Herpes Simplex Virus Epithelial Keratitis In Vivo Morphology

in the Human Cornea

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Helena M. Tabery, MD
Ögonkliniken UMAS
20502 Malmö
Sweden
[email protected]

ISBN: 978-3-642-01011-8     e-ISBN: 978-3-642-01012-5

DOI: 10.1007/978-3-642-01012-5

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 Preface

As a young ophthalmologist, I found corneal epithelial diseases a subject difficult to

grasp. One day, it occurred to me that the reason might be a lack of images showing
the nature of the components of the changes visible with the slit lamp. With the slit
lamp, the inevitable eye movements that blur the image limited the magnification
level, but perhaps photography might be the answer. It was not a short journey, but in
the end the idea proved right. By trial and error, the quality of the images improved,
and after some time, I found that the resolution allowed reasonable comparisons with
available images of histological preparations. Such comparisons allowed better under-
standing of the substructures of epithelial in vivo lesions and, in conjunction with their
in vivo dynamic features, eventually an understanding of at least some mechanisms
behind them.
This book, originating from over 20 years of experience with observations of ocular
surface changes at high magnification level, covers several aspects of corneal epithelial
lesions caused in humans by herpes simplex virus: various shapes of the lesions, their
substructure and mechanisms behind them; morphological features of the healing pro-
cess, sequelae, complications, and some accompanying signs; and some rare cases.
For those less familiar with the slit lamp image, I have added explanatory drawings to
facilitate comprehension.
It is my experience that once seen at a higher magnification level, these lesions are
much easier to recognize with the slit lamp, particularly when the mechanisms behind
them are understood. I hope that the reader will discover the same.

Malmö, Sweden Helena M. Tabery

March 2009

v
 Contents

1 The Morphology of Herpes Simplex Virus Epithelial Keratitis . . . . . . 1

HSV Cytopathic Effect: Early Changes . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
HSV Cytopathic Effect: Advanced Changes . . . . . . . . . . . . . . . . . . . . . . . 4
Early HSV In Vivo Lesions: Surface Elevation and Disruption . . . . . . . . . 6
An Advanced HSV In Vivo Lesion: Loss of Substance . . . . . . . . . . . . . . . 7
HSV Lesions: Surface Elevation, Depression, and Fluid Diffusion . . . . . . 8
HSV Lesions: Epithelial and Stromal Fluid Diffusion . . . . . . . . . . . . . . . . 9
Rose Bengal Dye Staining of HSV Lesions . . . . . . . . . . . . . . . . . . . . . . . . 10
An HSV Dendritic Figure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
An HSV Dendritic Figure (Continued) . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The Origin of HSV Dendritic Figures . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Various Shapes of HSV Dendritic Figures . . . . . . . . . . . . . . . . . . . . . . . . . 17
Some Other Shapes of HSV Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Precursors of HSV Geographic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
HSV Geographic Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
A Case of Primary HSV Keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Addendum: HSV Conjunctival Lesions . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2 Healing of Herpes Simplex Virus Epithelial Keratitis Treated
with Acyclovir Ointment and Short-Term Sequelae of the Infection . . 25
Healing of HSV Epithelial Keratitis with Acyclovir Ointment . . . . . . . . . 26
Healing of HSV Epithelial Keratitis with Acyclovir Ointment:
A Treatment Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Side Effects of Acyclovir Ointment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
3 Complications, Accompanying Signs, Recurrences, and Long-Term
Sequelae of Herpes Simplex Virus Epithelial Keratitis . . . . . . . . . . . . . 35
Case 1. HSV Epithelial Keratitis: A Fresh and an Older Lesion . . . . . . . . 36
Healing Followed by Epithelial Breakdown and a New Repair
(Case 1, cont.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
Case 2. Healing of HSV Epithelial Keratitis, Accompanying Signs,
and Sequelae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Healing of HSV Epithelial Keratitis, Accompanying Signs,
and Sequelae (Case 2, cont.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

vii
viii Contents

Case 3. HSV Epithelial Keratitis and Stromal Infiltrates . . . . . . . . . . . . . . 49

Case 4. HSV Epithelial Keratitis Preceded by Anterior
Uveitis and Disciform Keratitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
HSV Epithelial Keratitis and Dry Eye (Case 4, cont.) . . . . . . . . . . . . . . . . 51
Case 5. Recurrent HSV Epithelial Keratitis in a Patient with Dry Eye . . . 52
Bibliography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
 About Epithelial Keratitis

A healthy corneal epithelium covered by a normally functioning tear film is a prereq-

uisite for the clarity of vision; even minute epithelial changes located in the optical
zone impair visual acuity. Epithelial malfunction may also result in serious damage to
the subjacent stromal tissue, such as scarring or corneal melting and perforation. The
differential diagnosis of epithelial diseases might be easy but also difficult because
they often resemble each other. The reason is the paucity of morphological phenom-
ena occurring in the epithelium as a reaction to noxious stimuli, whether external (e.g.,
various forms of injuries, including virus infections), innate to the individual (e.g.,
dystrophies and manifestations of diseases such as rosacea and atopy), or of unknown
causes (e.g., Thygeson’s keratitis). Individual phenomena occurring in these condi-
tions (e.g., cell swelling, cyst formation, diseased surface cells, abnormal cells) are per
se not disease specific. It is their combination and distribution, both in depth and later-
ally, sometimes in conjunction with their dynamic features, that make them relatable
to a specific disease.

ix
 About Herpes Simplex Virus
Epithelial Keratitis

Herpes simplex virus (HSV) corneal epithelial infections are very common. Primary
eye infections, that is, those caused by virus transmission between individuals, may
be subclinical or manifest as a self-limiting conjunctivitis that passes undiagnosed.
Primary epithelial keratitis is only rarely seen, or diagnosed, particularly in an adult.
After the primary event, the virus is not eliminated from the organism; instead, it
travels by retrograde flow to neuron cell bodies in the trigeminal ganglion supplying
the eye and remains there in a latent state. The virus that infects the eye might have
gained access to the trigeminal ganglion also during facial infections, usually around
the mouth. The large majority of HSV epithelial keratitis seen in clinical practice are
recurrences caused by shedding of reactivated virus. They are usually caused by
HSV-1 (type 1); so far, HSV-2 (type 2, genital herpes) is rarely encountered.
Herpes simplex virus can seriously damage the eye. The recognition of the HSV
origin of epithelial keratitis is of great importance not only to avoid confusion with
other conditions but also because it may be a clue to help identify HSV as a cause of
a more serious eye involvement, such as stromal keratitis or uveitis. Such manifesta-
tions may precede or follow epithelial keratitis, both within a short time frame or
many years apart.
Herpes simplex virus epithelial keratitis is largely known as a branching figure
(dendrite). To diagnose nonbranching lesions, particularly small ones, as herpetic
and to differentiate dendritic lesions from other lesions also showing branching pat-
terns (e.g., herpes zoster, Thygeson’s keratitis, healing erosions, recurrent erosions),
it is mandatory to carefully observe both their shapes and their substructures.
Treatment with antiviral drugs that arrest virus replication (e.g., acyclovir oint-
ment) causes rapid changes in the morphology of epithelial keratitis. Knowledge of
the typical healing pattern is helpful in differentiating successful treatment from
treatment failure, and knowledge of side effects of treatment helps differentiate them
from epithelial infection.
Successful treatment eradicates replicating virus from the corneal epithelium. The
treatment, however early it starts (£24 h after onset), does not prevent the develop-
ment of subepithelial damage (often termed ghost figure), which in some individuals
disappears rapidly but in others clears only slowly and sometimes remains indefi-
nitely. This sequela might be helpful in suspecting a previous herpetic infection; how-
ever, it might be indistinguishable from sequelae of other epithelial virus infections,
such as adenovirus and herpes zoster.

xi
 About This Book

The photographs presented in this book have been chosen to show

–– The in vivo morphology of herpes simplex virus (HSV) corneal epithelial infection
and the mechanisms behind it (Chap. 1)
–– The morphology of healing of HSV lesions treated with a topical antiviral drug
(acyclovir) and the morphology of short-term sequelae of the infection (Chap. 2)
–– Five illustrative cases with complications, accompanying signs, recurrences, and
long-term sequelae of the infection (Chap. 3)
The photographs were taken by noncontact in vivo photomicrography, a method that
requires neither contact with the epithelium nor the use of anesthetics. By this method,
structures that optically differ from their regularly organized surroundings are visual-
ized; a normal corneal epithelium or stromal cells cannot be discerned. As there is no
contact with the ocular surface, the architecture of epithelial changes is not disturbed
during the examination, and there is no risk of spreading infection in diseases such as
HSV. The technique allows the use of various illumination modes to complement
each other and a free application of diagnostic dyes to expand the information, e.g. 1%
fluorescein sodium and 1% rose bengal (preservative-free solutions). These dyes are
commonly used in clinical practice.
The photographs of cell cultures were taken by the same method.
The HSV origin (type 1) of the lesions was verified by virus isolation test; in two
cases, the diagnosis was clinical.
The bars indicate 200 µm throughout the book.

Abbreviations

HSV Herpes simplex virus

CPE Cytopathic effect
Fluorescein Fluorescein sodium

xiii
 Chapter 1

The Morphology of Herpes Simplex Virus

Epithelial Keratitis

Before the introduction of newer methods, the gold dendrites are laid down early. That the variously shaped
standard of detection and identification of viruses was figures are the result of confluence of adjacent foci of
virus isolation test in cell culture. In living cells, virus infection, larger and smaller, is also clearly visible in
replication causes cell swelling and rounding (a phe- fresh dendrites.
nomenon termed the virus cytopathic effect, CPE) fol- Lesions that do not show the “HSV-typical” shapes
lowed by cell bursting and disappearance. are less common and might be a diagnostic pitfall:
When the multilayered living human corneal epithe- small lesions, oval or rounded, singular or multiple,
lium in situ becomes infected with HSV, the virus CPE resembling adenovirus infections; lesions with config-
generates secondary phenomena: Subsurface cell swell- urations reminiscent of mechanical injuries; elongated
ing causes volume increase, resulting in surface eleva- lesions lacking “terminal bulbs”; lesions that had lost
tions and disruptions; subsequent shedding of surface their original features because of extensive epithelial
cells, and bursting and disappearance of infected ones, destruction (“geographic” lesions). In such lesions,
causes loss of substance, resulting in surface depressions HSV features can be easily overlooked unless the
(epithelial erosions/ulcerations). This sequence of examination is careful.
events often occurs asynchronously. The early stages of It is well known that HSV epithelial keratitis is a self-
the infection clearly show a concurrent presence of limiting condition. Participation of natural defensive
incipient cell swelling and advanced epithelial destruc- forces during ongoing infection seems reflected by the
tion; in fact, it is the blended substructure due to the fairly well-defined configurations of lesions in patients
presence in adjacent areas of various degrees of epithe- presenting several days, or later, after the onset of symp-
lial damage that greatly contributes to the familiar toms; in fact, this phenomenon would be difficult to
appearance of HSV epithelial lesions. understand without presupposing a force hindering free
Among the various shapes of HSV lesions, one occu- lateral spreading of the infection. I can recall only two
pies an outstanding position: the well-known herpetic patients in whom the infection seemed to have pro-
dendrite. The possible mechanisms behind these gressed unopposed. One was a rare case of primary
branching figures often showing “terminal bulbs” infection (presented in this chapter); in the other one,
(rounded branch endings) have been debated for many swollen/rounded cells scattered over a largely epithe-
years. Helpful in elucidating this question is the initial lium-denuded corneal surface were reminiscent of
distribution of infected cells captured during the very advanced changes in cell cultures. This patient had inad-
early stages; it indicates that the patterns of the vertently been treated with a potent topical steroid.

H. M. Tabery, Herpes Simplex Virus Epithelial Keratitis

DOI: 978-3-642-01012-5_1, © Springer-Verlag Berlin Heidelberg 2010
2 Chapter 1 The Morphology of Herpes Simplex Virus Epithelial Keratitis

HSV Cytopathic Effect: Early Changes

Fig. 1.1 HSV cytopathic effect in cell culture infected with a laboratory strain of HSV type 1 (HSV-1). The figure shows foci
(arrows) containing swollen/rounded infected cells (arrowheads)

Fig. 1.2 In the living human corneal epithelium, incipient HSV cytopathic effect appears as foci (white arrow) containing swol-
len/rounded cells (arrowhead). Black arrows indicate a corneal nerve
 HSV Cytopathic Effect: Early Changes 3

a b

Fig. 1.3 a–b HSV cytopathic effect in the living human corneal epithelium. (a) Several partly confluent foci (arrows) contain-
ing swollen/rounded cells (arrowheads). (b) Individual swollen/rounded cells (arrowheads) close to each other

a b

Fig. 1.4 a–b HSV cytopathic effect in the living human corneal epithelium. (a) Two adjacent foci (arrows) containing swollen/
rounded cells (arrowheads). In the left focus, and in the periphery of the right one, the cells appear dull (black arrowheads). In
the center of the right focus are visible bright rounded cells (white arrowhead); here, the surface layer seems missing. (b) As in
(a), the dull-appearing cells (black arrowheads) seem situated below a preserved surface layer, and the bright ones (white
arrowhead) appear denuded. A few cells stained red with rose bengal

Comment
The condition of the surface can be visualized with fluorescein sodium (cf. Fig.1.10).
4 Chapter 1 The Morphology of Herpes Simplex Virus Epithelial Keratitis

HSV Cytopathic Effect: Advanced Changes

Fig. 1.5 This cell culture infected with a laboratory (HSV-1) virus strain shows advanced changes: All remaining cells show
the virus cytopathic effect (cell swelling and rounding, arrowheads); moreover, in the cell monolayer, cell bursting and dis-
appearance have resulted in cell-denuded areas (arrows)

Fig. 1.6 This HSV lesion in the living human corneal epithelium shows closely packed swollen/rounded cells, some appearing
dull (black arrowhead) and others bright (white arrowhead); in the multilayered epithelium, cell bursting and disappearance
have not resulted in cell-denuded areas yet (cf. Fig. 1.7, opposite page)
 HSV Cytopathic Effect: Advanced Changes 5

Fig. 1.7 a–b The appearance of these two HSV lesions in the living human corneal epithelium is the result of cell swelling
(arrowheads), bursting, and disappearance. In places, the loss of substance seems to have reached the level of the epithelial
basement membrane (arrows indicate apparently cell-denuded areas)

Comment
Level differences can be visualized with fluorescein sodium (cf. Fig.1.9).
6 Chapter 1 The Morphology of Herpes Simplex Virus Epithelial Keratitis

Early HSV In Vivo Lesions: Surface Elevation and Disruption

a b

Fig. 1.8 a–c (a) In these two confluent HSV epithelial lesions (arrows), cell swelling (arrowheads) causes (b) surface elevation (dark in
the tear film stained green with fluorescein sodium, arrow). The surface layer is preserved (no diffusion). (c) Two other lesions (arrows)
show massive diffusion of fluorescein, indicating loss of surface integrity. Inset: Both types of lesions are located close to each other
 An Advanced HSV In Vivo Lesion: Loss of Substance 7

An Advanced HSV In Vivo Lesion: Loss of Substance

a (a) Loss of substance caused by epithelial destruc-

tion resulted in surface erosion (depression). The
bottom of the lesion shows swollen/rounded cells
(arrowhead) and a partly cell-denuded area (arrow)

(b) The eroded (depressed) area (bowed black arrow)

b shows pooling of green-stained tear fluid. The major-
ity of the swollen cells visible in (a) have disappeared
below the level of the fluid; only a few cells are pro-
truding (arrowheads). Elevated areas adjacent to the
depressed ones appear dark (bowed white arrow);
early fluorescein diffusion into the surroundings
appears bright green (short arrow)

c
(c) The bright green fluorescein staining caused by
diffusion into the surroundings increases with time

Fig. 1.9 a–c A part of an advanced HSV dendrite before and after the
application of fluorescein sodium. (Adapted from [2])