
tion of endothelial blebs in 11 eyes of nine contact lens-
wearing patients. Eight types of contact lenses with various
oxygen transmissibilities (Dk/t) were used. The authors
demonstrated an inverse correlation between the number
of blebs and the Dk/t of the contact lens. In addition,
Hamano et al.8 demonstrated a significantly higher degree Figure 28.10 Corneal dystrophy depicting severe guttate changes.
of bleb formation with lenses of lower Dk/t values. (Courtesy of Charline Gauthier, Bausch & Lomb Slide Collection.)
The results outlined above imply that a comparison of the
severity of the bleb response could have clinical utility in
selecting lenses of optimal gas transmission characteristics. of cells throughout the field.27 Blebs have also been observed
However, Bruce and Brennan24 suggest that the bleb in clear corneal grafts fitted with hydrogel lenses.28
response is of little use for the longitudinal monitoring of Interestingly, transient phenomena that closely resemble
patients wearing a given lens type, in view of the lack of endothelial blebs have been observed in patients with acute
variability in the magnitude of its response relative to its superficial eye disorders. Specifically, Zantos and Holden29
test–retest reliability. noted such transient endothelial changes in cases of acute
‘red eye’ associated with extended contact lens wear; these
formations have exactly the same appearance as contact
Prognosis lens-induced blebs, but are different in that they persisted
for many days following cessation of lens wear.
The prognosis for recovery from endothelial blebs is excel-
lent. After removal of a contact lens, blebs disappear within References
45 minutes.2,7,12 Blebs will reappear when lens wear is rein-
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troduced and resolve when lenses are removed, but in any
and carbon dioxide in the in vivo cornea. I. The open eye in
event, blebs are harmless.
air and the closed eye. Exp Eye Res 1968;7:103–12.
2. Zantos SG, Holden BA. Transient endothelial changes soon
after wearing soft contact lenses. Am J Optom Physiol Opt
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of guttae and the transience of blebs. human cornea [PhD]. New South Wales, Australia:
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Chapter 28 Part VIII: Corneal Endothelium

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