Alan G. Kabat, O.D., FAAOAndrew S. Gurwood, O.D., FAAO, Dipl.Joseph W. Sowka, O.D., FAAO, Dipl.
SUPPLEMENT TO April 15, 2008
Published by Jobson Medical Information LLC www.revoptom.com
Tenth Anniversary EditionTenth Anniversary Edition
Sponsored by
EYELIDS AND ADNEXA
Acquired Anophthalmia - - - - - - - - - - - - - - - - - - - - - - 6A
Benign Essential Blepharospasm - - - - - - - - - - - - - - - - - 7A
Eyelid Myokymia - - - - - - - - - - - - - - - - - - - - - - - - - - - 8A
Madarosis & Poliosis - - - - - - - - - - - - - - - - - - - - - - - - 10A
Proptosis & Exophthalmos - - - - - - - - - - - - - - - - - - - - 12A
CONJUNCTIVA AND SCLERA
Viral Conjunctivitis - - - - - - - - - - - - - - - - - - - - - - - - - 14A
Atopic Keratoconjunctivitis - - - - - - - - - - - - - - - - - - - - 16A
Ocular Melanosis - - - - - - - - - - - - - - - - - - - - - - - - - - 18A
Pyogenic Granuloma - - - - - - - - - - - - - - - - - - - - - - - - 20A
CORNEA
Herpes SimplexVirus Epithelial Keratitis - - - - - - - - - - - 22A
Acanthamoeba Keratitis - - - - - - - - - - - - - - - - - - - - - - 23A
Filamentary Keratitis - - - - - - - - - - - - - - - - - - - - - - - - 25A
Fuchs' Endothelial Dystrophy - - - - - - - - - - - - - - - - - - 26A
Salzmann's Nodular Degeneration - - - - - - - - - - - - - - - 28A
UVEA AND GLAUCOMA
Choroidal Rupture - - - - - - - - - - - - - - - - - - - - - - - - - 30A
Metastatic Choroidal Tumors - - - - - - - - - - - - - - - - - - 31A
Pigmentary Glaucoma - - - - - - - - - - - - - - - - - - - - - - - 33A
Updating the Glaucoma Studies - - - - - - - - - - - - - - - - - 34A
Exfoliative Glaucoma - - - - - - - - - - - - - - - - - - - - - - - - 37A
VITREOUS AND RETINA
Sickle Cell Retinopathy - - - - - - - - - - - - - - - - - - - - - - 39A
Solar Retinopathy - - - - - - - - - - - - - - - - - - - - - - - - - - 40A
Acute Posterior Multifocal Placoid Pigment
Epitheliopathy - - - - - - - - - - - - - - - - - - - - - - - - - - - - 42A
Birdshot Retinochoroidopathy - - - - - - - - - - - - - - - - - - 44A
Myelinated Nerve Fibers - - - - - - - - - - - - - - - - - - - - - 46A
Congenital Hypertrophy of the RPE - - - - - - - - - - - - - - 47A
Cavernous Hemangioma of the Retina - - - - - - - - - - - - 49A
NEURO-OPHTHALMIC DISEASE
Neuroretinitis - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 51A
Tilted Disc Syndrome - - - - - - - - - - - - - - - - - - - - - - - 52A
Morning Glory Syndrome - - - - - - - - - - - - - - - - - - - - - 54A
Facial Nerve Palsy - - - - - - - - - - - - - - - - - - - - - - - - - - 56A
Hemifacial Spasm - - - - - - - - - - - - - - - - - - - - - - - - - - 58A
OCULOSYSTEMIC DISEASE
Herpes Zoster - - - - - - - - - - - - - - - - - - - - - - - - - - - - 60A
Gardner's Syndrome - - - - - - - - - - - - - - - - - - - - - - - - 61A
Antiphospholipid Antibody Syndrome - - - - - - - - - - - - - 63A
TABLE OF CONTENTS
A Peer-Reviewed Supplement
The articles in this supplement were subjected
to Review of Optometry's peer-review process.
The magazine employs a double-blind review
system for clinical manuscripts.Two referees
review each manuscript before publication.
This supplement was edited by the editors of
Review of Optometry.
2008. Reproducing editorial content and photographs require permission from Review of Optometry.
APRIL 15, 2008 REVIEW OF OPTOMETRY 5A
To Our Colleagues,
This year sees the publication of the tenth edition of The Handbook of Ocular Disease Management.
The years that we have been compiling this compendium have been professionally very rewarding to
us. We are forever grateful to the management and editorial staff at Review of Optometry. They have
given us a forum to reach our colleagues annually and allow us to provide this "second opinion" and
share our clinical experience.
When we think back upon the years that we have spent writing this supplement, we want to take a
moment and reflect back from where we came and those that have influenced us and our professional
development. We would not be in the position to share our knowledge and experience with our colleagues
had we not been taught and influenced by our mentors. We are forever grateful to the following
people for instructing us, guiding us, mentoring us, and providing professional role models: Drs.
Larry Gray, Bernie Blaustein, Chris Reinhart, Joel Silbert, George White, Lou Catania, Robert Walker,
Irving Gurwood, Lorraine Lombardi, Lester Janoff, Jeffrey Nyman, Neal Nyman, Ed Deglin, Bruce
Muchnick, G. Richard Bennett, Vincent Young, Richard Brilliant, and Joseph Toland.
To them we dedicate the tenth edition of The Handbook of Ocular Disease Management.
Joe
Andy
Al
Alan G. Kabat, O.D., F.A.A.O., is an associate professor at Nova
Southeastern University College of Optometry, where he teaches courses in
Clinical Medicine and Physical Diagnosis. He serves as an Attending Optometric
Physician in the Primary Care service at The Eye Care Institute, and is also
Residency Education Coordinator for the College. He can be reached at
(954) 262-1470 or at kabat@nova.edu.
The authors do not have a
financial interest in any of the
products mentioned.
Andrew S. Gurwood, O.D., F.A.A.O., Dipl., is a professor of clinical sciences
and staff optometrist atThe Eye Institute of the Pennsylvania College of
Optometry, where he teaches clinical medicine and ocular urgencies and
emergencies. He is a diplomate of the American Academy of Optometry's Primary
Care Section, a founding member of the Optometric Retina Society and a
member of the Optometric Glaucoma Society. He serves on the American
Academy of Optometry admittance committee and is the chairperson of the
fellowship candidate workshop. He can be reached at (215) 276-6134 or at
agurwood@pco.edu.
Joseph W. Sowka, O.D., F.A.A.O., Dipl., is a professor of optometry at Nova
Southeastern University College of Optometry, where he teaches Glaucoma
and Retinal Disease. He is the director of the Glaucoma Service and chief of the
Advanced Care Service. He is a diplomate of the Disease Section of the
American Academy of Optometry (Glaucoma Subsection) and a founding
member of the Optometric Glaucoma Society and the Optometric Retina
Society. He can be reached at (954) 262-1472 or at jsowka@nova.edu.
]
FROM THE AUTHORS
6A REVIEW OF OPTOMETRY APRIL 15, 2008
ACQUIRED ANOPHTHALMIA
Signs and symptoms
Patients with anophthalmia typically
present with an ocular prosthesis; less
commonly, they may simply wear a
patch to protect the empty socket.
While there is no eye, these individuals
remain susceptible to a variety of conjunctivitides
including allergy, infection
and inflammatory disorders.
Complaints may include itching, discharge,
swelling and erythema or
even pain of the lids. Moreover, the
anophthalmic patient is predisposed
to developing eyelid positioning
issues and/or discomfort from a
poorly fitted prosthesis.
Visual functioning can also represent
a significant challenge to those
with acquired anophthalmia. The
absence of one eye effectively diminishes
a patienťs field of vision by
15­20%.1
Additionally, the anophthalmic
patient loses stereopsis, which
can compromise the appreciation of
depth and parallax, hand-eye coordination
and ability to judge distances accurately.
Decreased overall acuity is also
likely, because monocular patients are
unable to benefit from the phenomenon
of binocular summation. Finally, there
is the potential for impairment in spatial
orientation, which results from a lack of
kinesthetic cues arising from convergence
and accommodation.2
All of this
may compromise the patienťs ability to
perform visually discriminating tasks
such as driving; a study by Keeney, et al.
suggests that monocular drivers have,
on average, seven times more automobile
accidents than the general population
of drivers.3
Pathophysiology
Anophthalmia refers to the loss or
lack of a functioning eye.While congenital
anophthalmia is rare, acquired
anophthalmia may result from a variety
of causes, most notably trauma.
Surgically induced anophthalmia (i.e.,
enucleation) is often indicated in cases
of malignant tumor growth (e.g., melanoma,
retinoblastoma), intractable glau-
coma,chronicinflammation,chronicretinal
detachment or endophthalmitis.4
The anophthalmic socket consists of
a shallow cul-de-sac bounded by conjunctival
tissue. The bulk of the orbital
space previously occupied by the eye is
typically filled with a spherical highdensity
porous polyethylene or coralline
hydroxyapatite implant covered in
donor sclera.5
The extraocular muscles
are sutured to this implant, and the
remaining palpebral conjunctiva is
drawn together to enclose the space.An
ocular prosthesis--essentially a convex
shell of polymethylmethacrylate, handpainted
to simulate the fellow eye--is
subsequently fitted to match the
appearance and posture of the remaining
eye.
Management
Patients with acquired anophthalmia
are prone to many of the disorders of
sighted individuals, including infection
and allergy, as well as unique problems
associated with ocular prostheses and
monocular vision.Appropriate management
of these individuals must include a
thorough history and examination of the
anophthalmic socket. Physicians should
ascertain the age of the prosthesis, how
frequently it is removed and cleaned
and whether the patient visits an ocularist
regularly. One should also evaluate
the cosmesis of the eye to determine
whether it appears proptotic or enophthalmic
with the prosthesis in place, and
whether translation of the prosthesis is
good as the patient looks from side to
side. Poorly fitted, too-small prostheses
often will not move well and can
become displaced; a secondary ptosis is
also possible in such cases. Similarly,
prostheses that are too large can cause
pain and incomplete lid closure.
Biomicroscopic inspection should
reveal pink conjunctiva free of papillae
or follicles. Excessive redness, purulent
or ropy mucous discharge or significant
odors emanating from the socket
usually signify infection. The clinician
must also ensure that the orbital
implant is not visible through the
conjunctiva, as any compromise to
the socket provides a direct route for
potential infectious spread to the
orbit. Finally, it is important to
inspect the prosthesis itself, ensuring
that the surface is smooth and not
crazed or cracked, because these
imperfections can harbor microbial
pathogens.
Lid ptosis, poor translation and
lagophthalmos are often the result of a
poorly fitted prosthesis. Such cases
should be referred to an ocularist for
modification or replacement. In some
patients, however, problems arise not
from the prosthesis but from alterations
in the ocular tissues over time. Atrophy
of orbital fat, acquired eyelid laxity and
dehiscence of the levator muscle can
lead to ptosis or involution of the lids,
manifesting as entropion. Individuals
with these issues are best referred for
consultation with an oculoplastics specialist.
Surgical intervention, including
volume augmentation of the orbit,
resection of the levator muscle or lid
resection may be employed to rectify
these problems.6,7
Conjunctival maladies in the anophthalmic
patient should be managed
intuitively. Bacterial conjunctivitis is
appropriately addressed using a broadspectrum
antibiotic such as Vigamox
(moxifloxacin 0.5%, Alcon) or Zymar
(gatifloxacin 0.3%, Allergan). Allergic
conjunctivitis responds well either to
antihistamine mast-cell stabilizers (e.g.,
Pataday; olopatadine 0.2%, Alcon) or a
topical corticosteroid (e.g.,Alrex; Loteprednol
etabonate 0.2%, Bausch &
Lomb). Giant papillary conjunctivitis
EYELIDS AND ADNEXA
Acquired anophthalmia.
APRIL 15, 2008 REVIEW OF OPTOMETRY 7A
EYELIDSANDADNEXA
(GPC) in prosthetic wearers is likewise
best managed with topical corticosteroids.
Regarding visual functioning, it
appears that patients are most susceptible
to the realities of adjustment in the
first weeks and months following enu-
cleation.8
Advise patients to pay special
attention to challenging activities such
as navigating stairs or curbs, crossing
busy streets and especially driving.
Clinical pearls
* Removal of the prosthesis and biomicroscopic
evaluation of the anophthalmic
socket is crucial, but it is often
neglected because of fear or squeamishness.
Inexperienced or apprehensive clinicians
should consider enlisting the
patienťs help rather than foregoing this
important aspect of the examination.
* Anophthalmic patients must be
educated regarding the need for protecting
their remaining functional eye.
From a clinico-legal standpoint, it is
necessary to prescribe protective eyewear
with polycarbonate lenses.
* While no treatment can fully
restore the peripheral field or binocularity,
low-vision rehabilitation can
often improve visual function and allow
anophthalmic patients to better cope
with their environment and day-to-day
activities. The use of mirrored systems
and visual scanning techniques are
some of the available options for these
individuals.2
1. Keeney AH. Current transitions in ophthalmic aspects of
licensure for motor vehicle drivers: Problems, hazards, and
working solutions. Trans Am Ophthalmol Soc
1993;91:197­202; discussion 202­6.
2. Politzer T. Implications of acquired monocular vision.
Neuro-Optometric Rehabilitation Association (NORA),
2004. Available at http://www.nora.cc/patient_area/
monocular_vision.html. Accessed August 25, 2007.
3. Keeney AH, Singh GC, Berberich S, Giesel J. Evaluation of
the Driver Limitation Program in Kentucky 1964­1984. J Ky
Med Assoc 1985;83(6):327­31.
4. Saeed MU, Chang BY, Khandwala M, et al. Twenty year
review of histopathological findings in enucleated/eviscerated
eyes. J Clin Pathol 2006;59(2):153­5.
5. Su GW,Yen MT. Current trends in managing the anophthalmic
socket after primary enucleation and evisceration.
Ophthal Plast Reconstr Surg 2004;20(4):274­80.
6. Murchison AP, Bernardino CR. Evaluation of the anophthalmic
socket. Rev Ophthalmol 2006;13(9):76­80.
7. Barnes JA, Bunce C, Olver JM. Simple effective surgery for
involutional entropion suitable for the general ophthalmologist.
Ophthalmol 2006;113(1):92­6. Epub Nov 23, 2005.
8.Linberg JV,TillmanWT,Allara RD.Recovery after loss of an
eye. Ophthal Plast Reconstr Surg 1988;4(3):135­8.
BENIGN ESSENTIAL
BLEPHAROSPASM
Signs and symptoms
Benign essential blepharospasm
(BEB) refers to the involuntary, tonic
spasm of the orbicularis oculi muscle,
producing, at the least intermittent closure
of the eyelids and at the worst a
bilateral syndrome, inducing focal
facial dystonia, temporary functional
blindness (patients simply can't get
their eyes open to see), depression and
feelings of social isolation.1
BEB is
often misdiagnosed as a psychiatric
condition, which delays correct identification
and treatment.1
True dystonic
activity can be uncovered by identifying
the presence of muscular weak-
ness.1
Patients whose BEB involves
adjacent focal motor activity of the
oral-mandibular region develop interrupted
speech, inability to eat and difficulty
swallowing and talking. This is
known as Meige's syndrome.1
These
individuals may also have pronounced
bruxism (clenching of the jaw).1
If the
eyelids are lax, entropion may ensue.
Patients with complete eyelid closure
who have lost the ability to open them
are said to have "apraxia" of lid open-
ing.1,2
Apraxia of lid opening occupies a
separate category because it is often
secondary to a supranuclear disorder
not demonstrating forceful orbicularis
contraction.
Secondary blepharospasm is a term
used to connote a reflexive, involuntary,
forceful closure of the eyelids.1
It occurs
after exposure to direct or indirect
painful ocular stimuli. Direct exposure
can be secondary to chemical injury
(solid, liquid, gas, phototoxic), blunt
trauma involving the adnexa, thermal
injury to the eye or adnexa, dry eye, foreign
body introduction and corneal or
conjunctival abrasion or laceration, to
name a few triggers. Secondary blepharospasm
is the result of pain, photophobia
and lacrimation produced by the
injurious, infective or inflammatory
ophthalmic processes. Endogenous
sources include but are not limited to
anterior uveitis, orbital pseudotumor,
dacryocystitis, corneal edema secondary
to injury or pupil block
glaucoma or other source of acute
intraocular pressure rise (neovascular
glaucoma, hyphema), vitritis,
pars planitis, optic neuritis and
retrobulbar hemorrhage. Here, as
the pain response to both the injury
and the intraocular inflammation
build, the patient simply cannot
hold the eye open. He or she
reflexively winces and squeezes,
attempting to find some relief
from the intense, throbbing discomfort.
Light aggravates the
inflammatory response, thus causing
photophobia.1
Pathophysiology
As the motor division of the seventh
cranial nerve (CN VII) is responsible
for delivering voluntary motor innervations
to the muscles of facial expression
(and to the stapedius muscle of the
inner ear, which dampens loud sounds),
any irritation by adjacent or direct
infection, infiltration, inflammation or
compression of cranial nerveVII nuclei
or its fascicles can produce involuntary
contracture of the affected region.1­18
Benign essential blepharospasm is
poorly understood; in most cases, laboratory
testing and neuroimaging do not
yield an identifiable underlying cause.1,2
As such, it is a diagnosis of exclusion.
Meige's syndrome, a form of benign essential blepharospasm
that also involves the oral-mandibular region.
8A REVIEW OF OPTOMETRY APRIL 15, 2008
Abnormal levels of neurotransmitters
and/or alterations of the structure, function
or architecture of the basal ganglia
and/or midbrain have been suspected.1
New research into benign essential blepharospasm
has uncovered a potential
neurochemical connection.19
Altered
kynurenine metabolism, a neuroactive
metabolite that plays a role in the normal
physiology of the human brain, has been
identified as a contributor in neurodegenerative
disorders such as Parkinson's
disease, Huntington's disease and now
the pathogenesis of focal dystonia.19
Management
The treatment of choice for benign
essential blepharospasm is chemodenervation
via direct subcutaneous injec-
tion.1,2,20
Botulinum toxins in Botox
(Allergan, Irvine, CA) are accepted as a
first-line treatment for patients suffering
from spasms secondary to facial dystonias
of all kinds.4
They work by inhibiting
the release of acetylcholine into the
synaptic cleft, thereby blocking neuromuscular
transmissions.1,20,22
These
treatments are extremely effective and
well tolerated.22
The onset of the effect
occurs within one to three days and can
last up to three months for cases of
essential blepharospasm, slightly
longer when used in cases of hemifacial
spasm.1
New agents are being developed
to create longer-lasting options to
improve the quality of life for patients
with facial dystonias who require the
paralytic agents to function.1,20
Treatment
failures via antibody production are possible,
so treatment more frequent than
Q3 months should be avoided.1
Dopamine-depleting agents, neuroleptics,
sedatives, centrally acting cholinergic
medications and gamma-aminobutyric
acid agonists all have had variable
documented success as therapies.7
In all cases of blepharospasm, an
easy-to-use "Disability Scale" has been
developed to quantify the contractures
and the changes that occur when treatment
is instituted.21
This allows both
patient and treating physician to understand
overall inconvenience and functioning
and the effectiveness of the
mode of intervention.21
Secondary blepharospasm will
resolve when the root cause has been
eliminated. Topical anesthesia is universally
helpful in cases where external
and superficial anterior segment injury
is inducing reflexive closure. Cycloplegia,
artificial tears, cold compresses,
topical nonsteroidal anti-inflammatory
medications and oral analgesics, along
with an attack aimed at the root cause
of the ocular or adnexal infection,
inflammation, intraocular pressure rise
or compression will stop the spasm.
Clinical pearls
* Never instill a topical anesthetic
until visual acuity has been assessed or
at least attempted. In cases where secondary
blepharospasm is too severe to
determine visual acuity (typically seen
in acute corneal injuries) the inability to
determine acuity should be documented.
Next, instill the anesthetic drop and
measure and record the acuity.
* Although it is a radical solution,
myectomy--removal of muscle tissue,
usually the orbicularis--is listed in the
literature as a potential treatment.
* Physical and emotional stress can
aggravate symptoms. Even something
as simple as participation in a social
gathering may cause an exaggeration of
the blepharospasm.
* Parkinson's disease and Huntington's
chorea (ceaseless jerky movements
with mental status changes) are
worthy of being placed into the differential
diagnosis.22
1. Faucett DC. Essential blepharospasm. In:Yanoff M, Duker
JS, Ophthalmology (2nd ed.), Philadelphia: Mosby, 2004, pp.
695­97.
2. Kerty E, Eidal K.Apraxia of eyelid opening: clinical features
and therapy. Eur J Ophthalmol 2006;16(2):204­8.
3. Tan EK, Chan LL. Young onset hemifacial spasm. Acta
Neurol Scand 2006;114(1):59­62.
4. NakamuraT, Osawa M, Uchiyama S.Arterial hypertension
in patients with left primary hemifacial spasm is associated
with neurovascular compression of the left rostral ventrolateral
medulla. Eur Neurol 2007;57(3):150­5.
5. Gurwood AS. The eyelid and neuro-ocular disease. In:
Blaustein BH, Ocular Manifestations of Neurologic Disease,
Philadelphia, PA: Mosby, 1996, pp. 127­51.
6. Gurwood AS, Tasca JM, Kulback E. A review of cranial
nerveVII palsy with emphasis on Belľs Palsy. South J Optom
1996;14(3):13­17.
7. May M, Galetta S.The facial nerve and related disorders
of the face. In: Glaser JS, Neuroophthalmology (2nd ed.),
Philadelphia, PA: J. B. Lippincott Co., 1990, pp. 239­77.
8. Bajandas FJ, Kline LB. Seven syndromes of the seventh
(facial) nerve. In: Bajandas FJ, Kline LB, Neuro-ophthalmology
Review Manual (3rd ed.),Thorofare, NJ: Slack, Inc., 1988,
pp. 151­6.
9. Jowi JO, Matende J, Macharia MI, et al. Hemifacial spasm:
Case report. East Afr Med J 2006;83(7):401­4.
10. Peker S, Ozduman K, Kiliç T, et al. Relief of hemifacial
spasm after radiosurgery for intracanalicular vestibular
schwannoma. Minim Invasive Neurosurg 2004;47(4):235­7.
11. Sindou MP. Microvascular decompression for primary
hemifacial spasm. Importance of intraoperative neurophysiological
monitoring. Acta Neurochir (Wien)
2005;147(10):1019­26.
12. Hatem J, Sindou M,Vial C. Intraoperative monitoring of
facial EMG responses during microvascular decompression
for hemifacial spasm. Prognostic value for long-term outcome:
A study in a 33-patient series. Br J Neurosurg 2001;
5(6):496­9.
13. James ML, Husain AM. Brainstem auditory evoked
potential monitoring:When is change in wave V significant?
Neurol 2005;65(10):1551­5.
14. Pulec JL.Total facial nerve decompression:Technique to
avoid complications. Ear NoseThroat J 1996;75(7):410­5.
15. Liu Z, Fang G. Mind-refreshing acupuncture therapy for
facial spasm, trigeminal neuralgia and stubborn facial paralysis.
JTrad Chin Med 2004;24(3):191­2.
16. Suthipongchai S, Chawalparit O, Churojana A, et al.
Vascular loop compressing facial nerve in hemifacial spasm:
Demonstrated by 3D-phase contrast magnetic resonance
angiography in 101 patients. J Med Assoc Thai
2004;87(3):219­24.
17. Harrison AR. Chemodenervation for facial dystonias and
wrinkles. Curr Opin Ophthalmol 2003;14(5):241­5.
18.Tan EK, Chan LL, Lim SH, et al. Role of magnetic resonance
imaging and magnetic resonance angiography in
patients with hemifacial spasm. Ann Acad Med Singapore
1999;28(2):169­73.
19. Hartai Z, Klivenyi P, Janaky T, et al. Peripheral kynurenine
metabolism in focal dystonia. Med Chem 2007;3(3):285­8.
20. Harrison AR. Chemodenervation for facial dystonias and
wrinkles. Curr Opin Ophthalmol 2003;14(5):241­5.
21. Grivet D, Robert PY,Thuret G, et al. Assessment of blepharospasm
surgery using an improved disability scale:Study
of 138 patients. Ophthal Plast Reconstr Surg
2005;21(3):230­4.
22. May M, Galeta S.The facial nerve and related disorders
of the face. In: Glaser JS. Neuro-ophthalmology 2ne Ed.
Philadelphia, PA, JB Lippincott Co 1990: 239-77.
EYELID MYOKYMIA
Signs and symptoms
The word myokymia is derived from
the Greek words myo, meaning "muscle"
and kyma, meaning "wave."1
It is
defined by complex, involuntary, repetitive
electrical discharges involving any
muscle in the body.2
With respect to the
eye it is known to affect two structures
primarily: the eyelid and the superior
oblique muscle.1­5
Patients with superior
oblique myokymia (SOM) present
with a vertical jerk nystagmus, oscillopsia
(the perception that the world is
APRIL 15, 2008 REVIEW OF OPTOMETRY 9A
EYELIDSANDADNEXA
moving) and transient diplopia.2­5
Patients with myokymia of the eyelid
present with a chief complaint of intermittent
"oscillating," "vibrating,"
"flickering," "quivering" or "twitching"
eyelid.5
Myokymia of the eyelid is the
result of repetitive bursts of discharges
that stimulate the Muscle of Müller and
the ciliary portion of the orbicularis
oculi.3,4
While most patients perceive
the unexpected quivering as an annoyance,
the seizures are not painful, nor
are they so exaggerated that an observer
can identify an episode without
being within three feet of the person
and directly looking at the moving area.
Myokymia occurs cyclically and seems
to arise at times of increased stress.
Patients may be aware or unaware of
their body's emotional fluctuations,
physical fatigue or illness.The episodes
may also be connected to increased
sympathetic tone, which can be voluntarily
or unknowingly altered by cigarette
smoking (nicotine), caffeinated
drinks (coffee, tea, sports drinks and
energy-boosting supplements or
drinks) and some medicines. The
episodes are transient, lasting from one
to 10 minutes, and can occur one time
or multiple times during the day for
weeks to months. During normal periods
of physical and emotional activity,
the episodes cease and the phenomenon
moves into hibernation, waiting for
the next opportunistic trigger.3
Pathophysiology
Traditionally, involuntary, spastic
twitching of muscles has been attributed
either to tissues recovering from
injury, demyelinating disease and neural
response to compression or irrita-
tion.2,5­8
In a study that examined acute
unilateral facial paralysis, transient
long-lasting motor dysfunction featuring
disorders of voluntary and involuntary
movement was observed.8
It seems
that after an injury (in this instance, the
insulted muscles that were studied were
around the face) some patients exhibited
an increase in their spontaneous
blink rate and a sustained, low-level
contraction of the muscles of the nonparalyzed
side.7,8
This occasionally lead
to full blepharospasm.8
This was
believed to be the result of increased
excitability of the facial motor neurons
and brainstem interneurons mediating
reflexes.7,8
As one recognized mechanism
of occurrence, full-blown "postparalytic"
facial syndrome has been
described as levels of muscular synkinesis
(muscles responding together),
myokymia and unwanted hemifacial
contractions accompanying normal
facial movements.7,8
Pathophysiological
mechanisms include abnormal axonal
branching after injury, with aberrant
axonal regeneration and enhanced
motor neuronal excitability.7,8
Myokymia of the eyelid is often a
benign, self-limited disorder, with no
relation to injury or paralysis.3,4
In a
study of 15 patients with a diagnosis of
isolated eyelid myokymia where the
patients in the study had at least 12
months of follow-up, all patients whose
symptoms began as unilateral, weekly
or biweekly intermittent eyelid spasms
with progression to daily spasms over
several months demonstrated no manifestation
of serious neurologic disease.3
Thirteen of the 15 patients (86.7%)
underwent neuroimaging with no
abnormalities found.2
In this group of
13 patients, the myokymia resolved
spontaneously in four participants, with
eight of the remaining nine opting to be
treated with botulinum toxin injection
at regular intervals. Most of the patients
electing to receive injections reported
improvement.3
Management
Patients who ask, "Why does my
eyelid twitch sometimes?" are most
likely experiencing benign eyelid
myokymia. The diagnosis can be solidified
by confirming the presence of the
classic clinical features: it is episodic,
limited to the eyelid, painless, has no
effect on function, is intermittent
throughout the day, seems to come in a
cyclic monthly pattern, and recollects
other previous symptoms with a repeatable
profile, including the possible
recognition that the symptoms return
when stress levels increase. Patients
should be educated that the condition
has a name and should be reassured
that in almost all instances, it is harmless.
They should be counseled regarding
signs that may indicate the need for
additional work-up. Since increased
sympathetic tone, worsened from
exogenous sources, can exaggerate or
even instigate the problem, patients
should be reminded that during stressful
situations, they may consciously or
unconsciously increase consumption of
energy drinks, coffee, sodas, teas or
nicotine. Patients should be educated
that these coping behaviors may kickstart
the aberrant activity. If a patient
has recently begun taking a new medication,
one should investigate the medication
for side effects. Treatments may
include modalities as simple as removing
the provoking stress, reducing nicotine
and/or caffeine consumption, discontinuing
a medication, observation,
rest, cold compresses and consuming
tonic water with quinine (anecdotal),
and may progress to medicinal solutions
such as topical beta-blockers,
anticonvulsants such as carbamazepine
100­200 mg. PO BID-QID as tolerated
(minimum medicine to achieve desired
effect), gabapentine 100 mg. PO BID
building to 300­600 mgs per day or
local injections of botulinum toxin.3­8
Clinical pearls
* Chronic isolated eyelid myokymia
is generally considered a benign condition.
It tends not to progress to other
facial muscles nor elaborate into other
facial movements or disorders.
* Excessive benign eyelid myokymia
responds well to botulinum toxin injection.
* Eyelid myokymia is rarely associated
with other neurologic disease.
However, eyelid twitching can be a
localized manifestation of underlying
brainstem disease, making persistent
cases of myokymia a diagnosis of
exclusion.
* Postparalytic facial dysfunction
may occur after idiopathic facial nerve
palsy (Belľs palsy), and seems to be the
result of increased background muscle
10A REVIEW OF OPTOMETRY APRIL 15, 2008
activity and enhanced motor neuron
recruitment.
1. Friel JP. Myokymia. In: Friel JP, Dorlanďs Illustrated Medical
Dictionary (26th ed.), Philadelphia, PA, W. B. Saunders Co.,
1985, p. 862.
2. Mancias P, Butler IJ.Trigeminal myokymia in a young girl. J
Child Neurol 2003;18(8):572­4.
3. Banik R, Miller NR. Chronic myokymia limited to the eyelid
is a benign condition. J Neuroophthalmol
2004;24(4):290­2.
4. Rubin M, Root JD. Electrophysiologic investigation of
benign eyelid twitching. Electromyogr Clin Neurophysiol
1991;31(6):377­81.
5. Straube A.Therapeutic considerations for eye movement
disorders. Dev Ophthalmol 2007;40:175­92.
6. Foroozan R, Buono LM, Sergott RC, et al. Jumping jack
flash. Surv Ophthalmol 2006;51(1):63­7.
7. Valls-Solé J, Montero J. Movement disorders in patients
with peripheral facial palsy. Mov Disord
2003;18(12):1424­35.
8. Valls-Sole J,Tolosa ES, Pujol M. Myokymic discharges and
enhanced facial nerve reflex responses after recovery from
idiopathic facial palsy. Muscle Nerve 1992;15(1):37­42.
MADAROSIS AND POLIOSIS
Signs and symptoms
There are few symptoms other than
patients' cosmetic complaints directly
associated with madarosis, alopecia or
poliosis.1­3
None of these three entities
cause frank symptoms by themselves.
Madarosis has been welldescribed
in ophthalmic literature as
a symptom of blepharitis, Demodex
infestation, ocular cicatricial pemphigoid,
dry eye syndrome, leprosy,
exposure to radiation, sarcoidosis,
lupus, skin cancer of the eyelids
(basal cell carcinoma, squamous cell
carcinoma, malignant melanoma),
sebaceous cell carcinoma, trauma,
thermal burns, contact dermatitis,
Steven-Johnson syndrome, eyelid
tattooing, miotics, Ehlers-Danlos syndrome,
anemia, human immunodeficiency
virus (HIV) and some medica-
tions.1­11
Most of the symptoms that
occur do so as a result of the root illness;
however, in some cases recurrent foreign-body
sensation caused by broken
lashes, falling hair or lashes trapped in
the fornix conjunctiva occur.
In most instances poliosis, a whitening
of the lashes, is overlooked or misinterpreted
as a sign of aging. Its most
infamous associations are with VogtKoyanagi-Harada
disease (VKH) and
vitiligo.12­15
VKH produces a bilateral
granulomatous panuveitis with a tendency
toward serous retinal detachment,
pleocytosis in the cerebrospinal fluid (a
greater than normal amount of cells),
alopecia, poliosis and vitligo.12,13
Vitiligo
is a separate entity that causes variable
depigmentation of the skin and hair.14,15
Pathophysiology
The word "madarosis" is derived
from the Greek madaros, meaning
"bald."16
It connotes loss of the eyelashes
or eyebrow hair. "Alopecia" is
derived from the Greek alopekia, referring
to a disease in which the hair falls
out.2,16
The word "poliosis" is derived
from the Greek words polio, meaning
"gray," and thrix, meaning "hair," and
describes premature graying of hair or
eyelashes.3,16
Hair follicles possess
regenerative potential.They are believed
to be crucial for epidermal homeostasis
and dermatologic reepithelialization.
Unfortunately, hair follicles may be disturbed
by systemic and local influ-
ences.17
The pathogenesis of hair, brow
and eyelash loss occurs by one of two
mechanisms: the scarring form, in
which primary inflammatory processes
or inflammation, by way of infection,
harm the hair follicles, causing hair loss;
or the non-scarring form, in which
inflammation may be present but the follicles
are spared.1,18
In primary scarring
alopecia, the hair follicle is the prime
target of destruction. In secondary scarring
alopecia, non-follicular processes
impinge upon adjacent follicles, ultimately
destroying them.18
Because hair
follicles are formed in the second to fifth
month of fetal growth, once follicles are
lost, hair loss is permanant.1
The scarring forms of madarosis are
induced by diseases that possess aggressive
inflammatory components as part
of their pathology, including syphilis,
lupus, HIV, leprosy and cancerous
tumors.1,7,9,10,17­21
Non-scarring madarosis
is caused by pathological entities in
which severe inflammation is not part of
the pathogenesis.1,20
Mechanical rubbing
from epidermal irritation, radiation
exposure, mild blepharitis or seborrhea
create a mild folliculitis without destroying
the hair follicle.1,4,5,20
Chronic irritation
of the area may initiate a lymphocytic
response, which shrinks the hair
bulb and hence the hair itself. In some
instances, the hair bulb may convert
from an angen (a growing hair) to a telogen
(a resting, thin or static hair).1
This
may appear as lost lashes or eyebrow
hair when, in fact, the hairs are there but
recovering. In some patients, this
process occurs secondary to genetic triggers
or systemic diseases such as
autoimmune disorders, diabetes mellitus
or thyroid disease.1
Androgenetic
alopecia (hormonally induced) and
telogen effluvium (a disorder of the
hair growth cycle) are also primary
non-scarring alopecias and sources
of reversible madarosis.20
Androgenetic alopecia is considered
the most common form of human
alopecia and is believed to affect
more than 50% of men by age 50.16
Alopecia areata (patchy loss of hair
in an otherwise healthy individual)
affects up to 2% of the U.S. popula-
tion.1,20
Telogen effluvium frequently
occurs after major life events, such as
severe illness, childbirth or high fever,
and it may be associated with the use of
certain medications or with iron defi-
ciency.16,22
When madarosis accompanies a granulomatous
uveitis, VKH should be sus-
pected.12
VKH is a poorly understood
inflammatory process with genetic linkage
to people of Asian, Hispanic and
NativeAmerican heritage. It has a female
preponderance and generally emerges in
the fourth to fifth decade of life.12
Madarosis results from chronic lid inflammation.
APRIL 15, 2008 REVIEW OF OPTOMETRY 11A
EYELIDSANDADNEXA
Poliosis appearing in isolation has
been associated with the use of topical
prostaglandin analogs.8
In one published
case series, seven patients
treated with different topical
prostaglandin medications for primary
open angle glaucoma developed
bilateral poliosis, either alone or
in combination with other predictable
side effects.8
In concert with skin
depigmentation, the poorly understood
autoimmune disease vitiligo
should be suspected.14
Management
No management proper exists for
the three entities. Rather, in each case
the underlying cause must be identified
and addressed. Since madarosis is
part of a larger clinical picture, keen
observational skills are necessary and
detailed history must be taken.
Carefully inspect the patienťs scalp,
face, neck and arms for diffuse patterns
of hair loss, rashes, inflammations,
masses, discolorations or infections.
In cases of madarosis secondary
to blepharitis, a mixture of baby shampoo
and tea tree oil (TTO) has been
documented as effective, in addition to
any medicinal therapy.4,5
Demodex is
resistant to a wide range of antiseptic
solutions. Lid scrubs with 50% TTO
and 50% shampoo have proven far
more effective in eradicating the infection
than either of the two substances
alone.4
In cases involving rosacea, oral
antibiotics such as doxycycline, tetracycline
or minocycline must be added
to the regimen.
In cases that involve eyelid or conjunctival
inflammation, such as contact
dermatitis, medicamentosa and lice
infestation, controlling the underlying
pathology is the key to reversing the
inflammatory process. The optometrist
or general practitioner should complete
systemic laboratory testing in
cases where undiagnosed systemic disease
is suspected. Diagnosis is critical,
because in cases where follicle
destruction is incomplete, the prompt
start of systemic immunosuppressive
therapy, in combination with topical
steroidal and nonsteroidal drops and
ointments, may bring about remission
or cure.6
In otherwise healthy individuals
without evidence of infectious/inflammatory
eyelid disease or evidence of
loss of the eyebrow or other alopecia,
skin cancers, such as basal cell and
squamous cell carcinoma, malignant
melanoma and sebaceous cell carcinoma,
must be suspected in any case of
madarosis.1
Thorough inspection of the
eyelids and adnexa is mandatory in
these cases, and any finding should be
referred to an oculoplastic surgeon
capable of completing the excision
using the Moh's micrographic tech-
nique.23
In some instances, biopsies
may be necessary to achieve a definitive
diagnosis.
In the cases of poliosis without suspected
systemic disease, the use of
newer medications should be considered
as a potential source with the possibility
of challenge (discontinuing it),
to improve cosmesis, as a treatment.24
In cases of poliosis associated with
vitiligo, conservative therapies include
photochemotherapy, phototherapy and
systemic steroids.14
Topical corticosteroids
are preferred for localized vitili-
go.14
Clinical pearls
* Madarosis and poliosis are not
diagnoses, but findings. Each requires
investigation to determine the underlying
cause.
* Trichotillomania is the purposeful
self-removal of hair from one's person
and should not be confused with
madarosis.
* Laboratory work-up should
include, but is not limited to, a complete
blood count, an erythrocyte sedimentation
rate, antinuclear antibody
test, a thyroid stimulating hormone test,
thyroxine level, triiodothyronine,
luteinizing hormone test and fluorescent
treponemal antibody absorption
test.
* Popular therapeutic options for
hair loss secondary to cicatricial etiology
include systemic corticosteroids,
systemic antimalarials, isotretinoin
and antibiotics.
1. Khong JJ, Casson RJ, Huilgol SC, et al. Madarosis. Surv
Ophthalmol 2006;51(6):550­60.
2. Shapiro J, Wiseman M, Lui H. Practical management of
hair loss. Can Fam Physician 2000;46:1469­77.
3. Chen CS,Wells J, Craig JE.Topical prostaglandin F(2alpha)
analog induced poliosis. Am J Ophthalmol
2004;137(5):965­6.
4. Gao YY, Di Pascuale MA, Li W, et al. In vitro and in vivo
killing of ocular Demodex by tea tree oil. Br J Ophthalmol
2005;89(11):1468­73.
5. Gao YY, Di Pascuale MA, Elizondo A, et al. Clinical treatment
of ocular demodecosis by lid scrub with tea tree oil.
Cornea 2007;26(2):136­43.
6. Dart J. Cicatricial pemphigoid and dry eye. Semin
Ophthalmol 2005;20(2):95­100.
7. Waziri-Erameh MJ, Omoti AE. Ocular leprosy in Nigeria:
A survey of an Eku leprosorium. Trop Doct
2006;36(1):27­8.
8. Tsina EK, Lane AM, Zacks DN, et al. Treatment of
metastatic tumors of the choroid with proton beam irradiation.
Ophthalmol 2005;112(2):337­43.
9. Kendrick CG, Brown RA, Reina R, et al. Cutaneous sarcoidosis
presenting as leonine facies. Cutis
2004;73(1):57­62.
10. Selva D, Chen CS, James CL, et al. Discoid lupus erythematosus
presenting as madarosis. Am J Ophthalmol
2003;136(3):545­6.
11. Kowing D. Madarosis and facial alopecia presumed secondary
to botulinum A toxin injections. Optom Vis Sci
2005;82(7):579­82.
12. Inomata H.Vogt-Koyanagi-Harada disease. In:Yanoff M,
Duker JS, Ophthalmology (second ed.), Philadelphia: Mosby,
2004, pp. 1196­9.
13. Yang P, Ren Y, Li B, et al. Clinical characteristics of VogtKoyanagi-Harada
syndrome in Chinese patients.
Ophthalmol 2007;114(3):606­14.
14. Forschner T, Buchholtz S, Stockfleth E. Current state of
vitiligo therapy--evidence-based analysis of the literature. J
Dtsch Dermatol Ges 2007;5(6):467­75.
15. Taeb A, Picardo M (VETF Members).The definition and
assessment of vitiligo: A consensus report of the Vitiligo
EuropeanTask Force. Pigment Cell Res 2007;20(1):27­35.
16. Friel JP. Madarosis. In: Friel JP, Dorlanďs Illustrated
Medical Dictionary (26th ed.), Philadelphia, PA, W.B.
Saunders Co., 1985, p. 769.
17. Wiedemeyeer K, Schill WB, Loser C. Diseases on hair
follicles leading to hair loss part I: nonscarring alopecias.
Skinmed. 2004;3(4):209-14.
Poliosis.
12A REVIEW OF OPTOMETRY APRIL 15, 2008
18. Sellheyer K, Bergfeld WF. Histopathologic evaluation of
alopecias.Am J Dermatopathol 2006;28(3):236­59.
19. Tan E, Martinka M, Ball N. Primary cicatricial alopecias:
clinicopathology of 112 cases. J Am Acad Dermatol
2004;50(1):25­32.
20. Hordinsky MK. Medical treatment of noncicatricial
alopecia. Semin Cutan Med Surg 2006;25(1):51­5.
21. Price VH.The medical treatment of cicatricial alopecia.
Semin Cutan Med Surg 2006;25(1):56­9.
22. Zouboulis CC, Chen WC, Thornton MJ, et al. Sexual
hormones in human skin. Horm Metab Res
2007;39(2):85­95.
23. Bindra M, Keegan DJ, Guenther T, et al. Primary cutaneous
mucinous carcinoma of the eyelid in a young male.
Orbit 2005;24(3):211­4.
24. Roberts A, Kaye LC, Memon A, et al. Unilateral poliosis
of the eyelashes in children associated with vitiligo. J AAPOS
2005;9(3):295­6.
PROPTOSIS & EXOPHTHALMOS
Signs and symptoms
Patients with proptosis and exophthalmos
may be symptomatic or
asymptomatic, depending upon the
severity and duration of the condition.
In general, unilateral cases of ocular
protrusion are more noticeable and
may prompt greater cosmetic concern.
The most common symptoms
involve ocular discomfort; patients
may complain of dryness, burning,
grittiness, foreign body sensation or
other complaints characteristically
associated with exposure. Pain may
be reported as well, but this is most
often associated with acute events
rather than chronic conditions.
Redness and swelling of the conjunctiva
are also frequent complaints.
Visual function may be
completely normal or profoundly
reduced, depending upon the severity
and nature of the underlying etiology.
Diplopia is another possible complication
of proptosis or exophthalmos
and can result from muscle entrapment,
infiltration or because of physical
displacement of the globe.
Proptosis and exophthalmos are
usually associated clinically with
increased palpebral fissure width and
lid retraction. Extraocular muscle testing
may show a restriction of motility,
depending on the extent and underlying
etiology. Biomicroscopic signs
include variable conjunctival hyperemia,
chemosis and epithelial keratopathy.
Evaluation by exophthalmometry
is a helpful diagnostic procedure
in these conditions; accepted normal
values are between 12 and 21mm
(measured from the lateral canthus to
the corneal apex), although slightly
greater values may be encountered in
patients of African descent.1
A difference
of 4­7mm or greater between the
eyes is likewise indicative of abnormal
ocular protrusion.
Pathophysiology
Proptosis and exophthalmos are
both terms that refer to a bulging forward
of one or both eyes. A great deal
of disagreement exists as to the circumstances
in which each of these
terms is appropriately used. The medical
dictionary suggests that "proptosis"
connotes "a forward projection or
displacement" of any organ, while
"exophthalmos" is specifically defined
as "an abnormal protrusion of the eye-
ball."2
Other references claim that
proptosis refers to unilateral conditions
only, while exophthalmos denotes a
bilateral condition.3
A frequently cited
textbook insists that the term exophthalmos
is reserved for cases that occur
secondary to endocrinological dysfunction,
while non-endocrine­ mediated
globe protrusion is appropriately
referred to as proptosis.4
However, the
vast majority of published papers seem
to use the terms interchangeably.
Proptosis or exophthalmos occurs
because of an increase in volume within
the bony orbital cavity. Accumulation
of extraorbital cellular material
or enlargement of any of the orbital
contents (e.g., extraocular muscles)
may result in forward displacement of
the globe. A wide range of etiologies
may underlie this phenomenon: infiltrative
disorders, infection, inflammatory
disease and vascular conditions are
the most common causes.
Thyroid eye disease (i.e., Graves'
disease, Graves' ophthalmopathy, thyroid
ophthalmopathy) is the most frequently
encountered etiopathology
associated with proptosis/exophthalmos
in adults.5
Infiltration of the
extraocular muscles and orbital fat by
immune cells (e.g., lymphocytes,
macrophages and plasma cells) creates
orbital congestion, which in turn causes
anterior dislocation of the eye.
Since thyroid disease is a systemic
condition, bilateral ocular involvement
is anticipated; however, some cases
may display marked asymmetry, even
to the point of unilateral proptosis.6
Other documented causes of exophthalmos/
proptosis include infection
(e.g., orbital cellulitis, phycomycosis),
orbital inflammatory disease,
lymphoid tumors (e.g., lymphoma,
leukemia), vascular disease (e.g.,
intraorbital and retrobulbar hemorrhage,
vasculitis, venous varices,
arteriovenous malformations, carotid
cavernous fistula), orbital metastasis,
lacrimal gland tumors, posterior
scleritis, trauma and invasive
sinus disease.7
Management
Management for any individual presenting
with proptosis or exophthalmos
begins with a thorough history.
Often, additional signs and symptoms
can steer the clinician toward the
appropriate diagnosis. For example,
patients describing intermittent proptosis
associated with Valsava maneuvers
or postural changes may harbor an
orbital venous varix, a low-flow vascular
hamartoma that communicates with
the normal orbital circulation.8
Constitutional complaints should also
be scrutinized, as these are often
Bilateral exophthalmos in severe thyroid eye disease.
APRIL 15, 2008 REVIEW OF OPTOMETRY 13A
EYELIDSANDADNEXA
indicative of specific systemic maladies.
Occasionally, patients may even
volunteer a previously undisclosed
medical condition (e.g., thyroid disease,
cancer) during pointed questioning.
The most crucial diagnostic test in
cases of proptosis/exophthalmos of
unknown etiology is orbital imaging.
Both computed tomography (CT) and
magnetic resonance imaging (MRI)
may be used, depending upon the suspected
pathology. Imaging of the orbit
is especially critical in cases of unilateral
involvement, as this technology
can identify and differentiate various
tumors, vascular malformations and
inflammatory lesions. Contrast
enhancement can further help to distinguish
orbital neoplasms. Orbital ultrasonography
can also help in the differential
of proptosis or exophthalmos.
This in-office technique is rapid, inexpensive,
more immediate, and less
invasive than either CT or MRI.
Unfortunately, ultrasonography can
only image the more anterior aspects
of the orbit, and it requires a highly
skilled and experienced operator to
obtain accurate results.
Additional laboratory testing may be
indicated if a systemic disorder is presumed.
A thyroid function panel--thyroid
stimulating hormone (TSH), serum
triiodothyronine (T3) and serum thyroxine
(T4)--is valuable in patients suspected
of having this disorder.9
In cases
where orbital inflammatory disease is
suspected as secondary to sarcoidosis,
pulmonary function tests, chest X-rays
and, in some cases, angiotensinconverting
enzyme levels may be diagnostic.A
complete blood count is always
helpful in identifying potential malignancies
such as leukemia and lymphoma.
Adjunctive testing for orbital
neoplasms may involve fine-needle
aspiration biopsy (FNAB) or open conjunctival
biopsy if FNAB is inadequate
to ensure a definitive diagnosis.
Therapeutic intervention in cases of
proptosis/exophthalmos may differ substantially,
depending on the underlying
etiology. Hyperthyroidism is treated
medically in most cases with ongoing
therapy with antithyroid drugs (e.g.,
propylthiouracil, methimazole) or singledose
therapy with radioactive iodine to
ablate the thyroid gland. Thyroidectomy
is reserved for severe, unresponsive
cases or for those in whom medical
treatment is contraindicated.9
Most cases
of orbital inflammatory disease are managed
with systemic corticosteroids,
although additional immunomodulatory
agents (e.g., methotrexate, azathioprine,
infliximab) may occasionally be
required.5
The preferred treatment for
orbital tumors, both vascular and neoplastic,
involves surgical resection.
Orbital surgery is a possibility, but it can
be difficult given the confined space and
delicate nature of the surrounding structures.
External beam irradiation may be
used adjunctively in cases of orbital
masses that do not lend themselves to
complete surgical excision.
Primary care management of proptosis/exophthalmos
entails protection
against corneal exposure. Supportive
therapy with ophthalmic lubricants
can be helpful, as can punctal occlusion.
Lid taping at night, in conjunction
with lubricating ointment, is additionally
beneficial in cases of
secondary lagophthalmos. Patients
with diplopia may benefit from temporary
occlusion of the involved eye
or from prismatic correction (e.g.,
Fresnel prism) until definitive treatment
can be offered.
Clinical pearls
* In general, bilateral proptosis/
exophthalmos is highly suggestive of
thyroid disease, while unilateral proptosis/exophthalmos
is indicative of tumor
or infection. There are many exceptions
to this rule however; cases of unilateral
Graves' disease and of bilateral orbital
neoplasms have been documented.10­14
* In cases in which thyroid dysfunction
is suspected, the clinician should
inquire about common signs and symptoms
of hyperthyroidism, including
nervousness, irritability or panic
attacks; insomnia; heat sensitivity or
increased perspiration; weight loss
(despite a normal appetite and diet);
tachycardia; hand tremors; muscular
weakness in the extremities; thinning of
the hair and/or skin; frequent bowel
movements; or lighter or less frequent
menstrual periods.15
* MRI is the preferred orbital imaging
technique in most cases of acute
proptosis. However, CT may be preferable
in conditions that display bony
erosion (e.g., sinus abscess); in the
evaluation of osseous, cartilaginous
and fibro-osseous lesions; and in cases
involving recent trauma. Some practitioners
also prefer CT for patients with
thyroid ophthalmopathy, since it provides
excellent detail of both the
extraocular muscles and bony architecture
of the orbit. CT is also required for
those with medical contraindications to
MRI, e.g., patients with pacemakers,
implanted cardiac defibrillator or
aneurysm clips.
1. Dunsky IL.Normative data for hertel exophthalmometry
in a normal adult black population. Optom Vis Sci
1992;69(7):562­4.
2. KMLE Medical Dictionary, 2007. Available at
http://www.kmle.com.Accessed August 25, 2007.
3. NHS Direct, 2007. Exophthalmos. Available at
http://www.nhsdirect.org.uk/articles/article.aspx?articleId=1
57.Accessed August 25, 2007.
4. Henderson JW, Campbell RJ, Farrow GM, Garrity JA
(eds). Orbital Tumors (third ed.). New York: Raven Press,
1994, pp. 43­52.
5. Lutt JR, Lim LL, Phal PM, Rosenbaum JT. Orbital inflammatory
disease. Semin Arthritis Rheum 2007;Aug 31 [Epub
ahead of print].
6. Soroudi AE, Goldberg RA, McCann JD. Prevalence of
asymmetric exophthalmos in Graves orbitopathy. Ophthal
Plast Reconstr Surg 2004;20(3):224­5.
7. Masud MZ, BabarTF, Iqbal A, et al. Proptosis: Etiology and
demographic patterns. J Coll Physicians Surg Pak
2006;16(1):38­41.
8. Islam N, Mireskandari K, Rose GE. Orbital varices and
orbital wall defects. Br J Ophthalmol 2004;88(8):1092­3.
9. Reid JR, Wheeler SF. Hyperthyroidism: Diagnosis and
treatment.Am Fam Physician 2005 15;72(4):623­30.
10. Kamminga N, Jansonius NM, Pott JW, LinksTP. Unilateral
proptosis: The role of medical history. Br J Ophthalmol
2003;87(3):370­1.
11. Adam A, Mishriki YY. The painful, protruding eye.
Unilateral euthyroid Graves' ophthalmopathy. Postgrad Med
1999;105(7):81­4.
12. Kumar S, Das S, Goyal JL, et al. Bilateral orbital tumor
formation and isolated facial palsy in Waldenstrom's
macroglobulinemia. Int Ophthalmol 2005;26(6):235­7.
13. Sivagnanavel V, Riordan-Eva P, Jarosz J, et al. Bilateral
orbital metastases from a neuroendocrine tumor. J
Neuroophthalmol 2004;24(3):240­2.
14. Buescu A,Teixeira P, Coelho S, et al. Orbital lymphoma
misdiagnosed as Graves' ophthalmopathy. Endocr Pract
2001;7(2):110­2.
15. Nayak B, Hodak SP. Hyperthyroidism. Endocrinol Metab
Clin North Amer 2007;36(3):617­56.
EYELIDSANDADNEXA
14A REVIEW OF OPTOMETRY APRIL 15, 2008
VIRAL CONJUNCTIVITIS
(PHARYNGOCONJUNCTIVAL
FEVER AND EPIDEMIC
KERATOCONJUNCTIVITIS)
Signs and symptoms
The two frequently encountered
forms of self limiting viral conjunctivitis
are pharyngoconjunctival fever
(PCF) and epidemic keratoconjunctivitis
(EKC).1­8
PCF is characterized
by a fever, sore throat--or at
least a history of recent upper respiratory
infection (URI)--and follicular
conjunctivitis.2,5,7,8
It may be
unilateral or bilateral with a classic
characteristic either of spreading
from one eye to the other or becoming
apparent in both eyes after realizing
infection in one.1­6
The cornea
is rarely affected and infiltrates are
uncommon.3
Although the virus can
be eradicated from the conjunctiva in
as soon as 14 days, it has the ability to
remain in fecal excretions for up to 30
days.5,6
This may explain why some
epidemics are centered around swimming
pools in the summer season.2,5,6
This disorder varies in severity and
persists clinically for four days to two
weeks.1­6
The principle symptoms
include global conjunctival redness
(the "pink" eye) watery discharge,
epiphora sometimes leading to a lateral
canthal fissure (splitting of the skin
at the lateral juncture of the upper and
lower eyelids) and variable irritation.1­8
Epidemic keratoconjunctivitis, in
contrast, may present as a unilateral or
bilateral inferior palpebral follicular
conjunctivitis, with epithelial and
subepithelial keratitis and normal
corneal sensation.9,10
The subepithelial
infiltrates (SEI) are typically concentrated
in the central cornea, uniquely
sparing the periphery.9­11
These localized
gatherings of leukocytes can persist
for months, and in one report were
documented to remain for more than
three years.11
Since the SEI are pockets
of cells underneath the corneal epithelium,
they are capable of producing
permanent corneal opacities. Conjunctival
injection, tearing, watery discharge,
red edematous eyelids, pinpoint
subconjunctival hemorrhages,
pseudomembrane (with occasional
true membrane) formation and palpable
painful swelling of the preauricular,
submandibular or submental
lymph nodes are fundamental clinical
signs of the entity.10­12
In severe cases,
conjunctival desiccation can result in
scarring of the palpebral and fornix
conjunctiva.11
Both conditions are contagious.7­9
As a rule, patients present with a history
of contact with a person who had
red eyes or had an upper respiratory
infection.
Pathophysiology
Viral conjunctivitis can be caused
by a number of different viruses.1­13
Most produce mild, self limiting disease,
while others have the potential to
produce severe, disabling visual diffi-
culties.1,2
Most forms of viral/follicular
conjunctivitis appear to be the result of
a host response to an exogenous substance.
Viral conjunctival infections
are thought to be caused by airborne
respiratory droplets or direct transfer
from fingers to the conjunctival surface.
After an incubation period of five
to 12 days, the disease enters an acute
phase, during which inciting particles
trigger cytokines and chemoattractants,
which initiate a watery discharge,
conjunctival hyperemia and
follicle formation.14
Lymphoid follicles
are elevated, avascular lesions ranging
from 0.2 to 2mm, and they consist of
lymphoid germinal centers that have
responded to an infectious agent. PCF
is commonly caused by adenovirus
types 3 and 5, and occasionally by adenoviruses
4 and 7.8
EKC is commonly
caused by adenovirus types 8 and 19.9
Acute hemorrhagic conjunctivitis
(viral/follicular conjunctivitis with
subconjunctival hemorrhage) is a variant
produced by adenovirus types
19 and 37 and the picornavirus.12,13
Adenoviruses also have the ability
to exert a number of self-limiting
effects on the respiratory, genitourinary
and gastrointestinal tracts.1
In
fact, adenoviruses account for 5 to
10% of respiratory illnesses in chil-
dren.7,8
Adenovirus 7a has the
potential to cause community epidemics
via transmission through
children.8
There is evidence that
adenovirus type 8 can produce a
more aggressive response, resulting
in extensive keratitis, subepithelial
opacities, subconjunctival hemorrhage
and pronounced lymphadenopathy.15
Subepithelial infiltrates are caused
by virus antigens and lymphocytes collecting
in the shallow anterior stroma,
just beneath the central epithelium.3,15
Confocal biomicroscopic examination
provides evidence of an inflammatory
response localized to the basal epithelium
and anterior stroma of the central
cornea.8
Some EKC variants include
conjunctival membrane formation.
Acute and chronic autoreactive mechanisms
can cause significant damage to
the eye.17,18
When severe and affecting
the corneal epithelium and substantia
propria of the palpebral conjunctiva,
cicatrization (scarring) may ensue,
leading to significant mechanical alter-
ations.17,18
The end result is fibrosis.17,18
Histologically, conjunctival membranes
consist of fibrin and leukocytes
with fibroblast and collagen deposition.
They occur in prolonged cases.
Pseudomembranes are differentiated
from true membranes by the ease with
which they are removed.11,17,18
As the
components accumulate, they interdigitate
on a molecular level with the
palpebral conjunctiva. As a result,
when they are stripped from the conViral
conjunctivitis (PCF).
CONJUNCTIVA & SCLERA
APRIL 15, 2008 REVIEW OF OPTOMETRY 15A
EYELIDSANDADNEXA
junctival surface, they produce trauma
to the underlying membrane that often
results in bleeding. In cases where the
buildup is considered a pseudomembrane,
removal is easier and less bleeding
occurs. In cases where the buildup
is substantial, creating a true, additional
membrane, removal is laborious,
traumatic, time-consuming and often
damaging to the underlying conjunctiva.
In these cases, bleeding is often
oozing and perfuse.
Diagnostically speaking, one report
showed that cultured viral conjunctivitis
yielded adenovirus as the most
common virus isolated from conjunctiva
(66%), herpes simplex virus 1 as the
most common virus isolated from the
eyelids and cornea (76% and 88%,
respectively) and cytomegalovirus as
the most common virus isolated from
the vitreous (27%).3
Clinically speaking,
a doctor's accurate recognition of
the common ocular viral syndromes
was measured at 88% for herpes simplex
virus 1, 88% for EKC, 70% for
acute hemorrhagic conjunctivitis and
100% for varicella zoster virus.3
However, some misdiagnosed cases
did occur. Thirteen percent of conjunctivitis
thought to be caused by herpes
virus I was determined by laboratory
testing to be secondary to adenovirus,
3.2% was determined to have been
caused by enterovirus, 3.2% was
caused by varicella zoster virus and
3.2% was caused by human
cytomegalovirus.3
Interestingly, 5% of
cases with a clinical diagnosis of herpes
virus I keratitis were discovered to
have been the result of adenovirus.3
These results indicate the sometimes
ubiquitous nature of viral conjunctivitis.
Fortunately, because most cases are
mild and self limiting with treatments
that are similar and supportive, clinical
therapies and diagnoses are officially
recorded by practitioners as accurate
and effective.
Management
In most cases, because viral conjunctivitis
is contagious and self-limiting,
the primary function of management
is to increase patient awareness
by providing education and to
increase patient comfort by relieving
symptoms. Patients should stay home
from work or school until contagious
discharge is eliminated,2
and should
be warned not to share common utensils,
glasses, linens or washcloths.
Medical management may range from
supportive cold compress and tears to
topical vasoconstrictors, topical nonsteroidal
anti-inflammatory medications
and topical steroids BID to QID.
If pseudo- or true membranes are
present, they should be removed using
a forceps or a moistened cotton-tipped
applicator soaked in a combination of
antibiotic solution and anesthetic.
Topical antibiotic steroidal combination
(Tobradex, Maxitrol, Zylet) therapy
QID can be employed following
the removal of the inflammatory
membrane.11
Currently, no specific topical antiviral
medication is recognized as an
effective treatment for viral conjunc-
tivitis.18
However, cidofovir and ribavirin
(nucleoside or nucleotide
analogs) have been described as
agents that affect adenovirus poly-
merase.4
Unfortunately, according to a
published report, cidofovir topical
ophthalmic solution tested on white
rabbits was shown to produce significant
narrowing of lacrimal canaliculus,
redness of eyelid and conjunctival
injection.18
Until these side effects can
be reduced or eliminated, a topical
antiviral medication for viral conjunctivitis
will not reach the marketplace.
Remarkable anti-adenoviral effects
have been observed from adenoviral
receptor inhibitors and natural products,
along with anti-HIV nucleoside
reverse transcriptase inhibitors such as
zalcitabin and sanilbudine.18
Interferon
beta and anti-osteopontin peptide are
two additional compounds that
demonstrate promise.18
One of the confounding issues that
surround this type of conjunctivitis is
that its mode of presentation permits
practitioners to speculate on diagnosis
rather than react to a positively identified
cause.3
Hence, doctors frequently
attempt an empiric, broad-spectrum
approach to an observed, nebulous red
eye by prescribing topical antibiotics
with combinations of topical steroids,
nonsteroidal anti-inflammatory medications
or mast-cell stabilizer/antihistiminic
agents. While one might argue
that little harm can come from initiating
these modalities separately or
together, there is clearly expense,
inconvenience and in some cases toxicity.
Further, if the patient does indeed
have viral conjunctivitis, he or she is
contagious and should be advised as
soon as possible of the potential to
spread the disease to colleagues and
coworkers.7,8
The Point of Care Diagnostic
Services Rapid Pathogen Screening
(RPS) Adeno Detector uses technology
based on lateral flow immunochromatography
to uncover the presence of
adenoviral antigens.19
Foreign substances
are captured by the testing tool
and presented to antigen-specific
monoclonal antibodies inside the
apparatus using a sandwich technique
(antibody, antigen, antibody). The
sample collector is designed to safely
gain and transfer an appropriate ocular
fluid sample from the lower conjunctiva
to the lateral flow immunoassay,
located in a plastic cassette. Once the
sample has been transferred, a result is
available in 10 minutes.19
The test has
a control indicator line; when it
appears in the result window, the test
is valid. The test is best administered
within seven days of the patienťs
developing a red eye.19
It requires a
reasonable viral antigen load to generate
a reading; false-negative readings
are possible and a negative reading
does not exclude other infectious eti-
ologies.19
Compared to the polymerase
chain reaction test (PCR), the RPS
Detector showed a sensitivity of 89%,
indicating that it is nearly as sensitive
as the gold standard.19
According to
FDA and product literature, the data
indicated for the RPS Detector a sensitivity
of 88%, specificity of 91%,
overall agreement between the two
CONJUNCTIVA&SCLERA
16A REVIEW OF OPTOMETRY APRIL 15, 2008
tests of 90%, a positive predictive
value of 76% and a negative predictive
value of 96%.19
However, three of the apparent
false positives found by the RPS
Detector were confirmed by the PCR,
making the specificity of the RPS
93%.19
Clinical pearls
* Office equipment, instruments
and areas should be meticulously
maintained so they do not become a
flashpoint for outbreak.
* Most practitioners reserve topical
steroidal therapy for the severely
symptomatic (SEI on the visual axis
decreasing acuity) or recalcitrant
cases.
* EKC infiltrates typically resolve
without scarring the cornea. Patients
should be told to expect worsening
over the first seven to 10 days and
improvement over three to six weeks.
Steroids should be tapered slowly as
the condition remits.
* Pseudoguttata (elevation of the
Descemeťs membrane) have been
reported secondary to superficial
corneal injury and keratitis.20
These
unexpected lesions may develop in
cases of EKC or PCF, but they are
known to dissipate as the inciting disease
resolves.20
* The adenovirus associated with
PCF can be fatal in children if not
promptly and properly identified and
supported. The URI that preceded the
red eye should not be discounted or
ignored.
1. Kinchington PR, Romanowski EG, Jerold Gordon Y.
Prospects for adenovirus antivirals. J Antimicrob
Chemother 2005;55(4):424­9.
2. Aoki K,TagawaY.A twenty-one year surveillance of adenoviral
conjunctivitis in Sapporo, Japan. Int Ophthalmol Clin
2002;42(1):49­54.
3. Marangon FB, Miller D, Alfonso E. Laboratory results in
ocular viral diseases: implications in clinical-laboratory correlation.
Arq Bras Oftalmol 2007;70(2):189­94.
4. Lenaerts L, Naesens L. Antiviral therapy for adenovirus
infections. Antiviral Res 2006;71(2-3):172­80.
5. ĎAngelo LJ, Hierholzer JC, Keenlyside RA, et al.
Pharyngoconjunctival fever caused by adenovirus type 4:
Report of a swimming pool­related outbreak with recovery
of virus from pool water. J Infect Dis 1979;140(1):42­7.
6. Harley D, Harrower B, Lyon M, et al. A primary school
outbreak of pharyngoconjunctival fever caused by adenovirus
type 3. Commun Dis Intell 2001 ;25(1):9­12.
7. Chen HL, Chiou SS, Hsiao HP, et al. Respiratory adenoviral
infections in children:A study of hospitalized cases in
southern Taiwan in 2001­2002. J Trop Pediatr 2004
;50(5):279­84.
8. Mitchell LS,Taylor B, Reimels W, et al. Adenovirus 7a: A
community-acquired outbreak in a children's hospital.
Pediatr Infect Dis J 2000;19(10):996­1000.
9. Schrauder A, Altmann D, Laude G, et al. Epidemic conjunctivitis
in Germany, 2004. Euro Surveill
2006;11(7):185­7.
10. Uchio E,Takeuchi S, Itoh N, et al. Clinical and epidemiological
features of acute follicular conjunctivitis with special
reference to that caused by herpes simplex virus type
1. Br J Ophthalmol 2000;84(9):968­72.
11. Murrah WF. Epidemic keratoconjunctivitis. Ann
Ophthalmol 1988;20(1):36­8.
12. Karki DB, Shrestha CD, Shrestha S. Acute haemorrhagic
conjunctivitis: An epidemic in August/September
2003. Kathmandu Univ Med J (KUMJ) 2003;1(4):234­6.
13. Chang CH, Sheu MM, Lin KH, et al. Hemorrhagic viral
keratoconjunctivitis in Taiwan caused by adenovirus types
19 and 37: Applicability of polymerase chain reactionrestriction
fragment length polymorphism in detecting
adenovirus genotypes. Cornea 2001;20(3):295­300.
14. Kaneko H, Kondo T, Fujiwara T, et al. Clinical and virological
studies of nosocomial conjunctivitis infection caused
by adenovirus type 37 variant. Nippon Ganka Gakkai
Zasshi 2005;109(8):489­96.
15. Chang C, Sheu M, Chern C, et al. Epidemic keratoconjunctivitis
caused by a new genotype of adenovirus
type 8 (Ad8)--a chronological review of Ad8 in Southern
Taiwan. Jpn J Ophthalmol 2001;45(2):160­6.
16. Alsuhaibani AH, Sutphin JE, Wagoner MD. Confocal
microscopy of subepithelial infiltrates occurring after epidemic
keratoconjunctivitis. Cornea 2006;25(9):1102­4.
17. Rashid S, Dana MR. Cicatrizing and autoimmune diseases.
Chem Immunol Allergy 2007;92:195­202.
18. Uchio E. New medical treatment for viral conjunctivitis.
Nippon Ganka Gakkai Zasshi 2005;109(12):962­84.
19. Rapid pathogen screening. Point-of-Care Diagnostic
Services Adeno Detector instructional insert. RPS Insert
2006:1­2.
ATOPIC KERATOCONJUNCTIVITIS
Signs and symptoms
Patients with atopic keratoconjunctivitis
(AKC) invariably have a
personal or family history of allergic
disease. This may include
atopic dermatitis (i.e., eczema),
asthma, hayfever, food allergies,
and/or urticaria.1,2
Patients are usually
male, older than 20 years, with
the peak incidence of AKC occurring
between ages 30 and 50.1­3
The
condition is marked by exacerbations
and remissions, with the most
symptomatic periods occurring
during colder winter months.1­4
Symptoms associated with AKC
primarily consist of intense bilateral
itching with associated hyperlacrimation.
Patients may also complain of a
stringy or ropy mucoid discharge.
Eyelid swelling may be substantial,
with painful burning of the lids and
periocular skin. Inspection of the eyelids
reveals characteristically scaly,
indurated and wrinkled skin, with the
possibility of fissure development at
the lateral canthus associated with
chronic ocular rubbing and epipho-
ra.2­4
Biomicroscopically there will be
pronounced conjunctival hyperemia
and edema, as well as tarsal papillae.
Gelatinous limbal papillae and
Horner-Trantas dots (i.e., collections
of degenerated epithelial cells and
eosinophils), considered pathognomonic
for vernal keratoconjunctivitis,
may also be seen in advanced cases.2­4
Notable corneal involvement may also
be encountered, including punctate
keratitis, persistent epithelial erosions,
"shield ulcers," mucus plaque
formation and neovascularization.
The chronic inflammation associated
with AKC has the capacity to
impart cicatricial changes within the
conjunctiva and cornea. Subepithelial
conjunctival fibrosis, symblepharon
(with subsequent entropion), corneal
lipid deposition and pannus are not
uncommon.4,5
Primary corneal ectasias,
such as keratoconus and pellucid
marginal degeneration, may also occur
in association with AKC. These
corneal changes often bring associated
astigmatic changes and scarring, with
subsequent visual impairment. Interestingly,
cataract development is posShield
ulcer in atopic keratoconjunctivitis.
PhotocourtesyofWilliamTownsend,OD,FAAO
APRIL 15, 2008 REVIEW OF OPTOMETRY 17A
CONJUNCTIVA&SCLERA
sible in AKC. Anterior subcapsular
opacities (sometimes called "shield
cataracts") are the predominant variety,
and these are thought to result
from atopic inflammation.2,4
Posterior
subcapsular cataracts may be encountered
to a lesser degree, especially in
cases of prolonged topical corticosteroid
usage.2,4
Pathophysiology
AKC is believed to manifest elements
of both Type I and Type IV
hypersensitivity reactions.6
Type I represents
an immediate or anaphylactic
reaction and involves the sudden
degranulation of mast cells mediated
by IgE antibodies; this is the response
seen in acute allergic conjunctivitis
(e.g., seasonal and perennial allergic
conjunctivitis). A Type IV reaction,
also known as a delayed or cell-mediated
hypersensitivity reaction,
involves T-lymphocytes and associated
lymphokines. Other examples of Type
IV reactions include contact dermatitis
and phlyctenulosis.
Histopathologic evaluation of conjunctival
samples from patients with
AKC reveals elevated levels of mast
cells, lymphocytes, eosinophils and
basophils.1
Mast cell degranulation--
which is seen in acute forms of ocular
allergy--initiates the release of histamine,
chymase, tryptase and heparin;
these mediators are responsible for
vasodilation, increased collagenase
activity and early fibrinogenesis.7
In
addition, degranulation of eosinophils
releases numerous toxic/ inflammatory
proteins, such as eosinophil cationic
protein, eosinophil peroxidase, and
eosinophil-derived neurotoxin.7
Not
only do these proteins induce cicatricial
changes in the conjunctiva, but
they have also been shown to cause
cytotoxic disruption in corneal epithelial
cells, suggesting a possible mechanism
for the extensive corneal pathology
seen in AKC.8
It has been suggested that inherent
feedback mechanisms that normally
regulate the allergic response may be
impaired in atopic disorders, resulting
in continuous T-cell activation.7
Research has identified several specific
genes that may be responsible, and
this theory is supported by the strong
role of family history in atopic diseases
such as AKC.9
Management
AKC is a chronic and potentially
blinding disease. Once it is identified,
treatment must be swift and aggressive.
The ultimate goals are to alleviate
the debilitating symptoms and preserve
vision while minimizing the
potential side effects of medical therapy.
Numerous palliative measures,
including cold compresses, ophthalmic
lubricants and topical vasoconstrictors,
may all be of short-term
benefit. In addition, topical antihistamines
or antihistamine-mast cell stabilizer
combinations (e.g., Pataday QD)
address the initial allergic response
and can provide longer-lasting relief
for many patients. However, since a
good portion of the pathology in AKC
is associated with leukocyte infiltration/
degranulation, topical corticosteroids
are almost invariably
required to suppress the inflammatory
response. Prednisolone acetate
1% is considered the gold standard
of topical ophthalmic steroids, but
this agent may also raise intraocular
pressure and induce cataract
formation with prolonged use.
Loteprednol etabonate 0.5% may
provide a safer, although possibly
less efficacious, alternative in cases
of AKC that require long-term corticosteroid
therapy.10
Dosing of
steroids varies depending on the
individual case; in general, we advocate
at least QID instillation, increasing
the frequency concurrent with
increased levels of inflammation.
Steroids should be continued for at
least one to two weeks before attempting
a slow taper. In the case of corneal
shield ulcers, topical cycloplegia (e.g.,
0.25% scopolamine BID) and broadspectrum
antibiotic prophylaxis (e.g.,
0.3% tobramycin or 0.3% ciprofloxacin
BID) may be warranted.
Some prefer the convenience of a
combination antibiotic/corticosteroid
such as TobraDex (Alcon) or Zylet
(Bausch & Lomb) in these situations.
Patients with AKC who are inadequately
controlled with topical corticosteroids
or those who experience
negative sequelae warranting discontinuation
of steroids may require alternative
immunomodulatory therapy.
Topical cyclosporine may be an effective
alternative in this situation; it has
been shown to specifically inhibit Tlymphocyte
proliferation while
imparting direct inhibitory effects on
eosinophil and mast-cell activation.11
Early research using 2% cyclosporine
in maize oil demonstrated a distinct
benefit12
; however, clinical studies
involving 0.05% cyclosporine emulsion
(Restasis, Allergan) have shown
mixed results.13,14
For significant atopic dermatitis
involving the lids, additional topical
therapy may be necessary. Corticosteroid
creams or ointments may be
highly beneficial in this capacity; some
options include 1% hydrocortisone,
0.1% triamcinolone acetonide or 0.05%
clobetasone butyrate. In lieu of steroids,
topical 0.1% tacrolimus ointment
(Protopic, Astellas Pharma) has demonstrated
equivalent safety and efficacy in
a head-to-head clinical study.15
Clinical pearls
* It is important to distinguish
between AKC and vernal keratoconPronounced
tarsal papillae with cicatricial scarring
in AKC.
18A REVIEW OF OPTOMETRY APRIL 15, 2008
junctivitis (VKC). VKC is another
form of chronic inflammatory ocular
allergy; however, unlike AKC, it tends
to be seen in younger male patients
(ages 3 to 25 years). VKC also has a
tendency to become exacerbated during
warmer months and in warmer climates,
compared with AKC, which
worsens in colder climates. Clinically,
VKC presents with classic "cobblestone"
papillae on the upper tarsus,
while the papillae in AKC have a
propensity for the lower cul-de-sac.1
* AKC must also be differentiated
from more acute conditions such as
contact eyelid dermatitis and preseptal
cellulitis. Contact dermatitis typically
involves a history of exposure to some
agent or object and presents with
edema, erythema and pronounced
itching. Corneal involvement is
exceedingly rare. Preseptal cellulitis
involves a focal infection within the
eyelid, presenting with acute unilateral
pain and swelling.
* "Shield ulcers," which are not
actually ulcers but epithelial erosions,
typically occur with VKC, but they
may occur with AKC as well. These
corneal defects are caused by a combination
of corrosive inflammatory
cytokines and the mechanical rubbing
of the tarsus over the cornea.
* While some have advocated the
use of topical nonsteroidal antiinflammatory
drugs (NSAIDs) in the
management of AKC, our experience
suggests that these agents provide little
benefit. In addition, there is a
potential risk of corneal melts when
these agents are used inappropriately.
Likewise, some sources recommend
oral antihistamines as adjunctive therapy
for AKC. Unfortunately, the histamine
response is such a minor element
of AKC and the amount of drug delivered
to the ocular tissues with oral formulations
(vs. topical agents) is so
minimal that there is likely to be little
clinical benefit.
* Despite the number of therapeutic
options, AKC can be exceedingly difficult
to treat, particularly in later
stages after multiple exacerbations.
Consultation and co-management
with an allergist, dermatologist and
corneal surgeon should be considered
for such patients.
1. Butrus S, Portela R. Ocular allergy: Diagnosis and treatment.
Ophthalmol Clin North Am 2005;18(4):485­92.
2. Bielory L. Allergic and immunologic disorders of the
eye. Part II: Ocular allergy. J Allergy Clin Immunol
2000;106(6):1019­32.
3. Ono SJ, Abelson MB. Allergic conjunctivitis: Update on
pathophysiology and prospects for future treatment. J
Allergy Clin Immunol 2005;115(1):118­22.
4. Zhan H, Smith L, Calder V, et al. Clinical and immunological
features of atopic keratoconjunctivitis. Int
Ophthalmol Clin 2003;43(1):59­71.
5. Bonini S. Atopic keratoconjunctivitis. Allergy
2004;59(S78):71­3.
6. Faraj HG, Hoang-Xuan T. Chronic cicatrizing conjunctivitis.
Curr Opin Ophthalmol 2001;12(4):250­7.
7. Abelson MB, Chapin MJ, Leonardi A. AKC: Current and
future treatments. Rev Ophthalmol 2001;8(4):100­2.
8. Leonardi A, Borghesan F, Faggian D, et al.Tear and serum
soluble leukocyte activation markers in conjunctival allergic
diseases. Am J Ophthalmol 2000;129(2):151­8.
9. Calder VL, Jolly G, Hingorani M, et al. Cytokine production
and mRNA expression by conjunctival T-cell lines in
chronic allergic eye disease. Clin Exp Allergy
1999;29(9):1214­22.
10. Novack GD, Howes J, Crockett RS, Sherwood MB.
Change in intraocular pressure during long-term use of
loteprednol etabonate. J Glaucoma 1998;7(4):266­9.
11. Whitcup SM, Chan CC, Luyo DA, et al. Topical
cyclosporine inhibits mast cell­mediated conjunctivitis.
Invest Ophthalmol Vis Sci 1996;37(13):2686­93.
12. Hingorani M, Moodaley L, Calder VL, et al. A randomized,
placebo-controlled trial of topical cyclosporin A in
steroid-dependent atopic keratoconjunctivitis. Ophthalmol
1998;105(9):1715­20.
13. Akpek EK, Dart JK,Watson S, et al. A randomized trial
of topical cyclosporin 0.05% in topical steroid-resistant
atopic keratoconjunctivitis. Ophthalmol
2004;111(3):476­82.
14. Daniell M, Constantinou M, Vu HT, Taylor HR.
Randomised controlled trial of topical ciclosporin A in
steroid dependent allergic conjunctivitis. Br J Ophthalmol
2006;90(4):461­4.
15. Nivenius E, van der Ploeg I, Jung K, et al. Tacrolimus
ointment vs. steroid ointment for eyelid dermatitis in
patients with atopic keratoconjunctivitis. Eye
2007;21(7):968­75.
OCULAR MELANOSIS
Signs and symptoms
Ocular melanosis represents a
pigmented discoloration of the
superficial ocular tissues. Patients
are not usually symptomatic with
regard to discomfort or visual disturbance,
but they often present
with cosmetic concerns, particularly
when the condition is newly
acquired. In some cases, patients
will report that their eyes are
chronically red, mistakenly interpreting
the ocular pigmentation as hyperemia.
Biomicroscopically, ocular
melanosis appears as a brown-todark-brown
discoloration of the
epibulbar conjunctiva. Depending
upon the etiology, it may be unilateral
or bilateral and flat to slightly elevated,
and it may take the form of irregular
patches, streaks or circumlimbal
darkening.
Racial melanosis is a congenitally
acquired condition that is exceedingly
common in patients of African
descent. It occurs on the order of 92%
according to some sources.1,2
This
condition tends to be bilateral and
symmetric, is most prominent circumlimbally
and remains relatively consistent
throughout a patienťs life.
Conjunctival nevi are the most
common type of conjunctival
melanosis. They present as discrete,
well-demarcated congenital lesions,
located most often on the interpalpebral
bulbar conjunctiva but occasionally
affecting the caruncle, plica or lid
margin.3
They may be flat to slightly
elevated with occasional cystic formations,
and may vary significantly
in pigment density. Caucasians are
most likely to develop conjunctival
nevi as compared to other races
accounting for 89% of cases according
to one clinical series.4
Primary acquired melanosis (PAM)
is less common than racial melanosis
and conjunctival nevi, and it tends to
occur much more frequently in
Caucasians than in those of African
Primary acquired melanosis is typically unilateral
and irregular.
APRIL 15, 2008 REVIEW OF OPTOMETRY 19A
CONJUNCTIVA&SCLERA
descent.3
It may be differentiated from
racial melanosis in that it is typically
unilateral and irregularly shaped,
demonstrating increased growth over
time and involving widespread areas of
the conjunctiva, including the fornices.
Malignant conjunctival melanoma
is a rare tumor of the ocular surface. It
is typically encountered in middleaged
or elderly white patients,
although a small number of cases
involving patients of African descent
have been documented.1,2,5­7
Clinically,
conjunctival melanomas are densely
pigmented elevated or nodular lesions
with intrinsic vascularization (sometimes
called "feeder vessels") arising
from the fornices. They are generally
unilateral but often multicentric, and
may involve areas of the bulbar and/or
tarsal conjunctiva.
Pathophysiology
The word melanosis is a generic
term referring to excessive darkening
of a tissue due to a disturbance in
melanin production or deposition. In
cases where the eye is involved, the
condition is sometimes called melanosis
oculi or melanosis bulbi. In
racial melanosis, there is an accumulation
of benign melanocytes and
melanin granules within the basilar
layer of the conjunctival epithelium,
typically limited to the perilimbal tis-
sues.8,9
Conjunctival nevi also represent
benign proliferations of
melanocytes within the basal layer of
the epithelium. As a patient ages however,
these nevus cells can migrate
deeper into the underlying stroma.3
In contradistinction to racial
melanosis and conjunctival nevi,
PAM is characterized by the presence
of abnormal melanocytes within or
near the basal layer of the epithelium.
Four types of cells--small
polyhedral, epithelioid, spindle
and dendritic--may be identified
in these lesions.3,10,11
Additionally,
PAM may display five distinct
growth patterns: basilar hyperplasia,
basilar nests, intraepithelial
nests, pagetoid growth (i.e., cell
invasion into the epithelium) and
melanoma-in-situ (i.e., the
replacement of normal epithelial
cells with melanocytes).3,10,11
PAM
is classified histopathologically,
based on the type of atypical cells and
the extent of intraepithelial growth.
Lesions that show a propensity toward
large, atypical (e.g., epithelioid) cells
and epithelial invasion constitute
PAM with atypia; those that are comprised
primarily of small polyhedral
cells and remain confined to the basal
epithelial layer are referred to as PAM
without atypia.3
These distinctions are
important, because atypia has been
shown to correlate to a lesion's
potential for malignant transfor-
mation.3,8­13
Conjunctival melanoma may
reflect malignant transformation
of pre-existing nevi or PAM; less
commonly, they arise de novo.1-6,9­13
These lesions often show prominent
nesting of atypical melanocytes
in the junctional region (i.e.,
between the epithelial and subepithelial
tissues), as well as pagetoid
extension of tumor cells into
the overlying epithelium.3
The
definitive diagnostic criterion for
invasive melanoma is extension of
atypical melanocytes into the underlying
conjunctival stroma (substantia
propria).12
Melanoma is a highly
malignant tumor and has significant
capacity for distant metastasis; its
spread to the ipsilateral facial lymph
nodes, brain, lung and liver are most
common.14,15
Management
Management strategies for ocular
melanosis are dependent upon the
nature of the condition. Racial
melanosis is considered benign and
warrants no intervention other than
education and reassurance for patients
with cosmetic concerns. Only in cases
that are unilateral or seemingly progressive
should the practitioner consider
additional testing. Conjunctival
nevi may require greater scrutiny.
Physicians should inquire regarding
any recent changes in lesional size,
elevation, color or irritation, and also
consider unusual features such as
increased vascularization or unusual
location. Suspicious lesions should be
referred for excisional biopsy to rule
out malignancy, but in most cases,
simple periodic observation constitutes
adequate management for conjunctival
nevi.4
PAM typically warrants greater
concern and investigation. Since PAM
may have a propensity for malignant
transformation and is potentially life-
threatening,11
practitioners should
routinely arrange for excisional biopsy
on these patients. Those cases that
do not display atypia or display only
mild atypia on histological evaluation
may be followed using the same
guidelines as with a conjunctival
nevus, as the risk of malignant conversion
in these lesions is quite low.3,12
However, if PAM with moderate or
Pronounced racial melanosis.
Mild racial melanosis.
20A REVIEW OF OPTOMETRY APRIL 15, 2008
severe atypia is noted, then prompt
removal of the lesion is indicated.
Management options may include
surgical excision with or without
cryotherapy, radiotherapy, exenteration
or extirpation and topical chemotherapy;
the individual treatment for any
given case depends on the lesion's size,
disposition and location.3
Cases of suspected conjunctival
melanoma should be referred promptly
to an ocular oncologist or oculoplastics
specialist for evaluation and
excisional biopsy. The management of
these lesions can be difficult and
varies based upon the extent and
severity of the presentation, although
surgical removal is typically the treatment
of first choice. Excision with
wide margins and adjunctive
cryotherapy to ensure destruction of
the malignant tissue is used for isolated
melanomas, while lesions that
extend into the globe or orbit may
warrant enucleation or orbital exenteration,
respectively.9
Despite treatment,
the risk of morbidity is high.
One long-term study found the following
results: The risk of local tumor
recurrence is 26% at five years, 51%
at 10 years, and 65% at 15 years;
metastasis was present in 16% of
patients at five years, 26% of patients
at 10 years, and 32% of patients at 15
years; and tumor-related death
occurred in 7% of patients at five
years and 13% at eight years.14
Clinical pearls
* Racial melanosis is exceedingly
prevalent in dark-skinned individuals,
but pigmented lesions of the conjunctiva
are otherwise relatively uncommon.
In general, lesions that are unilateral,
elevated, or more prominent in
the fornices or palpebral conjunctiva
have a greater tendency toward malignancy
and warrant close scrutiny.
* The transformation of conjunctival
nevi to malignant melanoma
occurs only in rare instances, about
4% of the time or less.4,14
Still, practitioners
should consider any changes in
size, elevation, color or vascularization
to be suspicious and an indication
for additional consultation or testing.
* PAM and malignant melanoma
may sometimes be overlooked or dismissed
in dark-skinned patients
because the conditions are similar in
appearance to racial melanosis.
Practitioners must remain diligent and
obtain appropriate testing in all cases
of atypical conjunctival melanosis,
regardless of the patienťs race.
* Both conjunctival nevi and
melanomas may occasionally present
as amelanotic lesions; i.e., devoid of
melanin pigment. In such cases, they
usually appear as pink, variably elevated
fleshy plaques or nodules. The
prognosis for these lesions is the
same as for the pigmented variety;
however, definitive diagnosis is often
delayed because of the atypical
appearance.16
1. Colby KA, Nagel DS. Conjunctival melanoma arising
from diffuse primary acquired melanosis in a young black
woman. Cornea 2005;24(3):352­5.
2. Singh AD, Campos OE, Rhatigan RM, et al. Conjunctival
melanoma in the black population. Surv Ophthalmol
1998;43(2):127­33.
3. Lin SM, Ferrucci S. Primary acquired melanosis of the
conjunctiva. Optom 2006;77(5):223­8.
4. Shields CL, Fasiuddin AF, Mashayekhi A, Shields JA.
Conjunctival nevi: Clinical features and natural course in
410 consecutive patients. Arch Ophthalmol
2004;122(2):167­75.
5. Schwab L, Green WR. Conjunctival melanoma in Africa.
Ophthalmic Surg 1987;18(12):900­3.
6. Crawford JB. Conjunctival melanomas: Prognostic factors
a review and an analysis of a series. Trans Am
Ophthalmol Soc 1980;78:467­502.
7. Charles NC, Stenson S,Taterka HB. Epibulbar malignant
melanoma in a black patient. Arch Ophthalmol
1979;97(2):316­8.
8. Jakobiec FA. The ultrastructure of conjunctival
melanocytic tumors. Trans Am Ophthalmol Soc
1984;82:599­752.
9. Shields CL, Shields JA. Tumors of the conjunctiva and
cornea. Surv Ophthalmol 2004;49(1):3­24.
10. Folberg R, McLean IW, Zimmerman LE. Primary
acquired melanosis of the conjunctiva. Hum Pathol
1985;16(2):129­35.
11. Corcoran KT, Marsich MM, Ward DC. Potentially lifethreatening
primary acquired melanosis. Clin Eye Vis Care
2000;12(3­4):185­8.
12. Shields JA, Shields CL, Mashayekhi A, et al. Primary
acquired melanosis of the conjunctiva: Risks for progression
to melanoma in 311 eyes. The 2006 Lorenz E.
Zimmerman Lecture. Ophthalmol 2007; [Epub ahead of
print].
13. Brownstein S. Malignant melanoma of the conjunctiva.
Cancer Control 2004;11(5):310­6.
14. Shields CL, Shields JA, Gunduz K, et al. Conjunctival
melanoma: risk factors for recurrence, exenteration,
metastasis, and death in 150 consecutive patients. Arch
Ophthalmol 2000;118(11):1497­507.
15. Esmaeli B, Eicher S, Popp J, et al. Sentinel lymph node
biopsy for conjunctival melanoma. Ophthal Plast Reconstr
Surg- 2001;17(6):436­42.
16. Paridaens AD, McCartney AC, Hungerford JL.
Multifocal amelanotic conjunctival melanoma and acquired
melanosis sine pigmento. Br J Ophthalmol
1992;76(3):163­5.
PYOGENIC GRANULOMA
Signs and symptoms
Considered overgrowths of vascular
tissue, pyogenic granulomas are
unsightly, sometimes pedunculated,
dome-shaped lesions that arise on the
face, eyes, lips, hands or mucosal
membranes after episodes of chronic
irritation or minor trauma.1­7
They are
also known to arise during pregnan-
cy.5
Pyogenic granulomas have also
been reported to arise within congenital
capillary malformations such as
port-wine stains.6
However, in these
cases they usually present following
cosmetic laser treatments.6
The
lesions possess the unusual characteristic
of bleeding easily.8
The eye, the adnexa, the eyelids,
the conjunctiva and rarely the cornea
may be affected.1­5
When the lesions
are seen on the cornea they are located
anterior to Bowman's layer, leaving
the corneal stroma unaffected.6
Patients may complain of tearing or
interrupted eyelid closure, depending
upon the location of the growth. The
lesions rarely induce pain or discomfort
of any kind. Visual acuity is only
affected if the lesion interrupts the
visual axis or induces a keratopathy
secondary to incomplete tear film
spreading. In most instances, the
patient presents with a concern over a
steadily growing, unattractive mass,
with fear that it is a cancerous tumor.6
There is no gender or racial predilection;
nor is there a common decade of
evolution.7
Evidence supports unexplained,
spontaneous development of
pyogenic granulomas.9
In one study,
clinicians reported an anomalous
occurrence of multiple, eruptive pyogenic
granulomas in a previously
healthy 17-year-old girl, who developed
more than 200 spontaneous
APRIL 15, 2008 REVIEW OF OPTOMETRY 21A
lesions over eight months.9
Pathophysiology
Pyogenic granulomas are neither
pyogenic (pus-producing) nor granulomatous
(being a collection of
fibroblasts and macrophages surrounded
by lymphocytes produced
secondary to inflammation or infec-
tion).1­7
Pyogenic granulomas (lobular
capillary hemangioma) are polypoidal
vascular proliferations, often accompanied
by inflammatory infiltrates,
that may affect the skin and mucosal
linings of the body.1­5
Pyogenic granulomas
are considered to be among the
most common acquired vascular
growths of the eyelids.5
They typically
arise following an episode that
incites a local vasoproliferative
inflammatory response, such as trauma,
chronic irritation (the friction created
by an exposed suture, punctal
plug or prosthesis post, toxic substances
and infection) or a surgical
procedure such as cataract extraction
or a chalazion removal, proximal to
the area.1­13
The inflammatory infiltrate
seen in cases involving the
cornea is composed mainly of
mononuclear cells, with no multinucleated
giant cells. The lesions are not
malignant.5,13,14
Management
Treatment begins with differential
diagnosis. Chalazia, internal hordeola,
squamous cell carcinoma and
sebaceous cell carcinoma are all differential
diagnoses. Once the definitive
diagnosis is made, one can make
a conservative effort to regress tissue
proliferation by removing the inciting
factor and prescribing topical ophthalmic
steroidal creams, ointments
and drops BID­QID.7,11
Should less
invasive therapy fail, excision and
biopsy (removing the lesion at its
base) is common practice.2,7
When the
lesions are properly excised with
direct closure, recurrences are uncom-
mon.7
Uncomplicated pyogenic granulomas
(away from the lid margin and
free from intimate involvement with
adjacent tissues) can be removed
using single-shave excision and elec-
trocautery.8
A pulsed dye laser has
been employed to treat pyogenic granulomas
due to its ability to induce
selective destruction of superficial
cutaneous capillaries, thus minimizing
trauma and scarring.15
The procedure
seems particularly applicable in
apprehensive patients and in chil-
dren.15
Another set of investigators
reported success using a combined
continuous-wave/pulsed carbon dioxide
(CO2
) laser.16
Promising results
have been recorded, with few adverse
effects and low recurrence rates with
excellent tolerability.16
It has been
suggested recently that continuouswave/pulsed
CO2 laser should be considered
as the treatment of first
choice.16
Cryotherapy has also been
used to treat these lesions.17
Due to
imperceptible scarring in the majority
of cases, cryotherapy should be welcomed
into the armamentarium of
management options.17
Silver nitrate
cauterization has also been used by
dermatologists.18
In one published
investigation, successful cauterization
of skin-based masses using silver
nitrate applicators following blunt
removal resulted in complete resolution
in 85% of patients, after an average
of 1.6 treatments (range: one to
three treatments).18
Clinical pearls
* Pyogenic granulomas induced by
punctal plugs can spontaneously produce
punctal plug extrusion (the
movement and/or dislodgement of the
plug).
* Larger punctal plug sizes and
sharp plug edges (relating to either
punctal plug design or deformity) are
also associated with pyogenic granuloma
formation.
* When corneal mass lesions are
discovered, pyogenic granuloma
should be considered and ruled out to
avoid unnecessarily aggressive inter-
vention.
1. Googe JM, Mackman G, Peterson MR, et al. Pyogenic
granulomas of the cornea. Surv Ophthalmol
1984;29(3):188­92.
2. Carmen González-Vela M, Fernando Val-Bernal J,
Francisca Garijo M, et al. Pyogenic granuloma of the sigmoid
colon. Ann Diag Pathol 2005;9(2):106­9.
3. Gupta S, Radotra BD, Kumar B. Multiple, genital lobular
capillary haemangioma (pyogenic granuloma) in a young
woman: A diagnostic puzzle. Sex Transm Infect
2000;76(1):51­2.
4. Neff AG, Carter KD. Benign eyelid lesions. In:Yanoff M,
Duker JS, Ophthalmology (second ed.), Philadelphia:
Mosby, 2004, pp. 698­710.
5. Mietz H, Arnold G, Kirchhof B, et al. Pyogenic granuloma
of the cornea: Report of a case and review of the literature.
Graefes Arch Clin Exp Ophthalmol 1996
;234(2):131­6.
6. Sheehan DJ, Lesher JL. Pyogenic granuloma arising within
a port-wine stain. Cutis 2004;73(3):175­80.
7. Giblin AV, Clover AJ, Athanassopoulos A, et al. Pyogenic
granuloma--the quest for optimum treatment: Audit of
treatment of 408 cases. J Plast Reconstr Aesthet Surg
2007; Epub ahead of print.
8. Pagliai KA, Cohen BA. Pyogenic granuloma in children.
Pediatr Dermatol 2004;21(1):10­13.
9. Shah M, Kingston TP, Cotterill JA. Eruptive pyogenic
granulomas: A successfully treated patient and review of
the literature. Br J Dermatol 1995;133(5):795­6.
10. Yazici B, Akova B, Sanli O. Complications of primary
placement of motility post in porous polyethylene implants
during enucleation.Am J Ophthalmol 2007;143(5):828­34.
11. Chou TY, Perry HD, Donnenfeld ED, et al. Pyogenic
granuloma formation following placement of the
Medennium SmartPLUG punctum plug. Cornea
2006;25(4):493­5.
12. Kim BM, Osmanovic SS, Edward DP. Pyogenic granulomas
after silicone punctal plugs: A clinical and histopathologic
study. Am J Ophthalmol 2005;139(4):678­84.
13. Proia AD, Small KW. Pyogenic granuloma of the
cornea induced by "snake oil." Cornea 1994;13(3):284­6.
14. Papadopoulos M, Snibson GR, McKelvie PA. Pyogenic
granuloma of the cornea. Aust NZ J Ophthalmol
1998;26(2):185­8.
15. TayYK,Weston WL, Morelli JG.Treatment of pyogenic
granuloma in children with the flashlamp-pumped pulsed
dye laser. Pediatrics 1997;99(3):368­70.
16. Raulin C, Greve B, Hammes S.The combined continuous-wave/pulsed
carbon dioxide laser for treatment of
pyogenic granuloma. Arch Dermatol 2002;138(1):33­7.
17. Mirshams M, Daneshpazhooh M, Mirshekari A, et al.
Cryotherapy in the treatment of pyogenic granuloma. J Eur
Acad Dermatol Venereol 2006;20(7):788­90.
18. Quitkin HM, Rosenwasser MP, Strauch RJ.The efficacy
of silver nitrate cauterization for pyogenic granuloma of
the hand. J Hand Surg [Am] 2003;28(3):435­8.
CONJUNCTIVA&SCLERA
A pyogenic granuloma of the bulbar conjunctiva.
22A REVIEW OF OPTOMETRY APRIL 15, 2008
HERPES SIMPLEX VIRUS
EPITHELIAL KERATITIS
Signs and symptoms
Patients with herpes simplex virus
(HSV) epithelial keratitis tend to be
young, though more patients in older
age groups are acquiring HSV for the
first time.1,2
HSV epithelial keratitis also
occurs in children, who may have bilateral
involvement.3,4
There is no gender or
racial predilection.1
Epithelial keratitis is the most common
presentation of ocular infection by
HSV-1.2
Epithelial keratitis caused by
HSV typically presents as a unilateral
red eye with a variable degree of pain or
ocular irritation. Bilateral HSV epithelial
keratitis, while uncommon, does
occur in 1­2% of cases and is often
complicated by immunosuppression,
occult malignancy, or atopic disease.5
Photophobia and epiphora are common.
Vision may or may not be affected,
depending upon the location and extent
of the corneal lesion. A vesicular skin
rash and follicular conjunctivitis may be
seen with the initial primary infection,
but are less common with recurrent
HSV.1
Secondary uveitis is often
encountered with the keratitis.
The hallmark sign of HSV infection
involves a dendritic ulceration of the
corneal epithelium, accompanied by a
stromal keratitis in more severe presen-
tations.1,2
Endothelial inflammation with
edema and underlying keratic precipitates,
known as endotheliitis, can also be
present.1,2
These lesions may begin as
nondescript punctate keratopathies that
quickly coalesce to form the familiar
branching patterns that stain brightly
with sodium fluorescein dye. Early
corneal epithelial changes in primary
HSV infections often show clear epithelial
vesicles and rounded limbal epithelial
foci, which eventually form the
stereotypical HSV dendrites.6
Because
the virus invades and compromises the
epithelial cells surrounding the ulcer, the
leading edges (the so-called terminal
end-bulbs) exhibit staining with rose
bengal dye and lissamine green dye.
However, various factors, including
duration since onset, medication use,
atopic disease and history of corneal
transplantation, can give HSV epithelial
keratitis lesions an atypical appearance
that may be misdiagnosed.7
HSV epithelial keratitis commonly
recurs.8,9
The disease itself often recurs
in the same clinical pattern as the first
episode, with a recurrence rate of 0.6
episodes per year.9
Precipitating trigger
factors include fever, hormonal changes,
ultraviolet sun exposure, psychological
stress, ocular trauma, trigeminal nerve
manipulation, steroid use, ocular surgery,
exposure to ultraviolet radiation,
immunosuppressive agents and glaucoma
treatment with prostaglandin
analogs.1,10­14
Pathophysiology
HSV is the most common virus in
humans and can be found in the trigeminal
ganglion in almost 100% of those
older than 60 years.1
HSV-1 affects predominantly
the upper half of the body;
HSV-2 is associated mainly with the
lower half of the body.15
HSV is transmitted
via bodily fluids--usually saliva--and
may affect the skin and mucous
membranes of the host.1
Primary herpetic
infections occur most often in children
ages 6 months to 5 years.The manifestation
of this infection is generally a
vesicular rash, sometimes affecting the
skin of the eyelids (which may go unnoticed)
but more commonly resulting in a
"fever blister" or "cold sore" in or
around the mouth.1
After resolution, the
virus remains dormant in the body.
Reactivation of the virus may be triggered
by an array of known factors.1
While many ocular manifestations of
HSV are immune and inflammatory in
nature (stromal and disciform keratitis,
iridocyclitis), epithelial dendritic keratitis
represents infection by the live virus.1,15,16
Viralreplicationisusuallyconfinedtothe
corneal epithelium, with stromal invasion
impeded by an early onset of non-specific
defense mechanisms.These are rapidly
complemented by the specific, mainly
cellular, immune response.15
As the
epithelial cells die, a dendritic ulcerative
keratitis results.After several recurrences,
the corneal stroma may become
involved.15
Disciform stromal scarring,
conjunctivitis and uveitis are natural
sequelae to corneal inflammation.
Management
Corneal epithelial disease secondary
to HSV infection must be managed
aggressively and quickly to prevent
deeper corneal penetration. The treatment
of choice consists of topical trifluridine
(Viroptic) 1% given at twohour
intervals nine times daily.2,17,18
As
regression of the dendrites becomes evident,
the dosage may be tapered to Q34H
until complete resolution (usually
seven to 10 days). At this point, the
patient should be observed closely for
another week to ensure adequate suppression
of the virus. Debridement of
the ulcer bed to remove active virus cells
has been advocated as an adjunctive
therapy to topical antiviral therapy and
appears to enhance the speed of resolu-
tion.17
Cycloplegia (homatropine 2%
TID-QID or scopolamine 0.25% BIDQID)
may be initiated, depending upon
the severity of the uveitic response and
the patienťs subjective discomfort.
In cases where significant toxicity or
other adverse response to the topical
antiviral therapy exist, oral antiviral
medications can effectively treat HSV
epithelial dendritic keratitis.4,19,20
Valacyclovir
100 mg/kg BID or acyclovir 50
mg/kg 5 times/day for 5 days are suggested
dosings.19
Beyond therapeutic
treatment of HSV epithelial keratitis,
oral antiviral medications may serve in a
CORNEA
The characteristic dendritic epitheliopathy
associated with HSV keratitis.
APRIL 15, 2008 REVIEW OF OPTOMETRY 23A
CORNEA
preventative role by reducing the number
of clinical infective outbreaks
through the course of one year. Most
practitioners however, extend prophylais
beyond that time frame.21,22
Acyclovir
400 mg BID PO is the standard suppressing
dosage.21,22
Studies have shown that HSV replicates
more rapidly when corticosteroids
are present and worsen the course of the
disease.23
Topical steroids are generally
contraindicated in the presence of HSV
epithelial keratitis and have been implicated
in prolonging the course of herpetic
eye disease.24
However, judicious topical
steroid therapy can be beneficial
when used with antiviral coverage following
several days of initial protective
treatment. Topical steroids are also an
invaluable addition to therapy should
stromal inflammation develop.24
Clinical pearls
* A unilateral red eye in an adult
patient that is inconsistent with the
symptoms (i.e., the patient seems to be
in far less discomfort than the appearance
of the eye would indicate) should
raise suspicions of HSV keratitis, particularly
if the individual has a previous
history of similar infections.
* Each recurrence induces greater
damage to the corneal nerves, leading to
hypoesthesia. The cotton-wisp test used
for measuring corneal sensitivity is positive
in cases of HSV keratitis, and should
be utilized whenever HSV is suspected.
* Consider a history of prolonged sun
exposure or extreme psychological
stress to be significant in diagnosing
HSV epithelial keratitis.
* Most adverse steroid-related outcomes
in HSV epithelial keratitis have
arisen from improper diagnosis, in which
steroid use was initiated without antiviral
coverage. Judicious use of a topical
steroid concurrent with and following
several days of antiviral treatment can
help reduce scarring should the stroma
become inflamed. However, if the infection
remains solely epithelial with no
stromal involvement, then the benefit of
adding a topical steroid is outweighed by
the risks of perpetuating infection.
* Anecdotal reports have associated
some HSV dendritic outbreaks with the
use of prostaglandin analogs. Many
practitioners discontinue the use of these
agents upon dendrite development. We
do not discontinue prostaglandin use
because of HSV epithelial keratitis for
two reasons: First, no compelling evidence
exists that prostaglandin analogs
cause HSV epithelial outbreak. Second,
HSV epithelial keratitis can be easily
treated with antiviral medications, while
blindness from glaucoma cannot.
* Beware of toxicity related to topical
antiviral medications. Some chronic
cases may seem resistant to therapy,
when in reality the virus has been killed
and the medication is perpetuating a
non-healing pseudodendrite.
* Not every case of HSV epithelial
keratitis manifests in a classic dendritic
appearance, especially early in the disease
course. Consider a trial of antiviral
medications in atypical or unusual
epitheliopathy.
* Upon first HSV epithelial keratitis
outbreak, we educate patients about the
role of long-term suppressive therapy
with low-dose oral acyclovir, and we
give the patient this option. At the second
outbreak, we recommend suppressive
therapy more strongly.
1. LiesegangTJ.Herpes simplex virus epidemiology and ocular
importance. Cornea 2001;20(1):1­13.
2. Wilhelmus KR. The treatment of herpes simplex virus
epithelial keratitis.Trans Am Ophthalmol Soc 2000;98:505­32.
3. Chong EM,Wilhelmus KR, Matoba AY, et al. Herpes simplex
virus keratitis in children.Am J Ophthalmol 2004;138(3):474­5.
4. Schwartz GS, Holland EJ. Oral acyclovir for the management
of herpes simplex virus keratitis in children. Ophthalmol
2000;107(2):278­82.
5. Souza PM, Holland EJ, Huang AJ. Bilateral herpetic keratoconjunctivitis.
Ophthalmol 2003;110(3):493­6.
6. Tabery HM. Epithelial changes in early primary herpes simplex
virus keratitis. Photomicrographic observations in a case
of human infection. Acta Ophthalmol Scand
2000;78(6):706­9.
7. Koizumi N, Nishida K,Adachi W, et al. Detection of herpes
simplex virus DNA in atypical epithelial keratitis using polymerase
chain reaction. Br J Ophthalmol 1999;83(8):957­60.
8. Herpetic Eye Disease Study Group.Predictors of recurrent
herpes simplex virus keratitis. Cornea 2001;20(2):123­8.
9. Saini JS, Agarwala R. Clinical pattern of recurrent herpes
simplex keratitis. Indian J Ophthalmol 1999;47(1):11­4.
10. Shtein RM, Stahl RM, Saxe SJ, et al. Herpes simplex keratitis
after intravitreal triamcinolone acetonide. Cornea
2007;26(5):641­2.
11. Barequet IS, Wasserzug Y. Herpes simplex keratitis after
cataract surgery. Cornea 2007;26(5):615­7.
12. Miyajima S, SanoY, Sotozono C, et al. Herpes simplex keratitis
after ophthalmic surgery. Nippon Ganka Gakkai Zasshi
2003;107(9):538­42.
13. Rezende RA, Uchoa UB, Raber IM, et al. New onset of
herpes simplex virus epithelial keratitis after penetrating keratoplasty.Am
J Ophthalmol 2004;137(3):415­9.
14. Dios Castro E, Maquet Dusart JA. Latanoprost-associated
recurrent herpes simplex keratitis. Arch Soc Esp Oftalmol
2000;75(11):775­8.
15. Garweg JG, Halberstadt M.The pathogenesis of herpetic
keratitis. Klin Monatsbl Augenheilkd 2002; 219(7):477­86.
16. Holland EJ, Schwartz GS. Classification of herpes simplex
virus keratitis. Cornea 1999;18(2):144­54.
17. Wilhelmus KR.Therapeutic interventions for herpes simplex
virus epithelial keratitis. Cochrane Database Syst Rev
2007;(1):CD002898.
18. Labetoulle M.The latest in herpes simplex keratitis therapy.
J Fr Ophtalmol 2004;27(5):547­57.
19. Higaki S, Itahashi M, DeaiT, et al. Effect of oral valaciclovir
on herpetic keratitis. Cornea 2006;25(10:Suppl 1):S64­7.
20. Sozen E,Avunduk AM,Akyol N.Comparison of efficacy of
oral valacyclovir and topical acyclovir in the treatment of herpes
simplex keratitis: A randomized clinical trial. Chemother
2006;52(1):29­31.
21. Herpetic Eye Disease Study Group.Oral acyclovir for herpes
simplex virus eye disease: Effect on prevention of epithelial
keratitis and stromal keratitis. Arch Ophthalmol
2000;118(8):1030­6.
22. Langston DP. Oral acyclovir suppresses recurrent epithelial
and stromal herpes simplex. Arch Ophthalmol
1999;117(3):391­2.
23. Haruta Y, Rootman DS, Xie LX, et al. Recurrent HSV-1
corneal lesions in rabbits induced by cyclophosphamide and
dexamethasone. Invest OphthalmolVis Sci 1989;30(3):371­6.
24. Wilhelmus KR.Diagnosis and management of herpes simplex
stromal keratitis. Cornea 1987;6(4):286­91.
ACANTHAMOEBA KERATITIS
Signs and Symptoms
Patients with Acanthamoeba ocular
infection typically present insidiously
with a unilateral red eye. Pain may be
variable; some individuals manifest only
a mild foreign body sensation, while
others report severe pain disproportionate
to the clinical appearance.1,2
The initial
epitheliopathy associated with
Acanthamoeba may be non-descript,
demonstrating coarse opaque streaks or
fine curvilinear opacities, amorphous
stippling, microcystic edema or dendritiform
keratitis. The finding of radial perineuritis
(i.e., irregularly thickened
corneal nerves in the anterior to midstroma,
with shaggy borders) is noted in
one-third of cases.3
Other common signs
associated with Acanthamoeba keratitis
include anterior uveitis with hypopyon
and diffuse anterior scleritis. Ultimately,
a large disciform corneal ulcer may be
seen. Most texts describe these ulcers as
being classically associated with a stro-
24A REVIEW OF OPTOMETRY APRIL 15, 2008
mal ring infiltrate, though retrospective
studies indicate that only 6% of early
cases and 16% of late cases actually
present with this clinical finding.4,5
Pathophysiology
Acanthamoeba keratitis is historically
associated with contact lens wear and
poor hygiene, usually involving exposure
to non-sterile water. However,
numerous other risk factors have been
identified: These include bacterial keratitis,
herpes simplex keratitis, anterior
basement membrane dystrophy, bullous
keratopathy, neurotrophic keratopathy,
radial keratotomy and corneal foreign
bodies. While there are many species of
Acanthamoeba, only a few are known to
cause keratitis in humans. The most
common of these include A. castellani,
A. polyphaga and A. culbertsoni.3
These
microbes are ubiquitous and can be isolated
from numerous environments.
Water is a common medium, and
Acanthamoeba inhabit virtually all
water sources, including lakes, rivers,
seas, oceans, chlorinated swimming
pools, hot tubs and domestic tap water.
In addition, Acanthamoeba can be
encountered in soil, dust and sewage.
These organisms are impervious to cold,
surviving at temperatures as low as
­20C (­4F); however, they are typically
susceptible to heat above 42C
(107F).3
Acanthamoeba normally exist
in a motile, trophozoite phase, but they
can survive adverse elements and conditions
by encysting.
Acanthamoeba adhere to corneal
epithelial cells by virtue of their acanthopodia--small,
foot-like projections
from the organism's cell membrane--
which are more numerous and specialized
than in non-pathogenic species of
amoebae.6
Once bound to the ocular surface,
they secrete proteases, which have a
toxic effect on corneal epithelial cells and
help degrade the corneal stroma, facilitating
invasion into deeper tissue.7
Acanthamoeba derivenutritionfromnormal
bacterial flora such as
Staphylococcus epidermidis and S.
aureus, and hence they can persist indefinitely
in an a microbe-rich ocular environment.
For this reason, bacterial
corneal ulcers are always susceptible to
amoebicsuperinfectioninat-riskpatients.
Management
Acanthamoeba keratitis can be
exceedingly difficult to identify clinically.
Often, it requires corneal scrapings
and/or cultures using non-nutrient agar
overlaid with Escherichia coli or
Enterobacter to achieve a definitive
diagnosis. Note that cultures for Acanthamoeba
may take up to 10 days to yield
definitive results, and even then the sensitivity
and specificity is typically only
60% at best.3,4
Encysting of the organisms
is the most common reason for
delayed or false-negative results. Other
beneficial diagnostic techniques include
staining of scrapings with Calcofluor
white (which can demonstrate Acanthamoeba
cysts as well as trophozoites),
confocal microscopy and polymerase
chain reaction of biopsy specimens.
Regrettably, such techniques are often
expensive and not widely available.
Treatment of Acanthamoeba ulcers
may involve a variety of therapeutic
options, because no single agent is
100% effective. Recognized treatments
include amoebicidal drugs such as
propamidine isethionate (i.e., Brolene)
and hexamidine; surfactant detergent
agents such as polyhexamethylene
biguanide (PHMB) and chlorhexidine
digluconate; antifungal agents such as
metronidazole, ketaconazole and clortrimazole;
neomycin and other antibiotics
(e.g. ofloxacin).3,8
Most often, two or
more agents are employed in concert
(e.g., PHMB) plus Brolene or neomycin
plus Brolene plus ketaconazole. Mainstay
therapy is with a biocide (chlorhexidene
or PHMB and an aromatic
diamidine (Brolene). The use of topical
corticosteroids in active phases of
Acanthamoeba keratitis is extremely
controversial. Some maintain that these
agents help limit corneal melting and
scarring and prolong graft survival.9
Experts agree, however, that steroids
should only be used with concurrent
antiamoebic therapy.3,8-10
Corneal healing and visual outcome
withtopicaltherapyvaries,althoughmost
patients with Acanthamoeba keratitis
actually fare rather well. One published
report noted an overall success rate of
79% using a regimen of PHMB and
Brolene, with "success" defined as final
visual acuity of 20/50 or better.10
Of those
individuals who were successfully diagnosed
within 28 days of presentation,
91% had a successful outcome.10
Hence,
the value of therapeutic intervention
depends greatly upon the duration of the
infection prior to treatment. Penetrating
keratoplasty may be considered in
patients who have sustained significant
visual loss following Acanthamoeba keratitis
infection; however, this procedure is
only performed after the infection is considered
fully resolved. Otherwise, the
likelihood of recurrent infection and graft
failure is nearly certain.9
Clinical Pearls
* Acanthamoeba keratitis may have a
variable appearance and can often coexist
with bacterial and/or herpetic ulcers;
hence, it is rarely identified in the early
stages of infection.
* Acanthamoeba keratitis is partially
amenable to non-protozoan treatments,
e.g., topical antibiotic or antiviral agents.
These formulations, as well as the
preservatives that they contain, create a
hostile environment for the microbe,
rather than actually killing the organism.
In response, Acanthamoeba will encyst
and become dormant. While the symptoms
and signs may improve temporarily,
the keratitis waxes and wanes until
Acanthamoeba keratitis may present with disciform
stromal inflammation and perineuritis.
APRIL 15, 2008 REVIEW OF OPTOMETRY 25A
definitive anti-amoebic therapy is prescribed.
However, antibiotic and antifungal
drugs should not be considered true
therapeutic agents for Acanthamoeba
keratitis and should never replace the
amoebicidal drugs. Their main activity
is combating co-infections.
* While ring infiltration has historically
been associated with Acanthamoeba
keratitis, it is a relatively rare
finding and typically occurs late in the
disease process. Non-specific epitheliopathy
in the setting of acutely red eye
is the more common presenting feature.
* Acanthamoeba keratitis can present
initially as a dendritic keratitis similar to
HSV keratitis, with one critical exception:
The classic "terminal end­bulbs"
that are seen in herpetic keratitis are
characteristically absent in Acanthamoeba
keratitis.
* Acanthamoeba play a part in coinfections,
sometimes explaining why
other corneal infections do not respond
to conventional therapy.
1. Tabin G,Taylor H, Snibson G, et al.Atypical presentation of
Acanthamoeba keratitis. Cornea 2001;20(7):757­9.
2. Roters S, Aisenbrey S, Severin M, et al. Painless
Acanthamoeba keratitis. Klin Monatsbl Augenheilkd
2001;218(8):570­3.
3. Chong EM, Dana MR. Acanthamoeba keratitis. Int
Ophthalmol Clin 2007;47(2):33­46.
4. Bacon AS, Frazer DG, Dart JK, et al. A review of 72 consecutive
cases of Acanthamoeba keratitis, 1984­1992. Eye
1993;7(6):719­25.
5. Bernauer W, Duguid GI, Dart JK. Early clinical diagnosis of
Acanthamoeba keratitis. A study of 70 eyes. Klin Monatsbl
Augenheilkd 1996;208(5):282­4.
6. Khan NA, Jarroll EL, Paget TA. Molecular and physiological
differentiation between pathogenic and nonpathogenic
Acanthamoeba. Curr Microbiol 2002;45(3):197­202.
7. Na BK, Kim JC, Song CY. Characterization and pathogenetic
role of proteinase from Acanthamoeba castellani. Microb
Pathog 2001;30(1):39­48.
8. Sun X, Zhang Y, Li R, et al. Acanthamoeba keratitis: Clinical
characteristics and management. Ophthalmol 2006;
113(3):412­6.
9. Ficker LA,Kirkness C,Wright P.Prognosis for keratoplasty in
Acanthamoeba keratitis. Ophthalmol 1993;100(1):105­10.
10. Duguid IG, Dart JK, Morlet N, et al. Outcome of
Acanthamoeba keratitis treated with polyhexamethyl biguanide
and propamidine. Ophthalmol 1997;104(10):1587­92.
FILAMENTARY KERATITIS
Signs and symptoms
Patients with filamentary keratitis
typically present with variable reports of
ocular discomfort, ranging from grittiness
to mild foreign body sensation to
pronounced pain. Tearing, photophobia
and even blepharospasm may accompany
these symptoms in more severe
cases.1
The condition may be unilateral
or bilateral, depending upon the underlying
etiology. Signs associated with filamentary
keratitis include ocular hyperemia,
particularly in the limbal area, as
well as a pseudoptosis in some individuals.
The hallmark finding is the presence
of corneo-mucus filaments; these
usually consist of a focal "head" that
may firmly adhere to compromised
areas of the corneal epithelium, and a
strand-like "tail" of varying length that
extends across the ocular surface.
Filaments can be seen more readily on
biomicroscopy with the application of
vitals dyes such as rose bengal and, to a
lesser degree, lissamine green and sodium
fluorescein.1
Other ocular findings
that may accompany filamentary keratitis
include a reduced tear break up time
(TBUT) and a punctate epithelial ker-
atopathy.
Experience suggests that filamentary
keratitis is more common in elderly
patients (particularly women), those
with connective tissue disorders and
those with immune deficiency.1
Coincidentally, these same populations
tend to demonstrate a greater incidence
of keratoconjunctivitis sicca and other
ocular surface disorders. The condition
also may develop in those with relative
atopy, where the pathognomonic
changes surface as a side effect of systemic
therapy.
Pathophysiology
Filamentary keratitis is seen most
commonly in association with advanced
dry eye disease, although a variety of
other ocular surface disorders can
induce this condition.2
Among the various
etiologies are superior limbic keratoconjunctivitis
(SLK) of Theodore, prolonged
patching following cataract or
other ocular surgery, epitheliopathy
from aerosol or radiation keratitis, herpetic
keratitis, recurrent corneal erosion,
neurotrophic keratitis and bullous ker-
atopathy.1­5
Clinicians must also recognize
that some systemic disorders (e.g.,
Sjögren's syndrome, diabetes) and systemic
medications (e.g., oral antihistamines
or diuretics) can exacerbate ocular
surface inflammation and aqueous
deficiency, further contributing to the
development of filamentary keratitis.6
The precise pathogenesis of filamentary
keratitis is unclear. Research suggests
that the process involves some
degree of corneal epithelial disruption
and concurrent tear film corruption.2,7
According to researchers, subjects with
filamentary keratitis suffer progressive
dysfunction within the deeper epithelial
layers of the cornea, leading to focal
detachments at the level of the basement
membrane. Under constant shear pressure
from the eyelids, these corneal foci
become elevated and inflamed, and
epithelial desquamation ensues.7
Filaments
arise as a result of these liberated,
compromised epithelial cells binding
with abnormal, excessive mucins within
the tear film. Diminished tear volume
(i.e., aqueous-deficient dry eye) is the
most common cause of excessive tear
mucin, although ocular surface inflammation
also contributes heavily to this
process.2
Filamentary keratitis is said to
occur when motile filaments within the
tear film adhere to compromised areas of
the corneal surface. Lid movement across
these filaments induces vertical traction
and shearing of the corneal epithelium,
with each blink resulting in inflammation
and stimulation of the pain-sensitive
corneal nerves. Thus, a vicious cycle of
epithelial damage, inflammation and filament
formation ensues.
CORNEA
Large mucous plaques may be noted in severe
filamentary keratitis.
26A REVIEW OF OPTOMETRY APRIL 15, 2008
Management
Treatment for filamentary keratitis is
targeted toward eliminating the mucus
filaments while addressing the underlying
cause of the pathology. In most
cases, management begins with physical
removal of the filaments at the slit lamp,
using jeweler's forceps under topical
anesthesia. The copious use of ocular
lubricants (e.g., Systane Q 1 hour while
awake) may be helpful in addressing the
ocular discomfort and stabilizing the
tear film in mild-to-moderate cases.
Alternatively, some have suggested the
use of hypertonic saline (e.g., Muro 128
TID-QID) for filamentary keratitis;
studies have shown this treatment effective
in as many as 95% of subjects.8,9
More recalcitrant cases of filamentary
keratitis may warrant the use of
pharmaceutical agents. Anti-inflammatory
drugs, including corticosteroids and
non-steroidal agents, have been used
with some success.3,8,10
In theory, these
agents have the capacity to diminish filament
formation and restore the damaged
epithelial regions where filaments
may accumulate.4,11,12
Caution is advised,
however, regarding long-term use of corticosteroids,
due to the propensity for
intraocular pressure elevation and
cataract formation. In this capacity, topical
cyclosporine (i.e., Restasis BID)
may provide a safer alternative for prolonged
therapy.10
N-acetylcysteine (Mucomyst, Apothecon)
is another potential remedy for
patients with advanced filamentary keratitis.
This mucolytic agent is utilized
primarily as an inhalant for patients with
bronchial disease (e.g., emphysema,
cystic fibrosis), but in topical ophthalmic
form (2­10%), acetylcysteine
has been shown to effectively dissolve
corneal mucus plaques and reduce filament-producing
pathogenesis.13
While
not commercially available in the United
States, acetylcysteine can be readily
obtained from most compounding pharmacists.
A 5% acetylcysteine solution is
available in the United Kingdom under
the trade name Ilube (Alcon Laboratories
UK, Ltd).
Cases of filamentary keratitis that do
not respond to topical therapy alone may
benefit from temporary employment of a
soft bandage contact lens.11
In all cases,
practitioners should be prepared to manage
this condition for prolonged periods.
Filamentary keratitis may take weeks or
even months to resolve, depending upon
the etiology and the aggressiveness of
therapy. Even after the filaments dissi-
pate,theunderlyingdiseaseorcausemust
be controlled, or recurrences are likely.
Clinical pearls
* Filamentary keratitis is not a disease
entity itself, but a sign of a severe
ocular surface disease.The root cause of
this condition must be determined
before initiating therapy.
* Patients should be educated that
prolonged therapy may be necessary to
alleviate this condition, which is often
chronic.
* Although practitioners are often
tempted to use antibiotic solutions, they
are not beneficial as a primary therapy
for filamentary keratitis. However, they
may be necessary for prophylaxis in
cases of severely compromised corneas.
* Topical 5% acetylcysteine BIDQID
is often a helpful adjunct in managing
filamentary keratitis.Advise patients
that this solution may have an unusual
color and a peculiar odor. Also, because
it is typically formulated without preservatives,
it must be discarded after
approximately 30 days.
* Soothe XP, a lipid-restorative emollient
eyedrop, may be particularly helpful
in managing recalcitrant filamentary
keratitis. In a small series, patients treated
with Soothe four times daily for three
to five weeks showed complete resolution
of filaments and significant
improvement in subjective symptoms.14
It is theorized that this oil-in-water emulsion,
which has been shown to increase
lipid layer thickness, improves the wiping
action of the eyelid on the ocular surface
and hence inhibits epithelial breakdown
and filament formation.
1. Diller R,Sant S.A case report and review of filamentary keratitis.
Optom 2005;76(1):30­6.
2. Albietz J,Sanfilippo P,Troutbeck R,Lenton LM.Management
of filamentary keratitis associated with aqueous-deficient dry
eye. OptomVis Sci 2003;80(6):420­30.
3. Perry HD, Doshi-Carnevale S, Donnenfeld ED, Kornstein
HS.Topical cyclosporine A 0.5% as a possible new treatment
for superior limbic keratoconjunctivitis. Ophthalmol
2003;110(8):1578­81.
4. Ram J, Sharma A, Pandav SS, et al. Cataract surgery in
patients with dry eyes. J Cataract Refract Surg
1998;24(8):1119­24.
5. Kakizaki H, Zako M, Mito H, Iwaki M. Filamentary keratitis
improved by blepharoptosis surgery: two cases. Acta
Ophthalmol Scand 2003;81(6):669­71.
6. Seedor JA, Lamberts D, Bergmann RB, Perry HD.
Filamentary keratitis associated with diphenhydramine
hydrochloride (Benadryl). Am J Ophthalmol
1986;101(3):376­7.
7. Zaidman GW, Geeraets R, Paylor RR, Ferry AP. The
histopathology of filamentary keratitis. Arch Ophthalmol
1985;103(8):1178­81.
8. Avisar R,Robinson A,Appel I,et al.Diclofenac sodium,0.1%
(Voltaren Ophtha), versus sodium chloride, 5%, in the treatment
of filamentary keratitis. Cornea 2000;19(2):145­7.
9. Hamilton W, Wood TO. Filamentary keratitis. Am J
Ophthalmol 1982;93(4):466­9.
10. Marsh P,Pflugfelder SC.Topical nonpreserved methylprednisolone
therapy for keratoconjunctivitis sicca in Sjögren syndrome.
Ophthalmol 1999;106(4):811­6.
11. Baum JL.The Castroviejo Lecture. Prolonged eyelid closure
is a risk to the cornea. Cornea 1997;16(6):602­11.
12. Grinbaum A, Yassur I, Avni I. The beneficial effect of
diclofenac sodium in the treatment of filamentary keratitis.
Arch Ophthalmol 2001;119(6):926­7.
13. Fraunfelder FT, Wright P, Tripathi RC. Corneal mucus
plaques.Am J Ophthalmol 1977;83(2):191­7.
14. Greiner JV, Korb DR, Kabat AG, et al. Successful treatment
of chronic idiopathic recurrent filamentary keratopathy using a
topical oil-in-water emulsion:A report of 5 cases. Poster presented
at the 25th Biennial Cornea Research Conference,
Boston, MA, October 11­13, 2007.
FUCHS' ENDOTHELIAL
DYSTROPHY
Signs and symptoms
Fuchs' endothelial dystrophy, a bilateral
though often asymmetric condition,
is relatively common in adults. While it
may occasionally be diagnosed earlier
based upon biomicroscopic findings,
Fuchs' dystrophy is rarely symptomatic
before age 50.1
Patients typically presFilamentary
keratitis with numerous stringlike
precipitates.
APRIL 15, 2008 REVIEW OF OPTOMETRY 27A
ent with complaints of diminished
vision, foreign body sensation and pain
or discomfort, particularly upon awakening.The
key clinical finding is central
corneal guttae (historically--though
incorrectly--referred to as "guttata"),
which represent focal thickenings at the
level of Descemeťs membrane. When
viewed in direct illumination, guttae
appear as gold-colored, hyper-reflective
bodies on the posterior corneal surface;
when retroillumination is used, they
resemble small bubbles or holes in the
endothelium. Fine endothelial pigment
dusting is also commonly seen in association
with guttae. In later stages, one
may observe stromal edema with folds
in Descemeťs membrane and corneal
pannus and bullous keratopathy in
severe presentations.
Fuchs' dystrophy is encountered
more commonly and with greater severity
in women than in men (3:1).1,2
Hypermetropes and those with shallow
anterior chambers may also have a higher
incidence.3
Early reports suggested
that patients with Fuchs'dystrophy may
have an increased prevalence of open
angle glaucoma,4
though this association
has not been corroborated by more
recent literature.
Pathophysiology
Fuchs' dystrophy stems from a primary
malfunction of the corneal endothe-
lium,whichislikelyinheritedviaanautosomal
dominant mechanism with
incomplete penetrance.1
This leads to
widespread loss of endothelial cells and
subsequent disruption of the endothelial
pump mechanisms, which are responsible
for maintaining normal stromal
hydration.5
The consequence is an excessive
influx of aqueous, resulting in
corneal stromal edema and a physiologically
and optically compromised tissue.
The clinical and histopathological
progression of Fuchs' dystrophy has
been well-described.6,7
A number of
stages are recognized, usually spanning
a period of 10 to 20 years. Stage 1 is
marked by central, irregularly distributed
guttae and geographically arranged
pigment dusting. Histologically, the
endothelial cells show degeneration and
deposition of abnormal Descemeťs
membrane material. Patients with Stage
1 Fuchs'are generally asymptomatic. In
Stage 2, patients may begin to experience
glare and diminished visual acuity,
particularly upon awakening. These
symptoms are directly related to an
increase in corneal edema, which can be
noted in both the stroma (seen as central
corneal thickening) and the epithelium
(represented by fine microcysts). As
stromal edema increases, folds may be
observed in Descemeťs membrane, and
vision diminishes accordingly. Stage 3
of Fuchs'dystrophy is heralded by more
profound corneal damage in the form of
epithelial and subepithelial bullae. The
pressure exerted by these lesions on
sensitive corneal nerves can induce pain
and photophobia, which can be significantly
exacerbated when the bullae rup-
ture.1
Stromal edema is persistent, as is
diminished acuity throughout the day.
Permanent corneal scarring occurs in
Stage 4, due to the development of subepithelial
tissue in the central cornea.
Clinically, it appears as an irregular,
dense, gray avascular sheet; histologically,
this tissue is composed of active
fibroblasts and collagen fibrils sandwiched
between the superficial stroma
and the epithelium.7
The corneal bullae
dissipate at this point, as do the painful
episodes. Unfortunately, profound
vision loss accompanies the scarring.
Management
Treatment for Fuchs'endothelial dystrophy
varies depending upon the severity
of the disease. Patients with early
stromal and/or epithelial edema may be
treated conservatively with 5% sodium
chloride solution throughout the day
(e.g., Muro 128 every two-six hours) and
5% sodium chloride ointment overnight.
These hypertonic agents diminish
corneal edema and improve vision.
Another non-invasive measure intended
to deturgesce the cornea involves the use
of a hair dryer, held at arm's length and
directed toward the eyes.8
As patients become more symptomatic
with pain and/or reduced vision,
additional treatment options may be
employed. Topical nonsteroidal antiinflammatory
drugs (NSAIDs, e.g.,
Acular LS, Allergan) may be helpful in
managing patients with painful bullae;
however, the practitioner must understand
that these agents merely provide
analgesia in cases of Fuchs' dystrophy.
In addition, corneal melts have been
associated with the use of certain
NSAIDs, and hence these drugs should
be used judiciously.9
Ocular hypotensive
agents may be therapeutically beneficial
also, even for patients in whom intraocular
pressure is within normal limits.2
By
reducing the anterior chamber fluid volume,
stress on the endothelial pump
mechanisms is decreased, and this subsequently
helps to diminish corneal
edema.
All classes of ocular hypotensives
may be used in this capacity, with the
possible exception of the carbonic anhydrase
inhibitors (i.e., dorzolamide, brinzolamide,
acetazolamide), as these may
actually disrupt the endothelial Na-K
ATPase pump.10
Therapeutic (bandage) soft contact
lenses may also alleviate patient discom-
CORNEA
Fuchs' dystrophy.
Guttae are a hallmark sign of Fuchs' dystrophy.
28A REVIEW OF OPTOMETRY APRIL 15, 2008
fort in advanced cases. A flatly fit,
high­water content lens helps mask
the irregular astigmatism and diminish
pain associated with epithelial bul-
lae.1,2
Silicone hydrogel lenses also
have been used in this capacity, with
some success.11
Despite medical treatment, most
patients with Fuchs' dystrophy will
ultimately require keratoplasty.8,12
If
this surgery is performed before
involvement of the peripheral cornea
occurs, the patient has an 80% likelihood
of the graft remaining clear for at
least two years.13
Also, because cataract
surgery in eyes with Fuchs' dystrophy
often leads to further endothelial failure
and greater corneal compromise, it
is frequently preferable to perform
cataract extraction and penetrating keratoplasty
as a combined procedure.2,5
Recently, a modified form of
corneal transplantation known as
Descemeťs stripping endothelial keratoplasty
(DSEK) has emerged as a
preferred technique for those with
Fuchs' dystrophy and other forms of
corneal endothelial dysfunction.14
In
DSEK, only the endothelial cell layer
is removed and replaced with donor
tissue. Although this procedure
requires much greater skill than other
treatments, it has several distinct
advantages: It is sutureless, requires
significantly less healing time, and
typically results in greater visual
recovery.14
Clinical pearls
* The presence of excessive central
guttae in the absence of corneal edema
is commonly referred to as endothelial
cell dystrophy.5
Endothelial cell dystrophy
may remain stable or progress to
Fuchs' dystrophy, which by definition
includes some degree of stromal and/or
epithelial edema.
* Mid-peripheral or peripheral corneal
guttae may occasionally be seen in
asymptomatic patients over age 40.These
are known as Hassle-Henle bodies and
are of no particular clinical significance.
* In place of hypertonic saline, we
have experienced modest success with
FreshKote (FOCUS Laboratories) for a
variety of corneal disorders.This prescription
ophthalmic lubricant uses high col-
loidaldensityratherthanosmoticpressure
from salts to address epithelial edema. In
addition, it has the advantage of enhanced
lubricity, increased contact time and
improved comfort upon instillation.
* While topical NSAIDs may be
helpful in ameliorating pain associated
with Fuchs' dystrophy, corticosteroids
have not been shown to be of significant
benefit.15
1. Bergmanson JP, Sheldon TM, Goosey JD. Fuchs' endothelial
dystrophy:A fresh look at an aging disease. Ophthalmic Physiol
Opt 1999;19(3):210­22.
2. Borboli S,Colby K.Mechanisms of disease:Fuchs'endothelial
dystrophy. Ophthalmol Clin North Am 2002;15(1):17­25.
3. Pitts JF, Jay JL.The association of Fuchs's corneal endothelial
dystrophy with axial hypermetropia, shallow anterior chamber,
and angle closure glaucoma. Br J Ophthalmol
1990;74(10):601­4.
4. Buxton JN,Preston RW,Riechers R,Guilbault N.Tonography
in cornea guttata. A preliminary report. Arch Ophthalmol
1967;77(5):602­3.
5. Seitzman GD. Cataract surgery in Fuchs' dystrophy. Curr
Opin Ophthalmol 2005;16(4):241­5.
6. Laing RA,Leibowitz HM,Oak SS,et al.Endothelial mosaic in
Fuchs' dystrophy. A qualitative evaluation with the specular
microscope.Arch Ophthalmol 1981;99(1):80­3.
7. Waring GO III, Rodrigues MM, Laibson PR. Corneal dystrophies.
II. Endothelial dystrophies. Surv Ophthalmol
1978;23(3):147­68.
8. Adamis AP, FilatovV,Tripathi BJ,Tripathi RC. Fuchs' endothelial
dystrophy of the cornea. Surv Ophthalmol
1993;38(2):149­68.
9. AsaiT,NakagamiT,Mochizuki M,et al.Three cases of corneal
melting after instillation of a new nonsteroidal anti-inflammatory
drug. Cornea 2006;25(2):224­7.
10. Egan CA, Hodge DO, McLaren JW, Bourne WM. Effect of
dorzolamide on corneal endothelial function in normal human
eyes. Invest OphthalmolVis Sci 1998;39(1):23­9.
11. Kanpolat A, Ucakhan OO.Therapeutic use of Focus Night
& Day contact lenses. Cornea 2003;22(8):726­34.
12. Afshari NA, Pittard AB, Siddiqui A, Klintworth GK. Clinical
study of Fuchs' corneal endothelial dystrophy leading to penetrating
keratoplasty: A 30-year experience. Arch Ophthalmol
2006;124(6):777­80.
13. Price FW Jr,Whitson WE, Marks RG. Graft survival in four
common groups of patients undergoing penetrating keratoplasty.
Ophthalmol 1991;98(3):322­8.
14. Price MO, Price FW. Descemeťs stripping endothelial keratoplasty.
Curr Opin Ophthalmol 2007;18(4):290­4.
15. Wilson SE, Bourne WM, Brubaker RF. Effect of dexamethasone
on corneal endothelial function in Fuchs' dystrophy.
Invest OphthalmolVis Sci 1988;29(3):357­61.
SALZMANN'S NODULAR
DEGENERATION
Signs and symptoms
Patients with Salzmann's nodular
degeneration are often asymptomatic,
particularly in the early stages of the disease.
Some may present with diminished
visual acuity if the nodules are situated
on or near the visual axis.1,2
Non-specific "dry eye" complaints, e.g.,
burning, grittiness and foreign body sensation,
may also be reported.3
Eyes with
a more advanced form of the disease are
prone to intermittent bouts of recurrent
corneal erosion. During these episodes,
patients may experience pronounced
discomfort, photophobia, blepharospasm
and excessive tearing.1
Clinically, Salzmann's degeneration
appears as an accumulation of round-tooval,
bluish-white (and sometimes yellowish-white)
subepithelial corneal nodules,
often arranged in a circular or
semicircular shape.1
Usually the nodules
are situated in the mid-peripheral
cornea, but central and peripheral
lesions have also been noted.1
Vascularization of Salzmann's nodules
is likewise variable. The condition is
non-inflammatory; hence, the involved
eye is typically white and quiet, unless
there is associated corneal erosion. In
that event, there will be limbal injection,
corneal edema and an anterior chamber
reaction. Conflicting historical reports
exist regarding the laterality of
Salzmann's degeneration, with the
prevalence of bilateral involvement
ranging from 20% to 80%;4,5
however,
the largest retrospective series to date
noted bilateral disease in approximately
63% of cases.3
The condition affects
individuals of various ages and races, but
appears to occur far more frequently in
women than in men.1­3
Pathophysiology
The underlying etiology of Salzmann's
nodular degeneration is not fully
understood, but it has been suggested
that chronic ocular surface irritation is
contributory.1
The condition is often preceded
by some form of ocular inflammation,
which may occur many years
antecedent.1,3,5
Some associated disorders
include phlyctenular disease, meibomian
gland dysfunction (including
ocular rosacea), vernal keratoconjunctivitis,
trachoma and interstitial keratitis;
APRIL 15, 2008 REVIEW OF OPTOMETRY 29A
additionally, patients with a history of
epithelial basement membrane dystrophy,
rigid contact­lens wear, keratoconus,
filamentary keratitis, chemical
(or thermal) trauma or incisional corneal
surgery may be at increased risk.1­6
One theory behind the development
of Salzmann's degeneration suggests
that the inciting corneal trauma creates
an irregular surface, allowing for uneven
tear film distribution and exposure.5
The
subsequent chronic irritation and
inflammation provokes histopathologic
and functional changes to the superficial
stroma and particularly Bowman's
layer.1,3,5­8
As corneal nodules proliferate,
concurrent damage occurs to the basement
membrane, often leading to
painful epithelial erosions.3
At the cellular level, the nodules seen
in Salzmann's degeneration represent
hyaline plaque formation between the
corneal epithelium and Bowman's mem-
brane.9
Oxytalan fibers, which are present
in other degenerative corneal disorders
including keratoconus and Fuchs'
endothelial dystrophy, have also been
identified in Salzmann's nodular degen-
eration.8
As the condition progresses,
there is subsequent degradation of
Bowman's layer in the area overlying the
nodules, and this is replaced by accumulation
of a basement-membrane-like
substance. The corneal epithelium associated
with these areas thins accordingly,
and in some specimens consists of only
a single layer of flattened squamous
cells. Descemeťs membrane and the
corneal endothelium characteristically
remain intact.
Management
It has been suggested that asymptomatic
patients with Salzmann's degeneration
require no therapy;1,9
however,
since chronic low-grade irritation of
the ocular surface has been proposed
as a driving force for disease progres-
sion5
, it seems reasonable and appropriate
to employ topical lubrication in
these individuals (e.g., Systane, Alcon
Laboratories, QID). In one large series
of patients with Salzmann's nodular
degeneration, 68% of patients
responded favorably to conservative
medical therapy (i.e., artificial tears,
lid hygiene and systemic doxycycline
for associated meibomianitis), and did
not require surgical intervention.3
Corneal surgery is warranted for
more severe or symptomatic cases of
Salzmann's degeneration; the most
common indication for surgical intervention
is visual disturbance, followed
by subjective discomfort associated
with recurrent corneal erosions.3
Superficial keratectomy is beneficial
in cases of subepithelial lesions on or
near the visual axis or for mid-peripheral
lesions inducing irregular astig-
matism.1
Phototherapeutic keratectomy
(PTK) with the excimer laser is
another option. Unfortunately, these
procedures tend to induce scar formation
and/or recurrence in some cases.
Recent papers10,11
suggest that application
of the antimetabolite mitomycinC
can improve outcomes and diminish
recurrent disease in those undergoing
superficial keratectomy or PTK.10,11
If
central or deep stromal scarring is
present, or if chronic epithelial breakdown
makes the condition otherwise
unmanageable, lamellar or penetrating
keratoplasty may be the only recourse.
Clinical pearls
* The critical issue in managing
Salzmann's degeneration is proper
diagnosis. Conditions such as band
keratopathy, spheroid degeneration
(i.e., climatic droplet keratopathy) and
corneal keloids may all present with a
similar clinical appearance. Consultation
with a corneal specialist is advisable
in cases in which diagnosis is
questionable.
* It may be tempting to prescribe
topical corticosteroids for Salzmann's
degeneration, particularly if the
patient is symptomatic. However,
since this condition is non-inflammatory,
steroids are merely palliative and
do not alter the progression of the disease.
Additionally, their use introduces
several unnecessary risks, including
intraocular pressure elevation and secondary
infection.
* Patients with associated corneal
erosions require specific treatment
aimed at diminishing pain and promoting
reepithelialization. This is best
accomplished with cycloplegia (e.g.,
0.25% scopolamine BID) and topical
nonsteroidal anti-inflammatory
agents, as well as prophylactic, broadspectrum
antibiotics and copious
lubrication with artificial tears. Some
sources also recommend bandage contact
lenses in cases of recurrent
corneal erosion.12,13
1. Das S,Link B,Seitz B.Salzmann's nodular degeneration of the
cornea:A review and case series. Cornea 2005;24(7):772­7.
2. Oster JG, Steinert RF, Hogan RN. Reduction of hyperopia
associated with manual excision of Salzmann's nodular degeneration.
J Refract Surg 2001;17(4):466­9.
3. Farjo AA, Halperin GI, Syed N, et al. Salzmann's nodular
corneal degeneration: Clinical characteristics and surgical outcomes.
Cornea 2006;25(1):11­15.
4. Katz D. Salzmann's nodular corneal dystrophy. Acta
Ophthalmol 1953;31(4):377­83.
5. Vannas A, Hogan MJ,Wood I. Salzmann's nodular degeneration
of the cornea.Am J Ophthalmol 1975;79(2):211­9.
6. Werner LP, Issid K, Werner LP, et al. Salzmann's corneal
degeneration associated with epithelial basement membrane
dystrophy. Cornea 2000;19(1):121­3.
7. Frising M,Pitz S,Olbert D,et al.Is hyaline degeneration of the
cornea a precursor of Salzmann's corneal degeneration? Br J
Ophthalmol 2003;87(7):922­3.
8. Obata H, Inoki T,Tsuru T. Identification of oxytalan fibers in
Salzmann's nodular degeneration. Cornea 2006;25(5):586­9.
9. Yoon KC,ParkYG.Recurrent Salzmann's nodular degeneration.
Jpn J Ophthalmol 2003:47(4):401­4.
10. Bowers PJ Jr, Price MO, Zeldes SS, Price FW Jr. Superficial
keratectomy with mitomycin-C for the treatment of Salzmann's
nodules. J Cataract Refract Surg 2003;29(7):1302­6.
11. Marcon AS, Rapuano CJ. Excimer laser phototherapeutic
keratectomy retreatment of anterior basement membrane
dystrophy and Salzmann's nodular degeneration with topical
mitomycin C. Cornea 2002;21(8):828­30.
12. OzkurtY,Rodop O,OralY,et al.Therapeutic applications of
lotrafilcon a silicone hydrogel soft contact lenses. Eye Contact
Lens 2005;31(6):268­9.
13. Kanpolat A, Ucakhan OO.Therapeutic use of Focus Night
& Day contact lenses. Cornea 2003;22(8):726­34.
CORNEA
Salzmann's degeneration; note the accumulation
of bluish-white nodules.
30A REVIEW OF OPTOMETRY APRIL 15, 2008
CHOROIDAL RUPTURE
Signs and symptoms
Choroidal rupture is a common
occurrence following blunt trauma
directly to the eye.1­7
Patients developing
choroidal rupture are often younger men
involved in activities, such as ball sports,
which expose them to high-speed
impact to the eye or adnexa. While it
seems that men are more likely to experience
blunt ocular trauma, one report of
patients experiencing blunt orbital trauma
indicated that choroidal rupture
occurred more often in women.7
Common causes of blunt trauma directly
to the eye include impact injuries from
paintballs, bottle corks, elastic bands,
airbags and sports equipment.8­12
Choroidal ruptures may be single or
multiple, and may affect any part of the
posterior segment.2,13,14
They are not typically
seen acutely secondary to hemorrhages
that may be present from the
inciting trauma. Hemorrhages from
acute choroidal rupture may occur in
any layer of the eye, ranging from the
choroid to the vitreous.3,15
However, if
the trauma was many years antecedent,
there will only be hemorrhage if
choroidal neovascularization has developed
and is bleeding.16,17
Visual acuity and visual field may be
unaffected, depending upon the location
of the choroidal rupture and degree of
collateral damage that occurred at the
time of trauma. Unfortunately, choroidal
ruptures often herald more significant
damage throughout the eye with poor
visual results.7
Many patients will have
reduced acuity, sometimes dramatically,
if the rupture occurred within the posterior
pole, and especially with subfoveal
involvement.10-12,14,15
Ophthalmoscopically, there may be a
curvilinear lesion parallel to the ora serrata
or, more commonly, a posteriorly
located disruption which may be crescent-shaped.
Often, the rupture will have
the concave aspect toward the disc.
Many ruptures are concentric with the
optic nerve and are vertically oriented,
consistent with a break in Bruch's mem-
brane.2
There is usually significant reactive
retinal pigment epithelium (RPE)
hyperplasia, giving the rupture a pigmented
appearance. The sclera may be
seen underneath a choroidal rupture
depending upon the degree of damage
and exposure of the underlying tissue.
Pathophysiology
Direct or indirect injury can precipitate
a choroidal rupture. Direct ruptures are
usually located anteriorly at the exposed
part of the eye and parallel to the ora ser-
rata.18
More common are indirect ruptures
occurring at the posterior pole.
These are usually concentric to the optic
nerve.18
As the globe is compressed along
an anterior-posterior vector, it expands
outward, often resulting in a break in
Bruch's membrane. In most cases, the
sclera maintains the globe's integrity, lim-
itingthedamagetotheresultantchoroidal
rupture and the collateral injuries sustained
as a result of the trauma. Unfortunately,
in some cases the sclera tears
with a resultant ruptured globe.4,6,7
Hemorrhage and edema may be present
initially, but will resolve. Typically,
reactive retinal and choroidal pigment
epithelial hyperplasia will give the rupture
a heavily pigmented appearance. In
some cases, the overlying retina will be
undisturbed in choroidal rupture. However,
if the RPE is disturbed and becomes
hyperplasic, invading the sensory retina,
visual dysfunction will ensue.
Due to the subsequent disruption of
Bruch's membrane that occurs in
choroidal rupture, the possibility exists
for the development of choroidal neovascular
membranes within the rup-
ture.13,14,16,17­19
This may be a late development
and can occur years after the precipitating
trauma.18,20
Several factors
have been shown to be predictive of the
development of choroidal neovascular
membranes in choroidal rupture; namely,
proximity of the rupture to the center
of the fovea, length of the rupture, older
age and macular choroidal rupture.13,14
Hence, patients with these factors
should be monitored closely.
Management
There is no direct intervention in the
acute phase of choroidal rupture, as long
as the sclera is intact and no rupture of
the globe has occurred. Any acute management
is directed toward concomitant
traumatic iritis, potential hyphema, retinal
detachment or breaks and issues pertaining
to intraocular pressure. Patients
with choroidal ruptures should be educated
about their condition and counseled
to consider full-time protective
eye-wear (protective frame with polycarbonate
lenses). The patient must be
monitored funduscopically for the
development of choroidal neovascularization
within the rupture scar. The use
of home monitoring with anAmsler grid
is recommended. Any late bleeding
should receive a fluorescein angiogram
to determine whether a choroidal neovascular
membrane has developed.
Various therapeutic modalities have
been used to treat choroidal neovascularization
occurring from choroidal rupture.
Thermal laser photoablation has
been a mainstay for treating these mem-
branes.14,18
Newer modalities, such as
photodynamic therapy (PDT), have
been used with success.19­21
PDT often
reduces membrane leakage and can
completely eliminate the membrane
with few adverse effects. Surgical
removal of the neovascular membranes
has also been reported.17
At this time, no
reports are evident regarding the application
of the anti-angiogenic drugs commonly
used in exudative macular degeneration
for choroidal rupture­induced
neovascularization.
While choroidal rupture involving
the macula tends to have a poor visual
UVEA AND GLAUCOMA
Choroidal rupture.
APRIL 15, 2008 REVIEW OF OPTOMETRY 31A
prognosis, there are reported cases of
patients with foveal choroidal ruptures
regaining central vision over a protracted
recovery period.22
Clinical pearls
* Choroidal neovascular membranes
resulting from choroidal rupture may
spontaneously involute. For this reason,
close observation may be a management
option if there is no imminent
threat to vision.
* Choroidal neovascularization can
occur years after the initial trauma.
* Sub-retinal hemorrhage from
choroidal neovascularization is the most
common cause of late vision loss.
* Because the retina overlying a
choroidal rupture may be unaffected,
patients may retain excellent visual
function and present asymptomatically
years after the trauma has occurred.
* Gonioscopy should be performed
to rule out angle damage and an
increased risk for developing late traumatic
glaucoma.
1. Kuhn F, Morris R,Witherspoon CD, et al. Epidemiology of
blinding trauma in the United States Eye Injury Registry.
Ophthalmic Epidemiol 2006;13(3):209­16.
2. Wyszynski RE, Grossniklaus HE, Frank KE. Indirect
choroidal rupture secondary to blunt ocular trauma.A review
of eight eyes. Retina 1988;8(4):237­43.
3. Shakin JL,Yannuzzi LA. Posterior segment manifestations of
orbital trauma. Adv Ophthalmic Plast Reconstr Surg
1987;6:115­35.
4. Williams DF, Mieler WF, Williams GA. Posterior segment
manifestations of ocular trauma. Retina 1990;10(Suppl
1):S35­44.
5. Viestenz A, Küchle M. Blunt ocular trauma. Part II. Blunt posterior
segment trauma. Ophthalmologe 2005;102(1):89­99.
6. Viestenz A, Küchle M. Retrospective analysis of 417 cases
of contusion and rupture of the globe with frequent avoidable
causes of trauma: The Erlangen Ocular ContusionRegistry
(EOCR) 1985­1995. Klin Monatsbl Augenheilkd
2001;218(10):662­9.
7. ViestenzA.Rupture of the choroid after eyeball contusion--
an analysis based on the Erlangen Ocular Contusion Registry
(EOCR). Klin Monatsbl Augenheilkd 2004;221(8):713­9.
8. Viestenz A, Küchle M. Ocular contusion caused by elastic
cords: A retrospective analysis using the Erlangen Ocular
Contusion Registry. Clin Experiment Ophthalmol
2002;30(4):266­9.
9. ViestenzA,Küchle M.Eye contusions caused by a bottle cap.
A retrospective study based on the Erlangen Ocular Contusion
Register (EOCR). Ophthalmologe 2002;99(2):105­8.
10. Morris DS. Ocular blunt trauma: Loss of sight from an ice
hockey injury. Br J Sports Med 2006;40(3):e5.
11. Farr AK, Fekrat S. Eye injuries associated with paintball
guns. Int Ophthalmol 1998­1999;22(3):169­73.
12. Kim JM, Kim KO, KimYD, et al.A case of air-bag associated
severe ocular injury. Korean J Ophthalmol 2004;18(1):84­8.
13. Secrétan M, Sickenberg M, Zografos L, et al.
Morphometric characteristics of traumatic choroidal ruptures
associated with neovascularization. Retina 1998;18(1):62­6.
14. Ament CS, Zacks DN, Lane AM, et al. Predictors of visual
outcome and choroidal neovascular membrane formation
after traumatic choroidal rupture. Arch Ophthalmol
2006;124(7):957­66.
15. Yeung L, ChenTL, KuoYH, et al. Severe vitreous hemorrhage
associated with closed-globe injury. Graefes Arch Clin
Exp Ophthalmol 2006;244(1):52­7.
16. Abri A, Binder S, Pavelka M, et al. Choroidal neovascularization
in a child with traumatic choroidal rupture:Clinical and
ultrastructural findings. Clin Experiment Ophthalmol
2006;34(5):460­3.
17. Gross JG, King LP, de Juan E, et al. Subfoveal neovascular
membrane removal in patients with traumatic choroidal rupture.
Ophthalmol 1996;103(4):579­85.
18. O'Connor J. Choroidal rupture. Optom Clin
1993;3(2):81­9.
19. Harissi-Dagher M, Sebag M, Gauthier D, et al.
Photodynamic therapy in young patients with choroidal neovascularization
following traumatic choroidal rupture. Am J
Ophthalmol 2005;139(4):726­8.
20. Mennel S, Hausmann N, Meyer CH, et al. Photodynamic
therapy and indocyanine green guided feeder vessel photocoagulation
of choroidal neovascularization secondary to
choroid rupture after blunt trauma. Graefes Arch Clin Exp
Ophthalmol 2005;243(1):68­71.
21. Mehta HB, Shanmugam MP. Photodynamic therapy of a
posttraumatic choroidal neovascular membrane. Indian J
Ophthalmol 2005;53(2):131­2.
22. Raman SV,Desai UR,Anderson S,et al.Visual prognosis in
patients with traumatic choroidal rupture. Can J Ophthalmol
2004;39(3):260­6.
METASTATIC CHOROIDAL TUMORS
Signs and symptoms
Metastatic tumors to the choroid may
present with an assortment of signs and
symptoms. Most commonly, patients
complain of visual discomfort such as
metamorphopsia, decreased vision or
blurred vision.1
Additionally, patients
may report visual field defects, floaters,
photopsia, red eye and even pain in
some cases.1,2
Less commonly, patients
may be entirely asymptomatic.3
Ophthalmoscopically, choroidal metastases
appear as mildly to moderately
elevated placoid or oval lesions. They
are typically creamy yellow with variable
mottling, although the color may
vary from white to orange depending
upon the tumor's origin.1,4
These lesions
characteristically display irregular
brown pigment deposits overlying the
mass, which gives them a unique "leopard
skin" appearance; the pigment spots
have been shown histologically to represent
macrophages containing lipofus-
cin.5
Choroidal metastases are often
multilobular, multifocal and occasionally
bilateral,5
in contradistinction to
choroidal melanomas, which are almost
invariably isolated and unilateral.
Another very common finding with
choroidal metastases is the presence of
subretinal fluid and serous retinal
detachment, which may be present in as
many as 91% of cases.5
Choroidal metastases may occur at
virtually any age, although patients are
generally between 50 and 60 years, on
average, at the time of diagnosis.3,6
There is no known racial predilection.
Women are more commonly affected
than men, with a reported female
prevalence of up to 70%.2
Patients typically
have a concurrent history of
cancer, although on occasion the diagnosis
of ocular metastasis actually precedes
the discovery of a systemic
malignancy.3,4,7,8
Pathophysiology
Metastasis is the process by which
malignant cells disseminate through the
body from one organ system to another.
It is a complex mechanism that occurs
via vascular and lymphatic channels.
The choroid, which is particularly wellvascularized,
is the most common site of
ocular metastasis.3,9
Embolic tumor cells
reach the uvea by traveling through the
internal carotid artery, the ophthalmic
artery and the posterior ciliary arteries
until they arrive at the choriocapillaris.
Some theories suggest that the choroid
may also produce chemokines.
Metastatic lesions appear to have a preference
for the posterior pole.1,3,4
A number of specific tumor types
have been associated with metastic
choroidal tumor; the most common of
these is breast carcinoma, accounting
for 39%­49% of all uveal metastases.1,3,4
The second most common primary
tumor site is the lung (21%), followed
by the gastrointestinal tract (4%).4
Metastasis to the eye has been reported
for carcinomas of the kidney, skin,
prostate, pancreas, thyroid and testes, as
well as carcinoid tumors and cutaneous
melanoma.1,2,10
In roughly 18% of
intraocular metastases, the primary
tumor site remains unknown.2,4
UVEAANDGLAUCOMA
32A REVIEW OF OPTOMETRY APRIL 15, 2008
Management
Differentiating choroidal metastases
from other malignant and non-malignant
conditions is the first priority of
proper management. Usually this is
accomplished by direct clinical inspection,
but additional diagnostic testing
may be helpful in confirming the diagnosis.
Perhaps the most frequently used
ancillary techniques are fluorescein
angiography and ultrasonography.
Angiography of choroidal metastases
characteristically demonstrates early
hypofluorescence with diffuse late staining;
however, this is not entirely diagnostic,
as other entities may demonstrate
similar features.1,2
On ultrasound evaluation,
choroidal metastases show moderate-to-high
reflectivity and an irregular
internal structure.1,2
Ultrasonography can
also help demonstrate shallow serous
detachments that may not be discernable
with ophthalmoscopy alone. Additional
diagnostic modalities may include indocyanine
green angiography, magnetic
resonance imaging, fine needle aspiration
biopsy, serum carcinoembryonic
antigen levels and radioactive phosphorus
uptake.1
The most common differential
diagnoses when considering metastasis
include (amelanotic) choroidal
melanoma, choroidal hemangioma, disciform
macular scarring and rhegmatogenous
retinal detachment.
Treatment for choroidal metastases
depends on the degree of tumor activity,
the location of the tumor, the extent of
the ocular or visual symptoms and the
patienťs overall health status. For those
who are asymptomatic and/or show evidence
of clinical improvement with systemic
chemotherapy, periodic observation
alone may be sufficient.2
Likewise,
for patients who are terminally ill with
disseminated metastases and poor constitutional
health, surgeons may elect to
initiate palliative therapy only.7
Aside
from these scenarios, invasive treatment
is indicated if the metastasis is threatening
vision or the overall health of the
globe, or if the tumor continues to grow
despite concomitant systemic therapy.1,7
Therapeutic options for choroidal
metastases include conventional external
beam irradiation, cytotoxic chemotherapy,
hormonal therapy, biological
therapy, plaque brachytherapy, proton
beam irradiation, laser photocoagulation,
photodynamic therapy and transpupillary
thermotherapy.1,11
Several sources
recommend external beam irradiation or
proton beam irradiation as a first-line
option for lesions inducing acute visual
involvement.1,2,11
Plaque brachytherapy,
transpupillary thermotherapy, laser photocoagulation
and photodynamic therapy
are viable options for localized, smaller
lesions or as second-line treatments in
conjunction with external beam irradiation
or systemic chemotherapy.11
Enucleation, which is employed much
more readily for a variety of other ocular
malignancies, is generally reserved for
cases of choroidal metastasis that are
associated with severe, intractable pain
from secondary glaucoma.1,2,11
Despite numerous treatment options,
ocular metastasis carries an exceedingly
poor systemic prognosis. For these
patients, life expectancy is reported to
range from 0.2­48 months (median 6­9
months) from the time of diagnosis.11-15
In
general, patients with breast, thyroid and
carcinoid tumors seem to have a longer
survival rate than those with metastases
from the pancreas, kidney, gastrointestinal
tract or cutaneous melanoma.2
Given
the bleak outlook, quality of life should
be a key consideration when weighing
any invasive therapeutic options.
Clinical pearls
* Metastatic lesions are considered
the most common type of intraocular
tumor in adults.1
Despite this fact,
metastases are not typically encountered
in most clinical practices. Since these
patients are frequently terminally ill and
usually have concurrent metastases to
other organ systems, the diagnosis is
often made in an alternate setting, e.g., a
tertiary care center, a hospital or a nursing
home, or even on autopsy studies.
* While the choroid is the most common
site of ocular metastasis, numerous
other tissues can be involved, including
the eyelids, iris, ciliary body, retina,
optic nerve and even the vitreous.
Anterior segment metastases account
for less than 15% of reported cases.16
* Perhaps more important than treating
the choroidal lesions associated
with ocular metastasis is ensuring that
the primary neoplasm is properly
addressed, especially if the patient presents
without a prior diagnosis of cancer.
Immediate referral to an oncologist is
paramount in these cases.
1. Paul Chan RV,Young LH.Treatment options for metastatic
tumors to the choroid.Semin Ophthalmol 2005;20(4):207­16.
2. Ou JI, Wheeler SM, O'Brien JM. Posterior pole tumor
update. Ophthalmol Clin North Am 2002;15(4):489­501.
3. Demirci H, Shields CL, Chao AN, Shields JA. Uveal metastasis
from breast cancer in 264 patients. Am J Ophthalmol
2003;136(2):264­71.
4. Shields CL, Shields JA, Gross NE, et al. Survey of 520 eyes
with uveal metastases. Ophthalmol 1997; 104(8):1265­76.
5. Stephens RF, Shields JA. Diagnosis and management of cancer
metastatic to the uvea: A study of 70 cases. Ophthalmol
1979; 86(7):1336­49.
6. Lee J,Lee S,Sohn J,YoonYH.Clinical features of uveal metastases
in Korean patients. Retina 2003;23(4):491­4.
7. Amer R, Pe'er J, Chowers I,Anteby I.Treatment options in
the management of choroidal metastases. Ophthalmologica
2004;218(6):372­7.
8. WiegelT,Kreusel KM,Bornfeld N,et al.Frequency of asymptomatic
choroidal metastasis in patients with disseminated
breast cancer: Results of a prospective screening programme.
Br J Ophthalmol 1998;82(10):1159­61.
9. De Potter P. Ocular manifestations of cancer. Curr Opin
Metastatic choroidal carcinoma in a
patient with breast cancer.
The same choroidal tumor following proton
beam irradiation.
APRIL 15, 2008 REVIEW OF OPTOMETRY 33A
Ophthalmol 1998;9(6):100­4.
10. Haddow J, Muthapati D, Arshad I, et al. Multiple bilateral
choroidal metastasis from anal melanoma. Int J Clin Oncol
2007;12(4):303­4.
11. Kanthan GL,Jayamohan J,Yip D,Conway RM.Management
of metastatic carcinoma of the uveal tract:An evidence-based
analysis. Clin Experiment Ophthalmol 2007;35(6):553­65.
12. Ratanatharathorn V, Powers WE, Grimm J, et al. Eye
metastasis from carcinoma of the breast:Diagnosis,radiation
treatment and results. CancerTreat Rev 1991;18(4):261­76.
13. Kreusel KM,Wiegel T, Stange M, et al. Choroidal metastasis
in disseminated lung cancer: Frequency and risk factors.
Am J Ophthalmol 2002;134(3):445­7.
14. Mewis L, Young SE. Breast carcinoma metastatic to the
choroid.Analysis of 67 patients.Ophthalmol 1982;89(2):147­51.
15. Tsina EK, Lane AM, Zacks DN, et al. Treatment of
metastatic tumors of the choroid with proton beam irradiation.
Ophthalmol 2005;112(2):337­43.
16. Wickremasinghe S, Dansingani KK,Tranos P, et al. Ocular
presentations of breast cancer. Acta Ophthalmol Scand
2007;85(2):133­42.
PIGMENTARY GLAUCOMA
Signs and symptoms
Pigment dispersion syndrome is an
asymptomatic disorder typically discovered
upon routine evaluation.1
Pigmentary
glaucoma, a sequela of pigment dispersion
syndrome, is also mostly
asymptomatic. Rarely though, patients
present with complaints related to
episodic rises in intraocular pressure
secondary to exercise, such as colored
haloes around lights, blurred vision or
subtle ocular pain.2,3
Both conditions are
typically encountered in young, white
men between ages 20 and 40.4
A myopic
refractive error is a commonly associated
finding. One population-based study
observed pigment dispersion syndrome
in 2.45% of white patients undergoing
glaucoma screening.4
Pigment dispersion
syndrome and pigmentary glaucoma
also occur in black patients, though
less commonly than in white ones.5­7
The
majority of patients in this category are
older, female, and hyperopic.5­7
Patients with pigment dispersion syndrome
and pigmentary glaucoma
demonstrate liberation of iris pigment
within the anterior chamber. Often, this is
seen as diffuse accumulation or possibly
a granular brown vertical band along the
corneal endothelium known as a
Krukenberg's spindle.8­10
Pigment accumulation
may also be evident on the lens,
the surface of the iris and at the anatomic
boundary denoting the termination of
Descemeťs membrane known as
Schwalbe's line. When pigment accumulates
here, it is called Sampaolesi's line.5
Dense pigmentation may be seen
gonioscopically, often covering the trabecular
meshwork for 360°; but usually
it is most prominent in the inferior quadrant
due to gravity.8,11,12
The angle recess
remains unchanged and open. Radial,
spoke-like transillumination defects of
the mid-peripheral iris are common.5,7,8
There seem to be some differences in
the appearance of pigment dispersion
syndrome and pigmentary glaucoma in
black patients. In these patients, the
degree of corneal endothelial pigmentation
is quite mild and Krukenberg's spindles
are not usually present. The degree
of corneal endothelial pigmentation is
not predictive of the amount of trabecular
meshwork pigment that may have
accumulated. Iris transillumination
defects are rarely present, possibly due
to a thicker iris stroma.5,6,9
Intraocular pressure (IOP) may rise
sharply in cases of pigmentary glaucoma.
Patients with pigment dispersion syndrome
present with a normal optic nerve
appearance, while patients with pigmentary
glaucoma manifest evidence of glaucomatous
optic atrophy, nerve fiber layer
damage, and associated field loss.
Pathophysiology
The pathophysiology of pigmentary
glaucoma must be considered in two
parts: mechanism of pigment release
and mechanism of pressure elevation.
Pigment dispersion occurs as a result of
the proximity between the posterior iris
pigment epithelium and the zonular
fibers of the lens. The abrasive nature of
this physical contact leads to mechanical
disruption of the iris surface and release
of pigment granules into the posterior
chamber, which follows the flow of the
aqueous convection current into the
anterior chamber angle.13­15
Many patients with pigment dispersion
syndrome and pigmentary glaucoma
demonstrate a concave approach of
the iris as it inserts into the anterior
chamber angle, giving the iris a "backward
bowed" appearance on goni-
oscopy.15
This posterior bowing of the
iris places the posterior surface of the iris
in apposition to the lens zonules. As the
iris responds to light, iridozonular friction
results in pigment liberation from
the posterior iris. Sometimes the degree
of pigment loss in the mid-peripheral
areas produces visible transillumination
defects corresponding to packets of iris
zonular fibers.14
Although the majority
of these patients have a concave iris
approach, others may have a flat or planar
approach.15
It has been theorized that in cases with
a markedly concave iris insertion the iris
functions as a flap valve lying against the
anterior lens surface. When a pressure
gradient develops that is greater in the
anterior chamber, the iris is forced backwards,
closing the valve and trapping the
aqueous from moving into the anterior
chamber.Thisincreasedanteriorchamber
pressure subsequently forces the iris into
the aforementioned backward bowed
configuration of the iris and has been
termed "reverse pupillary block." The
blocked flow increases the IOP and over
time or in cases of chronic episodes, it
produces the expected neural damage.16,17
This phenomenon has been shown to
increase with patient blinking.14,18,19
Excessively released pigment accumulating
in the trabecular meshwork has
two possible consequences. First, pigment
may reside benignly in the
trabecular meshwork where IOP is unaffected,
and the condition remains pigment
dispersion syndrome. Alternatively,
the pigment causes a rise in IOP
and via the mechanisms described previously
and the patient may develop pig-
UVEAANDGLAUCOMA
Dense trabecular pigment accumulation may
be indicative of pigmentary glaucoma.
The Ocular Hypertension Treatment Study (OHTS),1,2
Collaborative NormalTension Glaucoma Study (CNTGS),3,4
Advanced
Glaucoma Intervention Study (AGIS)5,6
and Early Manifest Glaucoma
Treatment Study (EMGTS)7
are well-designed, well-executed glaucoma
investigations that have greatly advanced our understanding of the disease.While
most practitioners are familiar with the initial publications
and outcomes, we must not forget that new information from these
studies is published on an ongoing basis.These subsequent publications
have provided even greater understanding of glaucoma and have greatly
assisted clinicians in managing patients with glaucoma.
OHTS
The most notable finding from the original OHTS publication was
that lowering IOP in patients with ocular hypertension reduced the
risk of their developing primary open-angle glaucoma (POAG) over
five years from 9.5% to 4.4%.1
At the time of the publication of OHTS
in 2002, it had merely been noted that there was a trend for treatment
being protective in African-American patients. However, this
finding did not achieve statistical significance due to short follow-up
time for these patients at the time of initial publication.A subsequent
publication that allowed for proper follow-up time reported that,
among African Americans in the study, 16.1% of the control group
developed glaucoma but only 8.4% of the treated group progressed.
This confirmed the benefit of pressure reduction in African Americans
who had ocular hypertension. Further, African-American patients in
the study demonstrated twice the risk of developing POAG as white
patients, despite similar baseline and treated IOPs.8
An initial OHTS publication identified central corneal thickness as
a strong predictive factor for conversion to glaucoma from ocular
hypertension.2
A later ancillary study attempted to determine
whether any factors on confocal scanning laser ophthalmoscopy
(Heidelberg RetinalTomograph II --HRT II) could be associated with
a positive prediction for progression to POAG from ocular hypertension.
Notably, an overall HRT classification of "outside normal limits"
had a 14% positive predictive value for POAG development. If
the superior temporal sector of the optic disc had a classification of
"outside normal limits," there was a 40% positive predictive value for
the conversion to glaucoma.9
Using OHTS visual field data, it was found that a visual field endpoint
for conversion to glaucoma (identifying a decrease in threshold
perimetry beyond predetermined criteria) confirmed by three
consecutive visual fields appeared to have greater specificity and sensitivity
than either one or two consecutive visual field test results.
However, some eyes whose visual field POAG endpoint was confirmed
by three consecutive reliable test results still managed to have
one or more normal tests on follow-up. Clearly, these results mean
that before judging change in a visual field, multiple confirmatory
tests are required.10
A recent report from OHTS compared the rates of detection of
optic disc hemorrhages by clinical examination and by review of
optic disc photographs. Further, an attempt was made to determine
whether optic disc hemorrhages were predictive of the development
of POAG.11
Remarkably, 16% of disc hemorrhages were
detected both by clinical examination and review of photographs,
and 84% were detected only by review of photographs following clinical
examination.Thus, review of stereo photographs was more sensitive
at detecting optic disc hemorrhage than actual clinical exami-
nation.11
Clearly, the message from this report is that clinicians should
photograph patients when possible and critically examine the photographs
following the actual examination. The occurrence of an
optic disc hemorrhage was associated with an increased risk of
developing POAG (as defined by OHTS endpoints), although it must
be acknowledged that 86.7% of eyes in the study in which a disc
hemorrhage developed have not converted to POAG to date.11
CNTGS
The initial result of the CNTGS indicated that IOP is part of the
pathogenic process of normal tension glaucoma (NTG).3,4
Further, it
was seen that therapy that reduced IOP and was free of side effects
would be expected to be beneficial in patients who are at risk of disease
progression.3,4
However, the initial results of the CNTGS did not identify which
patients were at greatest risk of disease progression. Later analysis of
this data indicated that patients who were at risk of disease progression
included women, those with history of migraines (many of
whom were female) and those with manifesting disc hemorrhages.
Factors that were not associated with an increased risk of progression
included older age, higher mean IOP, and visual field defects
threatening fixation.12
The CNTGS attempted to identify which patients with NTG
might benefit most from lowering IOP. Factors associated with an
improved clinical course from treatment included patients without a
baseline disc hemorrhage, women, those with family history of glaucoma,
those without family history of stroke, those with no personal
history of cardiovascular disease and those with lesser amounts of
disc damage (cup-to-disc ratio of 0.7/0.7 or less). Characteristics not
associated with treatment benefit included disc hemorrhages and
migraine. Curiously, the presence of a disc hemorrhage was strongly
predictive of disease progression, but patients with this feature saw
no difference in the clinical course of their disease, either with or
without treatment.13
AGIS
One of the most referenced findings from AGIS was that low
IOP is associated with reduced progression of visual field defects.7
Later, an attempt was made to identify risk factors associated with
visual field progression. Fluctuations in IOP was the variable consistently
associated with visual field progression.14
This seems to illustrate
the importance not only of lowering IOP, but also of consistently
controlling the diurnal pressure curve.
An analysis was conducted to distinguish visual field fluctuations
from true deterioration in AGIS patients. A single confirmatory test
six months after detection of visual field worsening indicated at least
a 72% probability that defect would be persistent when the worsening
was defined by at least 2 decibels of Mean Deviation (MD).
When the number of confirmatory tests was increased from one to
two, the percentage of eyes that showed a persistent defect
increased from 72% to 84%.15
This further demonstrates the need
for multiple visual fields to truly judge progression.
Later analysis of the AGIS data investigated the association of
pre-intervention and post-intervention patient and eye characteristics
with respect to failure of argon laser trabeculoplasty (ALT) and
34A REVIEW OF OPTOMETRY APRIL 15, 2008
UPDATING THE GLAUCOMA STUDIES
APRIL 15, 2008 REVIEW OF OPTOMETRY 35A
mentary glaucoma.14
Interestingly, physical blockage of
the trabecular meshwork by pigment
granules is not the likely cause of the
pressure rise.20
Endothelial cells lining
the trabecular beams of the trabecular
meshwork quickly phagocytize small
amounts of accumulated pigment preserving
the normal architecture of the
trabecular meshwork.21­23
However, in
chronic cases of pigment dispersion,
greater amounts of pigment are more
difficult for the cells to phagocytize.
When this occurs, the endothelial cells
that line the trabecular meshwork
beams disintegrate. The resultant
degeneration of the trabecular meshwork
with the accumulation of debris,
collapsed beams and loss of intratrabecular
spaces is what produces the rise in
IOP.23
The IOP rise in pigmentary glaucoma
mostly occurs due to a breakdown
of normal phagocytic activity of the
endothelial cells and subsequent loss of
normal trabecular architecture and
function.23
Management
Because pigment dispersion syndrome
has no direct ramifications on
ocular health or vision other than potential
future development of pigmentary
glaucoma, patients with this condition
should be treated as glaucoma suspects.
Patients should be monitored for IOP
spikes and optic nerve changes three to
four times a year, with threshold visual
fields, diagnostic lasers and gonioscopy
performed annually. One study noted the
conversion rate from pigment dispersion
trabeculectomy. ALT failure was associated with younger age and
higher pre-intervention IOP. Trabeculectomy failure was associated
with younger age, higher pre-intervention IOP, diabetes and one or
more postoperative complications, particularly elevated IOP and
marked inflammation.16
EMGTS
A landmark study with an untreated control group of patients
who had early, newly diagnosed glaucoma found that progression of
the disease was less frequent in the treated group (45%) than in the
control (untreated) group (62%) and occurred significantly later in
treated patients.7
Interestingly, many of the patients remained stable
over time, even those in the untreated control group, while glaucoma
progressed in as many as 30% of treated patients after four years,
despite the clear effect of treatment,The time it took for glaucoma
to progress varied greatly among patients and was sometimes rather
brief, even in treated patients. Clearly, it was difficult to predict the
initial course of newly diagnosed early glaucoma.7
Later analysis using the EMGTS data aimed at identifying factors
associated with glaucoma progression, as well as the beneficial effect
of pressure reduction. It was later seen that patients treated in the
EMGTS had half of the progression risk of control patients.16
Further,
the magnitude of initial IOP reduction was a major factor influencing
outcome, with greater initial IOP reductions associated with the
greatest degree of disease stabilization. It was noted that glaucoma
progression was also increased with higher baseline IOP, exfoliation,
bilateral disease, worse mean deviation on visual fields and older age,
as well as frequent disc hemorrhages during follow-up.16
It can be
asserted that patients presenting with factors such as exfoliation or
recurrent disc hemorrhage may have a worse prognosis and would
likely need greater degrees of therapy and closer observation.
Clearly, we must not limit our knowledge to the initial reports
from landmark studies. It is important to review the literature constantly,
especially for follow-up reports from major studies. Often,
clinical data is analyzed long after the initial publications from milestone
studies.The subsequent publications are typically very strong
as they represent information from very well-designed and well-conducted
studies, powered by great numbers of patients.
1. Kass MA, Heurer DK, Higginbotham EJ, et al.The Ocular Hypertension Treatment Study. A
randomized trial determines that topical ocular hypotensive medication delays or prevents the
onset of primary open angle glaucoma. Arch Ophthalmol 2002;120:701­13.
2. Gordon MO, Beiser JA, Brandt JD, et al.The Ocular HypertensionTreatment Study: Baseline
factors that predict the onset of primary open angle glaucoma. Arch Ophthalmol
2002;120:714­20.
3. Collaborative Normal Tension Glaucoma Study Group. Comparison of glaucomatous progression
between untreated patients with normal tension glaucoma and patients with therapeutically
reduced intraocular pressures. Am J Ophthalmol 1998;126;487­97.
4. Collaborative NormalTension Glaucoma Study Group.The effectiveness of intraocular pressure
reduction in the treatment of normal tension glaucoma. Am J Ophthalmol
1998;126;498­505.
5. The AGIS investigators.The Advanced Glaucoma Intervention Study (AGIS): 7.The relationship
between control of intraocular pressure and visual field deterioration. Am J Ophthalmol
2000;130:429­40.
6. The AGIS Investigators:The Advanced Glaucoma Intervention Study (AGIS): 9. Comparison
of glaucoma outcomes in black and white patients within treatment groups. Am J Ophthalmol
2001;132:311­320.
7. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression.
Results from the early manifest glaucoma trial. Arch Ophthalmol
2002;120(10):1268­79.
8. Higginbotham EJ, Gordon MO, Beiser JA, et al. (Ocular Hypertension Treatment Study
Group). Topical medication delays or prevents primary open angle glaucoma in African
American individuals. Arch Ophthalmol 2004;122:813­20.
9. Zangwill LM,Weinreb RN, Beiser JA, et al. Baseline topographic optic disc measurements are
associated with the development of primary open angle glaucoma: The Confocal Scanning
Laser Ophthalmoscopy Ancillary Study to the Ocular Hypertension Treatment Study. Arch
Ophthalmol 2005;123(9);1188­97.
10. Keltner JL, Johnson CA, Levine RA, et al. Normal visual field test results following glaucomatous
visual field end points in the Ocular Hypertension Treatment Study. Arch Ophthalmol
2005;123(9):1201­6.
11. Budenz DL, Anderson DR, Feuer WJ, et al. Detection and prognostic significance of optic
disc hemorrhages during the Ocular Hypertension Treatment Study. Ophthalmol
2006;113(12):2137­43
12. Drance S, Anderson DR, Schulzer M, Collaborative Normal Tension Glaucoma Study
Group. Risk factors for the progression of visual field abnormalities in normal tension glaucoma.
Am J Ophthalmol 2001;131:699­708.
13. Anderson DR, Drance SM, et al. Factors that predict the benefit of lowering intraocular
pressure in normal tension glaucoma. Am J Ophthalmol 2003;136:820­9.
14. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al. Predictive factors for glaucomatous visual
field progression in the Advanced Glaucoma Intervention Study. Ophthalmol
2004;111(9):1627­35.
15. Kim J, Dally LG, Ederer F, et al. The Advanced Glaucoma Intervention Study (AGIS): 14.
Distinguishing progression of glaucoma from visual field fluctuations. Ophthalmol
2004;111(11):2109­16.
16. AGIS Investigators.The Advanced Glaucoma Intervention Study (AGIS): 11. Risk factors for
failure of trabeculectomy and argon laser trabeculoplasty. Am J Ophthalmol
2002;134(4):481­98.
17. Leske MC, Heijl A, Hussein M, et al. (Early Manifest GlaucomaTrial Group). Factors for glaucoma
progression and the effect of treatment: The early manifest glaucoma trial. Arch
Ophthalmol 2003;121(1):48­56.
UVEAANDGLAUCOMA
36A REVIEW OF OPTOMETRY APRIL 15, 2008
syndrome to pigmentary glaucoma at
20%, with the vast majority converting
within 10 years of a diagnosis of pigment
dispersion syndrome.24
However, patients
with pigment dispersion syndrome who
were followed for longer than 10 years
without developing pigmentary glaucoma
had a low risk of developing pigmentary
glaucoma subsequently.24
A more
recent study noted that the risk of developing
pigmentary glaucoma from pigment
dispersion syndrome was 10% at 5
years and 15% at 15 years. Young,
myopic men were more likely to convert
to pigmentary glaucoma, and an IOP
greater than 21 mm Hg at initial examination
was associated with an increased
risk of conversion.25
Medical treatment of pigmentary
glaucoma is similar to primary open
angle glaucoma.8
There has been conjecture
that prostaglandin medications
should be avoided in glaucomas in which
pigment liberation is involved in the etiology,
because these medications
increase the amount of melanin in stromal
melanocytes and could potentially
further impair drainage. However, this
fear is unfounded: The melanocyte size
increase occurs within the iris stroma,
and these cells are not liberated in the
disease. Prostaglandin medications have
been proven to successfully lower IOP in
eyes with pigment dispersion from pseudoexfoliative
glaucoma; thus, they are
good therapeutic options for pigmentary
glaucoma.26­28
Laser peripheral iridotomy (LPI) is a
consideration for patients with pigment
dispersion syndrome and pigmentary
glaucoma in which significant iris concavity
is evident.14­16
It has been well-reported that the iris
can convert from a concave to a planar
approach following LPI. In cases in
which there is significant iris concavity,
LPI should be considered to reduce the
amount of pigment being liberated.
However, very little information is available
regarding the effect of LPI on IOP in
pigmentary glaucoma.
In a retrospective analysis, it was shown
that LPI had very little effect on IOP in
patients with pigmentary glaucoma.29
Althoughthisstudydidnotprovidesupport
for the benefit of LPI regarding IOP control,
it also did not disprove value of LPI in
this patient population; rather, it identified
the need for a large, prospective study.29
Patients with pigmentary glaucoma
tend to respond well to argon laser trabeculoplasty,
presumably due to the
improved thermal effects secondary to the
increased meshwork pigmentation.30­34
Little published data appears to be
available regarding the efficacy of selective
laser trabeculoplasty in pigmentary
glaucoma. In one series involving four
patients, it was seen that post-SLT IOP
elevations can be a serious adverse event
in these patients.35
Trabeculectomy
remains an option for patients with pigmentary
glaucoma.35
However, because such patients tend to
beyounger,theremaybeanincreasedfailure
rate compared to that of older patients
because of fibrosis. Medical modulators
for wound healing, such as mitomycin-C,
are generally indicated in this group.37
Clinical pearls
* Pigmentary dispersion syndrome is
a common cause of glaucoma in younger
patients, and this diagnosis should be
strongly considered when encountering
glaucoma in young patients.
* Pigmentary glaucoma is often
underdiagnosed in black patients
because of the lack of corneal endothelial
pigment and iris transillumination
defects. Often, the trabecular hyperpigmentation
is incorrectly attributed to
overall racial pigmentation.
* Diurnal IOP variations can be quite
extreme in pigmentary glaucoma.
* The increased IOP is not from pigment
"clogging" the trabecular meshwork,
but from degradation of the trabecular
meshwork support structure.
1. Sugar HS,Barbour FA.Pigmentary glaucoma:A rare clinical
entity.Am J Ophthalmol 1949;32:90­2.
2. Schenker HI, Luntz M, Kels B, et al. Exercise-induced
increase of intraocular pressure in the pigmentary dispersion
syndrome.Am J Ophthalmol 1980;89;598­60.
3. HaynesWL,Johnson AT,AlwardWL.Inhibition of exerciseinduced
pigment dispersion in a patient with pigment dispersion
syndrome.Am J Ophthalmol 1990;109:599­601.
4. Ritch R, Steinberger D, Liebmann JM. Prevalence of pigment
dispersion syndrome in a population undergoing glaucoma
screening.Am J Ophthalmol 1993;115:707­10.
5. Roberts DK,Chaglasian MA,Meetz RE.Clinical signs of the
pigment dispersion syndrome in Blacks. Optom Vis Sci
1997;74(12):993­1006.
6. Roberts DK, Meetz RE, Chaglasian MA.The inheritance of
the pigment dispersion syndrome in blacks. J Glaucoma
1999;8:250­6.
7. Semple HC,Ball SF.Pigmentary glaucoma in the black population.Am
J Ophthalmol 1990; 109:518­22.
8. Farrar SM, Shields MB. Current concepts in pigmentary
glaucoma. Surv Ophthalmol 1993;37(4):233­52.
9. Roberts DK, Miller E, Kim LS. Pigmentation of the posterior
lens capsule central to Wieger's ligament and the Scheie
line:a possible indication of the pigment dispersion syndrome.
OptomVis Sci 1995;72(10):756­62.
10. Lehto I, Ruusuvaara P, Setala K. Corneal endothelium in
pigmentary glaucoma and pigment dispersion syndrome.Acta
Ophthalmol 1990;68:703­9.
11. Ritch R. Pigment dispersion syndrome.Am J Ophthalmol
1998;126(3):442­5.
12. Lehto I,Vesti E.Diagnosis and management of pigmentary
glaucoma. Curr Opin Ophthalmol 1998;9:61­4.
13. Campbell DG. Pigmentary dispersion and glaucoma: a
new theory.Arch Ophthalmol 1979;97;1667­72.
14. Campbell DG,Schertzer RM.Pathophysiology of pigment
dispersion syndrome and pigmentary glaucoma. Curr Opin
Ophthalmol 1995;6(2):96­101.
15. Potash SD,Tello C, Liebmann J, Ritch R. Ultrasound biomicroscopy
in pigment dispersion syndrome. Ophthalmology
1994;101:332­9.
16. Karickhoff JR. Pigmentary dispersion syndrome and pigmentary
glaucoma: a new treatment, and a new technique.
Ophthalmic Surg 1992;23(4):269­77.
17. Karickhoff JR. Reverse pupillary block in pigmentary glaucoma:
follow-up and new developments. Ophthalmic Surg
1993;24:562­3.
18. Campbell DG. Iridotomy, blinking, and pigmentary glaucoma.
Invest OphthalmolVis Sci 1993;34(4suppl):993.
19. Liebmann JM, Tello C, Ritch R. Pigment dispersion syndrome,
iris configuration, and blinking. Invest Ophthalmol Vis
Sci 1994;35(5suppl):1558.
20. Murphy CG, Johnson M,Alvarado JA. Juxtacanalicular tissue
in pigmentary and primary open angle glaucoma. The
hydrodynamic role of pigment and other constituents. Arch
Ophthalmol 1992;110(12):1779­85.
21. Rohen JW, van der Zypen EP.The phagocytic activity of
the trabecular meshwork endothelium: an electron microscopic
study of the vervet (ceropithicus aethiops). Graefes
Arch Clin Exp Ophthalmol 1968;175:143­60.
22. Sherwood M, RichardsonTM. Evidence for in vivo phagocytosis
by trabecular endothelial cells.Invest OphthalmolVis Sci
1980;19(4suppl):66.
23. Richardson TM, Hutchinson BT, grant WM. The outflow
tract in pigmentary glaucoma: A light and electron microcroscopy
study.Arch Ophthalmol 1977;95:1015­25.
24. Mastropasqua L,Ciancaglini M,Carpineto P,et al.Early stadiation
of pigmentary dispersion syndrome and long-term
analysis of progression to pigmentary glaucoma. Ann
Ophthalmol Glaucoma 1996,28:301­7.
25. SiddiquiY,Ten Hulzen RD, Cameron JD, et al.What is the
risk of developing pigmentary glaucoma from pigment dispersion
syndrome? Am J Ophthalmol. 2003Jun;135(6):794­9.
26. Konstas AG, Lake S, Maltezos AC, et al.Twenty-four hour
intraocular pressure reduction with latanoprost compared
with pilocarpine as third-line therapy in exfoliation glaucoma.
Eye2001;15(Pt1):59­62.
27. Nordmann JP, Mertz B, Yannoulis NC, et al. A double
masked randomized comparison of the efficacy and safety of
unoprostone with timolol and betaxolol in patients with primary
open angle glaucoma including pseudoexfoliation glaucoma
or ocular hypertension.6-month data.Am J Ophthalmol
2002;133(1):1­10.
28. Grierson I, Pfeiffer N, Cracknell K, et al. Histology and fine
APRIL 15, 2008 REVIEW OF OPTOMETRY 37A
structures of the iris and outflow system following Latanoprost
therapy. Surv Ophthalmol 2002;47Suppl1:S176­84.
29. Reistad CE, Shields MB, Campbell DG, et al; American
Glaucoma Society Pigmentary Glaucoma Iridotomy Study
Group.The influence of peripheral iridotomy on the intraocular
pressure course in patients with pigmentary glaucoma. J
Glaucoma. 2005Aug;14(4):255­9.
30. Goldberg I. Argon laser trabeculoplasty and the open
angle glaucomas.Aust NZ J Ophthalmol 1985;13:243­8.
31. Hagadus J,Ritch R,Pollack,et al.Argon laser trabeculoplasty
in pigmentary glaucoma. Invest Ophthalmol Vis Sci.
1984;25:(4Suppl):94.
32. Liebmann J, Ritch R, Pollack, et al. Argon laser trabeculoplasty
in pigmentary glaucoma: long-term follow-up.
Ophthalmology. 1993;100(6):909­13.
33. Robin AL, Pollack IP. Argon laser trabeculoplasty in secondary
forms of open angle glaucoma. Arch Ophthalmol
1983;101:382­4.
34. Lunde MW.Argon laser trabeculoplasty in pigmentary dispersion
syndrome with glaucoma. Am J Ophthalmol
1983;96:721­5.
35. Harasymowycz PJ, Papamatheakis DG, Latina M, et al.
Selective laser trabeculoplasty (SLT) complicated by intraocular
pressure elevation in eyes with heavily pigmented trabecular
meshworks.Am J Ophthalmol. 2005;139(6):1110­3.
36. Wakabayashi T, Higashide T, Sugiyama K. Case of pigmentary
glaucoma treated with medical therapy, laser treatment,
and trabeculotomy. Nippon Ganka Gakkai Zasshi.
2007;111(2):95­101.
37. Farrar SM, Shields MB, Miler KN, et al. Risk factors for the
development and severity of glaucoma in the pigment dispersion
syndrome.Am J Ophthalmol 1989,108:223­9.
EXFOLIATIVE GLAUCOMA
Signs and symptoms
Exfoliation syndrome and exfoliative
glaucoma occur throughout the world
but especially in high rates throughout
northern Finland, Iceland, Saudi Arabia,
Great Britain and Greece, and it is a
common phenomenon in patients with
these ethnic backgrounds.1­4
Exfoliation
occurs in 5% of older Americans.5
This
condition is considered uncommon in
patients of African descent, though it
does occur.6,7
The true overall prevalence
of exfoliation syndrome may be
underestimated as 15% of cases may be
missed clinically.8
Exfoliative glaucoma is predominately
a disease of the elderly and is rarely
found in patients younger than 50
years.4,9
The lowest age of onset reported
thus far occurred in a 17-year-old girl.10
The highest prevalence rates have been
found in patients older than age 70.11­15
Patients present with a fine, flaky
material on the anterior lens capsule at
the pupillary margin. Over time, this coalesces
into a characteristic "bulls-eye"
pattern typically seen in exfoliation syndrome.
This classic pattern is usually
only observable when the patienťs pupil
is dilated. Beyond the anterior lens surface,
exfoliative material is most commonly
seen accumulating at the pupillary
margin. This may be visible in an undilated
state. Pigment loss from the pupil
margin with subsequent deposition on
anterior chamber structures is a hallmark
of the condition.9
This leads to increased
transillumination of the iris at the pupillary
margin, which is termed peripupillary
transillumination defects.There may
be pigment granules on the corneal
endothelium and iris surface. Within the
angle, there may be observable pigment,
clear flaky material or both.16­18
Initially, intraocular pressure (IOP) is
unaffected in exfoliation syndrome;
however, over time, elevated intraocular
pressure can develop, and characteristic
glaucomatous cupping and visual field
loss may ensue.
In one report, 16% of patients with
clinically apparent exfoliative material
required treatment upon presentation,
with 44% of these developing a need for
therapy over the next 15 years.13
In another
study, roughly a 32% conversion rate
from exfoliation syndrome to exfoliative
glaucoma occurred over 10 years.14
Another report noted a 45% conversion
rate from exfoliation syndrome to
exfoliative glaucoma over a mean time
frame of five years.19
Clinically, exfoliation
is markedly asymmetric, with biomicroscopically
unilateral involvement
in many cases.4,5,13,14,20
Patientswithexfoliationaremoreprone
to developing cataracts as well as surgical
complications during extraction.21­25
Complications include poor pupillary
mydriasis, poor zonular integrity and
intraoperative zonular dialysis, spontaneous
lens dislocations and vitreous loss
during surgery. Occasionally, lens displacement
with pupil block and angle
closure may occur.26,27
Pathophysiology
Exfoliation involves the production
and accumulation of an abnormal fibrillar
extracellular material in the anterior
chamber of the eye as well as other various
parts of the eye and adnexa.28,29
The
accumulated material consists of a fibrillar
component and an amorphous
component, though the exact chemical
composition remains unclear.30­34
It
appears that the material represents
abnormal basement membrane secreted
by all structures in the anterior chamber
and deposited on the anterior lens capsule,
iris surface and trabecular mesh-
work.30­34
Because of the accumulation
of material at the pupillary margin, there
is increased lenticular apposition with
the iris, and subsequent erosion of iris
pigment as the pupil dilates and constricts.
This leads to increased iris transillumination
and deposition of pigment
granules on the endothelium, iris surface
and trabecular meshwork--similar to
pigment dispersion syndrome. As this is
a condition that involves deposition of
material on the anterior lens capsule and
not delamination of the lens capsule,
lensectomy is not curative.
The development of glaucoma typically
occurs as a result of a buildup in
the trabecular meshwork of pigment
granules and exfoliative material. The
primary cause of IOP elevation appears
to be phagocytosis of accumulated pigment
and material by the trabecular
cells and Schlemm's canal cells, with
subsequent degenerative changes of
Schlemm's canal and trabecular meshwork
tissues. Thus, this is a secondary
open-angle glaucoma mechanism.26,27
However, due to zonular dehiscence
from accumulations of exfoliative material,
there can be lens displacement with
secondary pupil block and angle closure
mechanisms.26,27
Patients with exfoliation have demon-
UVEAANDGLAUCOMA
Exfoliation on the anterior lens surface.
38A REVIEW OF OPTOMETRY APRIL 15, 2008
strated aggregates of similar material in
the fibrovascular connective tissue septa
of the skin as well as in some internal
organs (e.g., heart, lungs, liver and kidneys).
Some evidence suggests an association
with transient ischemic attacks,
aortic aneurysm formation and systemic
cardiovascular diseases.27,33
Exfoliation
syndrome is therefore considered a generalized
systemic disorder rather than
solely an ocular condition.33
Management
Exfoliation syndrome without IOP
rise requires periodic monitoring of IOP,
discs, nerve fiber layer and visual fields
in case IOP elevation later develops.13,14,19
Multiple IOP readings to establish a
diurnal pressure curve is especially
important as patients with exfoliation
syndrome and exfoliative glaucoma
demonstrate great variations in IOP.35,36
Patients with exfoliative glaucoma,
more than those with primary openangle
glaucoma (POAG), exhibit a diurnal
range greater than 15 mmHg. Fortyfive
percent of exfoliative glaucoma
patients demonstrate a peak IOP at times
outside normal physician office hours.37
Exfoliative glaucoma is medically
treated in the same manner as POAG.
The clinician may use, if not systemically
contraindicated, topical beta-blockers,
topical carbonic anhydrase inhibitors,
prostaglandin analogs and alpha-adrenergic
agonists. However, the IOP level in
exfoliative glaucoma is typically higher
than with POAG and is more difficult to
temporize.Typically a greater amount of
medical therapy is needed to control
patients with exfoliative glaucoma compared
to POAG patients.38-40
Laser trabeculoplasty
and trabeculectomy, both
viable treatment options, are often
employed earlier in cases of exfoliative
glaucoma than for patients with POAG.39
Clinical pearls
* Peripupillary iris transillumination
defects are a common and important
finding in patients with exfoliation. In
fact, they may precede the development
of clinically observable exfoliative material
on the lens surface. This finding
mandates a careful inspection of the
anterior lens surface following dilation.
* A pigment shower in the anterior
chamber can occur following diagnostic
dilation.
* Eyes with exfoliation typically do
not dilate well due to subclinical posterior
synechiae.
* Exfoliative glaucoma can be especially
difficult to control. Special care
should be given to earlier, aggressive
pressure reduction when exfoliation is
present.
* While exfoliation can appear to be
unilateral, it is actually bilateral and
asymmetric.
1. Forsius H. Exfoliation syndrome in various ethnic populations.Acta
Ophthalmol (Copenh) 1988;66(Suppl 184);71­85.
2. Summanen P, Tonjum AM. Exfoliation syndrome among
the Saudis. Acta Ophthalmol (Copenh) 1988;66 (Suppl
184):107­11.
3. Aasved H. The geographical distribution of fibrillopathia
epitheliocapsularis. Acta Ophthalmol (Copenh)
1969;47:792­810.
4. Kozobolis VP, Papatzanaki M, Vlachonikolis IG, et al.
Epidemiology of pseudoexfoliation in the island of Crete
(Greece).Acta Ophthalmol Scand 1997;75:726­9.
5. Hiller R, Sperduto RD, Krueger DE. Pseudoexfoliation,
intraocular pressure and senile changes in a population based
survey.Arch Ophthalmol 1982;100:1080­2.
6. Ball SF. Exfoliation syndrome prevalence in the glaucoma
population of South Louisiana. Acta Ophthalmol (Copenh)
1988;66(Suppl 184):93­8.
7. Crittendon JJ, Shields MB. Exfoliation syndrome in the
Southeastern United States II. Characteristics of patient population
and clinical course. Acta Ophthalmol (Copenh)
1988;66(Suppl 184);103­6.
8. Krause U,Tarkkanen A. Cataract and pseudoexfoliation. A
clinicopathological study. Acta Ophthalmol (Copenh)
1978;56;329­34.
9. Vesti E, Kivela T. Exfoliation syndrome and exfoliation glaucoma.
Prog Ret Eye Res 2000;19(3):345­68.
10. Konstas AG,Ritch R,BufidisT,et al.Exfoliation syndrome in
a 17 year old girl.Arch Ophthalmol 1997;115(8):1063­7.
11. Krause U,Alanko HI,Karna J,et al.Prevalence of exfoliation
syndrome in Finland. Acta Ophthalmol (Copenh) 1988;66
(Suppl 184);120­2.
12. Hirvela H,Tuulonen A, Laatikainen L. Intraocular pressure
and the prevalence of glaucoma in elderly people in Finland:A
population based study. Int Ophthalmol 1995;18:299­307.
13. Jeng SM, Karger RA, Hodge DO, et al.The risk of glaucoma
in pseudoexfoliation syndrome.J Glaucoma 2007;16(1):117­21.
14. Puska PM. Unilateral exfoliation syndrome: Conversion to
bilateral exfoliation and to glaucoma: A prospective 10-year
follow-up study. J Glaucoma 2002;11(6):517­24.
15. Konstas AG, Hollo G,AstakhovYS, et al. Presentation and
long-term follow-up of exfoliation glaucoma in Greece, Spain,
Russia, and Hungary. Eur J Ophthalmol 2006;16(1):60­6.
16. Mudumbai R,Liebmann JM,Ritch R.Combined exfoliation
and pigment dispersion: An overlap syndrome. Trans Am
Ophthalmol Soc 1999;97:297­321.
17. Ritch R, Schlötzer-Schrehardt U. Exfoliation syndrome.
Surv Ophthalmol 2001;45(4):265­315.
18. Ritch R. Exfoliation syndrome. Curr Opin Ophthalmol
2001;12(2):124­30.
19. Harju M. Intraocular pressure and progression in exfoliative
eyes with ocular hypertension or glaucoma. Acta
Ophthalmol Scand 2000;78(6):699­702.
20. Yarangümeli A, Davutluoglu B, Köz OG, et al.
Glaucomatous damage in normotensive fellow eyes of
patients with unilateral hypertensive pseudoexfoliation glaucoma:
Normotensive pseudoexfoliation glaucoma? Clin
Experiment Ophthalmol 2006;34(1):15­9.
21. Puska P,Tarkkanen A. Exfoliation syndrome as a risk factor
for cataract development: Five-year follow-up of lens opacities
in exfoliation syndrome. J Cataract Refract Surg
2001;27(12):1992­8.
22. Puska P. Lens opacity in unilateral exfoliation syndrome
with or without glaucoma. Acta Ophthalmol (Copenh)
1994;72.290­6.
23. Guzek JP, Holm M, Cotter JB, et al. Risk factors or intraoperative
complications in 1000 extracapsular cataract cases.
Ophthalmol 1987;94:461­6.
24. Ritch R. Cataract and exfoliative glaucoma. J Glaucoma
1998;7:178­81.
25. Rutner D, Madonna RJ. Spontaneous, bilateral intraocular
lens dislocation in a patient with exfoliation syndrome.Optom
2007;78(5):220­4.
26. Ritch R, Schlötzer-Schrehardt U, Konstas AG.Why is glaucoma
associated with exfoliation syndrome? Prog Retin Eye
Res 2003;22(3):253­75.
27. Schlötzer-Schrehardt U, Küchle M, Jünemann A, et al.
Relevance of the pseudoexfoliation syndrome for the glaucomas.
Ophthalmologe 2002;99(9):683­90.
28. Layden WE, Shaffer RN. Exfoliation syndrome.Trans Am
Ophthalmol Soc 1973;71:128­51.
29. Mudumbai R,Liebmann JM,Ritch R.Combined exfoliation
and pigment dispersion: An overlap syndrome. Trans Am
Ophthalmol Soc 1999;97:297­321.
30. Amari F, Umihira J, Nohara M, et al. Electron microscopic
immunohistochemistry of ocular and extraocular pseudoexfoliative
material. Exp Eye Res 1997;65:51­6.
31. Kubota T, Schlotzer-Schrehardt U, Inomata H, Naumann,
GO. Immunoelectron microscopic localization of the HNK-1
carbohydrate epitope in the anterior segment of PSEUDOEXFOLIATION
and normal eyes. Curr Eye Res
1997;16:231­8.
32. Naumann, GO, Schlotzer-Schrehardt, U, Kuchle M.
Pseudoexfoliation for the comprehensive ophthalmologist.
Ophthalmol 1998;105:951­68.
33. Lis GJ. Pathogenesis and histopathology of pseudoexfoliative
lesions. The eyeball disease or ocular manifestation
of a generalized process? Przegl Lek
2006;63(7):588­92.
34. Ludwisiak-Kocerba L, Hevelke A, Kecik D.
Pseudoexfoliation syndrome--etiopatogenesis and clinical
course. Klin Oczna 2006;108(1­3):82­6.
35. Nenciu A, Stefan C, Melinte D, et al. IOP diurnal fluctuations
in patients presenting pseudoexfoliative syndrome.
Oftalmologia 2006;50(2):121­5.
36. Altintafl O,Yüksel N, KarabaflVL, et al. Diurnal intraocular
pressure variation in pseudoexfoliation syndrome. Eur J
Ophthalmol 2004;14(6):495­500.
37. Konstas AG,Mantziris DA,StewartWC.Diurnal intraocular
pressure in untreated exfoliation and primary open angle
glaucoma.Arch Ophthalmol 1997;115:182­5.
38. Konstas AG, Stewart WC, Stroman GA, Sine CS. Clinical
presentation and initial treatment patterns in patients with
exfoliation glaucoma versus primary open angle glaucoma.
Ophthalmic Surg Lasers 1997;28:111­7.
39. Ritch R. Initial treatment of exfoliative glaucoma. J
Glaucoma 1998;7(2):137­40.
40. Konstas AG, Lake S, Maltezos AC, et al.Twenty-four hour
intraocular pressure reduction with latanoprost compared
with pilocarpine as third-line therapy in exfoliation glaucoma.
Eye 2001;15(Pt 1):59­62.
APRIL 15, 2008 REVIEW OF OPTOMETRY 39A
SICKLE CELL RETINOPATHY
Signs and symptoms
The ocular signs of sickle cell anemia
variably include comma-shaped
vessels in the bulbar conjunctiva, iris
atrophy, iris neovascularization, dull
gray fundus appearance, retinal
venous tortuosity, nonproliferative
retinal hemorrhages (which may be
subretinal, intraretinal or preretinal),
black sunbursts (retinal pigment
epithelial hypertrophy secondary to
deep retinal vascular occlusions),
glistening retractile deposits in the
retinal periphery (hemosiderin-laden
macrophages), salmon patch hemorrhages
(orange-pink-colored intraretinal
hemorrhage), angioid streaks
(breaks in Bruch's membrane radiating
from the optic nerve), "macular
depression sign" (a loss of the foveal
reflex), venous occlusion, artery
occlusion and peripheral neovascularization
(in a "sea fan" appearance)
with possible attendant vitreous hemorrhage
and tractional retinal detach-
ment.1­5
Ocular symptoms are uncommon
in the early stages of any form of
sickle cell disease.6,7
Pathophysiology
In all four variations of sickle cell
disease, systemic and ocular tissues
have the potential to become deprived
of oxygen secondary to inherited
abnormalities of the beta-globin
chain.6,7
The origin of the genetic
abnormality can be traced to the continent
of Africa where, data suggests,
the mutation of the hemoglobin chain
protected individuals from malaria
infection.6­8
Inheritance of the sickle
cell hemoglobinopathies is autosomal
co-dominant, with each parent providing
one gene for the abnormal hemo-
globin.5
Abnormal hemoglobin S
results following a single point mutation
substituting valine for glutamic
acid at the sixth position.2,3
Substituting lysine for glutamic acid
at this position results in the formation
of hemoglobin C. When both parents
contribute the
S mutation, classic
sickle cell anemia
or SS disease
ensues.3
When one
parent contributes
S-mutated hemoglobin
and the
other C-mutated
hemoglobin, the SC
form of the disease
occurs. Inadequate
production of either
normal or abnormal
globin chains creates
the S-thalassemia
(S-Thal)
variant.3
Incomplete
expression of
the disease with some of the genetic
mutations produces sickle cell trait
(AS).3
The retina erythrocytes, having lost
their biconcave shape, become rigid,
restricting blood flow, inducing
thromboses and inducing tissues to
become hypoxic.1­11
Vascular leakage
and liberation of angiogenic cytokines
with subsequent retinal neovascularization
(along with all of its attendant
complications) dictate the severity of
the condition.1­8,11,12
The pathogenesis
of the resultant retinopathy is ultimately
a manifestation of arterial and
capillary microcirculation obstructive
vasculopathy.10
Salmon-patch hemorrhages are
preretinal or superficial retinal hemorrhages
that often dissect into the
vitreous humor.3
They are the result of
disruptions of the medium-sized arterioles
secondary to chronic ischemicvascular
compromise.3
Although they
are initially bright red, their color
evolves as they age. Because they
have a tendency to push both forward
and backward within the retina, they
may leave a retinoschisis remnant
when they resolve.3
Since the movement
of this blood can disturb the retinal
pigment epithelium, irregularly
shaped hyperplastic changes occur,
producing the classic pigmentary
finding known as black sunbursts.
The hallmark proliferative sign of
sickle cell disease is the sea
fan­shaped frond of neovasculariza-
tion.11
A common trait of the SC and
S-Thal variations, sea fan neovascularization
represents the body's aggressive
attempt to supply oxygen to
hypoxic retinal tissue.3,5­8,11,12
Arteriovenous crossings are the preferential
site for sea fan development.12
Here, preretinal vascular formations
develop from a single or multiple
feeder vessels at the border of perfused
and non-perfused peripheral
retina.11,12
Since the retinal tissue is not
globally ischemic, the abnormal vessels
arborize along the border of perfused
and starved tissue.3,11,12
Drained
by single or multiple venules, the classic
kidney-shaped appearance is driven
by environment. Vascular endothelial
growth factors are associated with
these formations.11
The neovascularization
in sickle cell retinopathy can
arise both from the arterial and venous
sides of the retinal vasculature.12
Autoinfarction (complete or partial
spontaneous involution) appears to
occur initially at the preretinal capillary
level rather than at the feeding
arterioles, and it has been documented
to occur in up to 50% of cases.12
The abovementioned proliferative
VITREOUS AND RETINA
VITREOUSANDRETINA
Sickle cell retinopathy; note the arteriovenous changes and "black
sunbursts," representing peripheral retinal ischemia.
40A REVIEW OF OPTOMETRY APRIL 15, 2008
sickle cell retinopathy development is
classically broken down into five
stages. Stage 1 is recognized by
peripheral retinal arteriolar occlusions.
Stage 2 is marked by the appearance
of peripheral arteriovenous anastamoses.
Stage 3 is characterized by
the growth of neovascular sea fan
fronds. Stage 4 is marked by vitreous
hemorrhage, as tractional forces and
vitreous collapse tear fragile neovascular
membranes. Stage 5 is advanced
disease, identified by severe vitreous
traction and retinal detachment.1­4, 11,12
The diagnosis of clearly evident
clinical comorbidities such as leg
ulcer, osteonecrosis and retinopathy
are considered predictors for lethal
organ damage.10
Fifty-one percent of
patients with sickle cell disease who
eventually have a cerebrovascular
accident report a prior chronic collateral
condition.12
Management
The treatment goal for sickle cell
retinopathy is to reduce or eliminate
retinal neovascularization.6­9
Patients
with asymptomatic sickle cell disease
with no ocular manifestations should
be followed biannually with dilated
retinal evaluation.5­8
Referral to a retinal
specialist is indicated when proliferative
retinopathy is evident. Treatment
for proliferative disease involves
panretinal photocoagulation. Cryotherapy
has not been proven efficacious
and is associated with high
complication rates.5
Scleral buckle
procedure may be indicated in cases
of retinal detachment.5
Photodynamic
therapy and antiangiogenic compounds,
used in choroidal and retinal
neovascularization seen in other entities,
are not yet documented as therapies
for sickle cell retinopathy.1­4
Systemically, genetic risk factors
and other preventative possibilities
are now being explored.10,13
Stroke
prevention has been made possible by
advances in transcranial Doppler
ultrasonography, which permits
extensive examination and screening.5
Hydroxyurea, an anticarcinogenic
preparation, has significantly reduced
the number of deaths and complications
from sickle cell disease.14
It
increases fetal hemoglobin levels,
which seems to prevent red blood
cells from sickling.14
The medication
has demonstrated an ability to reduce
the number of vaso-occlusive crises
and acute chest problems, thereby
reducing the number of hospitalizations
and reducing the severity and
impact of the disease. It also has
demonstrated great efficacy and safety
in pediatric studies.10,14
Niprisan
(Nix-0699), another naturally occurring
anti-sickling agent, has demonstrated
promise in experiments with
mice. It may offer the promise of an
additional preventative solution.15
Clinical pearls
* Laboratory testing for detecting
sickle cell disease in patients with
suspicious findings includes the
Sickledex, Sickle Prep and plasma
hemoglobin electrophoresis.
* The sickle cell anemia variation
(SS) produces the greatest number of
systemic symptoms. The sickle cell
disease mutations SC and S-Thal produce
the greatest number of ocular
effects. Overall, the sickle cell trait
expression (AS) produces the fewest
complications.
* The sea fan frond of neovascularization
is so characteristic to this disease
that, when encountered, it must
be the prime consideration in undiagnosed
patients.
* Systemic symptoms include
recurrent, painful vaso-occlusive
crises with abdominal and musculoskelatal
discomfort.6,7
Other systemic
manifestations include jaundice,
cerebrovascular accidents and
infections (particularly by encapsulated
bacteria).8,9
1. Cullom RD, Chang B. Sickle Cell Disease. In: Cullom RD,
Chang B, The Wills Eye Manual: Office and Emergency
Room Diagnosis andTreatment of Eye Disease, Philadelphia
PA: J. B. Lippincott Co., 1994, pp. 335­37.
2. Alexander LJ. RetinalVascular Disorders. In:Alexander, LJ,
Primary Care of the Posterior Segment (2nd ed.), Norwalk,
CT:Appleton and Lange, 1994, pp. 171­275.
3. Ho AC. Hemoglobinopathies. In: Yanoff M, Duker JS,
Ophthalmology (2nd ed.), Philadelphia: Mosby, 2004, pp.
891­5.
4. Brown GC. RetinalVascular Disease. In:Tasman W,Taeger
EA,The Wills Eye Hospital Atlas of Clinical Ophthalmology,
Philadelphia: Lippincott-Raven, 1996, pp. 161­206.
5. Lutty GA, Phelan A, McLeod DS et al. A rat model for
sickle cell­mediated vaso-occlusion in retina. Microvas Res
1996;52(3):270­80.
6. Kaiser HM. Hematologic Disease. In: Blaustein, BH, Ocular
Manifestations of Neurologic Disease, Philadelphia: Mosby,
1996, pp. 165­77.
7. Rogers-Philips E, Philips A. Hematology and Oncology. In:
Muchnick BG, Clinical Medicine in Optometric Practice,
Philadelphia: Mosby, 1994, pp. 306­16.
8. Madani G, Papadopoulou AM, Holloway B, et al.The radiological
manifestations of sickle cell disease. Clin Radiol
2007;62(6):528­38.
9. Wang WC. The pathophysiology, prevention, and treatment
of stroke in sickle cell disease. Curr Opin Hematol
2007;14(3):191­7.
10. Powars DR, Chan LS, Hiti A, et al. Outcome of sickle cell
anemia: A 4-decade observational study of 1056 patients.
Medicine (Baltimore) 2005;84(6):363­76.
11. Cao J, Mathews MK, McLeod DS, et al. Angiogenic factors
in human proliferative sickle cell retinopathy. Br J
Ophthalmol 1999;83(7):838­46.
12. McLeod DS, Merges C, Fukushima A, et al.
Histopathologic features of neovascularization in sickle cell
retinopathy.Am J Ophthalmol 1997;124(4):455­72.
13. Cusick M,Toma HS, Hwang TS, et al. Binasal visual field
defects from simultaneous bilateral retinal infarctions in sickle
cell disease.Am J Ophthalmol 2007;143(5):893­6.
14. Anderson N. Hydroxyurea therapy: Improving the lives
of patients with sickle cell disease. Pediatr Nurs
2006;32(6):541­3.
15. Iyamu EW, Turner EA, Asakura T. Niprisan (Nix-0699)
improves the survival rates of transgenic sickle cell mice
under acute severe hypoxic conditions. Br J Haematol
2003;122(6):1001­8.
SOLAR RETINOPATHY
Signs and symptoms
Patients will variably present with
visual acuity loss, metamorphopsia,
positive or negative after-images and
central scotomas after intentional or
unintentional sungazing. However,
this history may not always be forthcoming.
In acute cases, the causative
factor is often apparent to the experienced
clinician. However, in chronic
cases, the etiology is often discovered
only after careful history guided by the
ophthalmoscopic findings. Solar
retinopathy occurs as a result of directfixation
retinal exposure to the sun for
a variety of reasons such as watching a
solar eclipse, religious rituals, mental
APRIL 15, 2008 REVIEW OF OPTOMETRY 41A
illness, mental or emotional immaturity,
sunbathing, drug use, the false
belief that it is therapeutic and alcohol
intoxication, to name a few.1­12
The characteristic early ophthalmoscopic
finding is a small, irregularly
shaped lamellar defect, often
described as yellowish-white, in the
foveal center.1,2,13­15
There may be a
surrounding circular area of hyperpigmentation.
After several weeks, the
yellowish lesion fades to reveal a
sharply defined foveal cyst-like defect
with irregular borders, surrounded by
a coarse, pigmented halo.2,13
Presenting visual acuity is highly
variable and contingent upon many
factors, including duration of exposure
and time of onset. Patients may
present many months to years following
the sungazing event with normal
Snellen acuity but distortions on
Amsler grid testing or macular threshold
perimetry.6
Alternately, patients
may present acutely or chronically
following the incident with markedly
reduced acuity in the range of 20/50
to 20/200.9,13,16
Solar retinopathy can present unilaterally
or bilaterally. Unilateral and
asymmetric bilateral cases typically
show more effects in the patienťs
dominant eye. The duration of the sun
gazing needn't be extreme; effects
have been demonstrated after only 20
seconds of direct viewing.9
Pathophysiology
Solar retinopathy
likely develops from
a combination of photochemical
and thermal
mechanisms.16­19
Retinal cells die by
apoptosis in response
to light-induced injury,
and the process of cell
death is perpetuated
by diverse, damaging
mechanisms.19
Two
classes of photochemical
damage have been
recognized. The first
type is characterized
by the rhodopsin action spectrum and
is thought to be mediated by visual
pigments, with the primary lesions
located in the photoreceptors. The
high-energy wavelengths and low levels
of ultraviolet A (UV-A) radiation
are absorbed by the outer retinal layers,
with subsequent photochemical
damage that likely involves oxidative
events.13,19
The second type of damage
is generally confined to the retinal
pigment epithelium (RPE). The RPE
pigmentation absorbs sunlight energy,
converting it to heat, with a resultant
rise in temperature that results in a
burning of the RPE.14
This RPE damage
is often permanent.
Fluorescein angiography does not
consistently identify the underlying
pathophysiology in solar retinopathy.
Occasionally, fluorescein angiography
will reveal small window defects or
other mild RPE defects.2,3,13
Often,
however, fluorescein angiography
reveals no abnormalities.13,16,17
In acute onset, optical coherence
tomography (OCT) demonstrates
increased reflectivity of the inner
foveal retina as well as a hyporeflective
area of the underlying RPE and an
increase in retinal thickness.1,13,14,20
OCT also has demonstrated abnormal
reflectivity at the outer foveal retina,
with fragmentation and interruption of
the inner high reflective layer corresponding
to the junction between the
photoreceptor inner and outer seg-
ments.21
Involvement of the entire photoreceptor
reflective layer at the fovea
has also been observed in patients
with poor acuity.21
In chronic cases,
hyporeflective spaces within the RPE
have been observed, corresponding to
the damaged RPE and photorecep-
tors.13,20
Essentially, multiple findings
in OCT analyses have been seen with
alterations in different levels. These
are likely representative of the different
types of photochemical and thermal
damage occurring within the retina
and RPE. Abnormalities in the
multifocal electroretinogram have
been found, and this may also be a
helpful diagnostic modality.22­24
Management
Thus far, no successful intervention
for vision loss occurring from solar
retinopathy has been identified. However,
it is important to understand the
natural history of this condition so
that patients can be counseled regarding
their visual prognosis.
Reports of spontaneous visual
recovery vary greatly. In perhaps the
majority of reported cases, visual acuity
returns to normal or near-normal
levels, though slight deficits such as
central scotomas, after-images and
metamorphopsia may persist despite
good Snellen acuity.1,5­8,11,14,15,24
However,
in many reported cases patients have
had little-to-no visual recovery and, in
some cases, had significant visual
impairment.2­4,7,9­11,19,21,25,26
One study
with long-term follow-up saw
improvement in participants' visual
acuity occur mostly during the first
two weeks to one month after viewing
an eclipse. Further improvement in
visual acuity was not observed in any
of the eyes after 18 months.17
Clinical pearls
* While it is not common to ask
patients in a routine history whether
they have ever stared at the sun, the
presence of small unexplained foveal
cysts or visual acuity loss should ini-
VITREOUSANDRETINA
Solar retinopathy.
42A REVIEW OF OPTOMETRY APRIL 15, 2008
tiate this unusual line of questioning.
We have encountered patients who
didn't readily admit to or associate
their vision loss with sungazing and
this history didn't become apparent
until the patients were pointedly
asked.
* Visual recovery is unpredictable.
Duration of exposure, degree of intensity,
macular pigmentation, lenticular
opacification and geographic location
of exposure are some of the many
variables that work in concert to create
retinal damage. It is best to counsel
patients that although there may be
some visual recovery, there is no guarantee.
The chances of late visual
recovery are lower than in patients
who have recently had exposure.
* Prevention is still the best management
approach. In cases of
impending eclipse, place warnings in
all common patient waiting areas.
* OCT and fluorescein angiography
demonstrate no consistent diagnostic
pattern for solar retinopathy but
may confirm visible retina changes
associated with the disorder.
1. Macarez R, Vanimschoot M, Ocamica P, et al. Optical
coherence tomography follow-up of a case of solar maculopathy.
J Fr Ophtalmol 2007;30(3):276­80.
2. Yeh LK,Yang CS, Lee FL, et al. Solar retinopathy: A case
report. Zhonghua Yi Xue Za Zhi (Taipei)
1999;62(12):886­90.
3. Mwanza JC, Kayembe DL, Kaimbo DK, et al.. Solar
retinopathy acquired after gazing at the sun during prayers.
Bull Soc Belge Ophtalmol 2000;275:41­5.
4. Hope-Ross M, Travers S, Mooney D. Solar retinopathy
following religious rituals. Br J Ophthalmol
1988;72(12):931­4.
5. Michaelides M, Rajendram R, Marshall J, et al. Eclipse
retinopathy. Eye 2001;15(Pt 2):148­51.
6. Stokkermans TJ, Dunbar MT. Solar retinopathy in a hospital-based
primary care clinic. J Am Optom Assoc
1998;69(10):625­36.
7. Awan AA, Khan T, Mohammad S, et al. Eclipse retinopathy:
Follow up of 36 cases after April 1995 solar eclipse in
Pakistan. J Ayub Med Coll Abbottabad 2002;14(4):8­10.
8. Rai N, Thuladar L, Brandt F, et al. Solar retinopathy. A
study from Nepal and from Germany. Doc Ophthalmol
1998;95(2):99­108.
9. Källmark FP, Ygge J. Photo-induced foveal injury after
viewing a solar eclipse. Acta Ophthalmol Scand
2005;83(5):586­9.
10. Verma L, Sharma N,Tewari HK, et al. Retinopathy after
solar eclipse, 1995. Natl Med J India 1996;9(6):266­7.
11. Ukponmwan CU, Dawodu OA, Ayanru JO. Solar
retinopathy in Benin City, Nigeria. West Afr J Med
2003;22(4):356­7.
12. Devadason DS, Mahmood S, Stanga PE, et al. Solar
retinopathy in a patient with bipolar affective disorder. Br J
Ophthalmol 2006;90(2):247.
13. Garg SJ, Martidis A, Nelson ML, et al. Optical coherence
tomography of chronic solar retinopathy.Am J Ophthalmol
2004;137(2):351­4.
14. Macarez R, Vanimschoot M, Ocamica P, et al. Optical
coherence tomography follow-up of a case of solar maculopathy.
J Fr Ophtalmol 2007;30(3):276­80.
15. Chen JC, Lee LR. Solar retinopathy and associated optical
coherence tomography findings. Clin Exp Optom
2004;87(6):390­3.
16. Calvo-González C, Reche-Frutos J, Santos-Bueso E, et
al. Optical coherence tomography in solar eclipse retinopathy.
Arch Soc Esp Oftalmol 2006;81(5):297­300.
17. Atmaca LS, Idil A, Can D. Early and late visual prognosis
in solar retinopathy. Graefes Arch Clin Exp Ophthalmol
1995;233(12):801­4.
18. Codenotti M, Patelli F, Brancato R. OCT findings in
patients with retinopathy after watching a solar eclipse.
Ophthalmologica 2002;216(6):463­6.
19. Wu J, Seregard S,Algvere PV. Photochemical damage of
the retina. Surv Ophthalmol 2006;51(5):461­81.
20. Kaushik S, GuptaV, Gupta A. Optical coherence tomography
findings in solar retinopathy. Ophthalm Surg Lasers
Imaging 2004;35(1):52­5.
21. Jorge R, Costa RA, Quirino LS, et al. Optical coherence
tomography findings in patients with late solar retinopathy.
Am J Ophthalmol 2004;137(6):1139­43.
22. Mack G, Uzel JL, Sahel J, et al. Multifocal electroretinogram
for assessing sun damage following the solar eclipse
of 11 August 1999. J Fr Ophtalmol 2002;25(4):380­7.
23. Arda H, Oner A, Mutlu S, et al. Multifocal electroretinogram
for assessing sun damage following the solar
eclipse of 29 March 2006: Multifocal electroretinography in
solar maculopathy. Doc Ophthalmol 2007;114(3):159­62.
24. Schatz P, Eriksson U, Ponjavic V, et al. Multifocal electroretinography
and optical coherence tomography in two
patients with solar retinopathy. Acta Ophthalmol Scand
2004;82(4):476­80.
25. Wong SC, Eke T, Ziakas NG. Eclipse burns: A prospective
study of solar retinopathy following the 1999 solar
eclipse. Lancet 2001;357(9251):199­200.
26. Thanos S, Heiduschka P, Romann I. Exposure to a solar
eclipse causes neuronal death in the retina. Graefes Arch
Clin Exp Ophthalmol 2001;239(10):794­800.
ACUTE POSTERIOR MULTIFOCAL
PLACOID PIGMENT
EPITHELIOPATHY
Signs and symptoms
Acute posterior multifocal placoid
pigment epitheliopathy (APMPPE) is
an idiopathic, typically bilateral
inflammatory disorder of the posterior
segment seen in otherwise healthy
young adults.1­9
It manifests as patchy
inflammatory defects in the choriocapillaris,
retinal pigment epithelium
(RPE) and outer retina.1­8
It is characterized
by multiple, whitish-yellow,
creamy inflammatory lesions in the
form of flat, large, irregularly shaped
discs located at the level of the
choroid, RPE and outer retina.1­6
Common onset occurs between the
second and third decades of life.5
There seems to be no predilection for
men or women.5
Often, a systemic viral prodrome
precedes the onset of ocular signs and
symptoms.5
Patients may complain of
headache, stiff neck and tinnitus before
realizing that their vision has
changed.5,10
Patients present with variable
visual acuity, which may be
markedly asymmetric. They may
describe vision reduction yet still measure
20/20; conversely, visual acuity
may be as poor as 20/400.1,2,5
Alterations in vision and in visual
recovery seem dependent upon where
the choroidal placoid inflammatory
patches reside and the level of inflammation
and ischemia within the affected
regions.1,2
When the patches reside
in or adjacent to the macula relative
scotomas can profoundly affect vision
and the patienťs ability to track and
read.1,2
When the patches lie outside
this critical viewing zone, vision and
function may be unaffected. In the
instances where retinal anoxia is mild,
only temporary visual disturbances are
reported, with full recovery anticipat-
ed.1,2
However, when lesions present
with significant inflammation, the
visual disturbances tend to be more
profound, leaving permanent visual
defects as remnants despite resolution
of the condition.1,2
Other noted signs
and symptoms associated with
APMPPE include episcleritis, disc
hyperemia and neurosensory retinal
detachment.5,9
Indocyanine green and
sodium fluorescein angiography
demonstrate early hypofluorescence of
the placoid lesions with late staining.1,3,5
A potential new entity has been
proposed, with clinical features similar
to APMPPE and serpiginous
choroiditis. It has a prolonged progressive
clinical course with more
widespread distribution of lesions.11
This condition is noted for being clin-
APRIL 15, 2008 REVIEW OF OPTOMETRY 43A
ically atypical, demonstrating prolonged
periods of pathologic activity
that result in the appearance of more
than 50 and sometimes hundreds of
lesions scattered throughout the fun-
dus.11
The appearance of new lesions
may continue for as long as five to 24
months after initial examination.11
It
is unclear whether this is a variant of
serpiginous choroiditis, APMPPE or
a new entity altogether.11
It has been
named for the characteristics of its
behavior: Relentless Placoid
Chorioretinitis.11
Pathophysiology
In the literature, APMPEE has been
recognized and categorized as one of
the uveomeningeal syndromes, a
group of disorders that share involvement
of the uvea, retina and
meninges.8
Inflammatory and autoimmune
etiologies are the frequently
recognized cause of the uveomeningeal
syndromes.8
Acute posterior
multifocal placoid pigment epitheliopathy
is caused by vasculitic
inflammation of the choriocapil-
laris.1,2,11,12
Evidence suggests that the
vascular inflammation causes transient
occlusion of these vessels, producing
mild ischemia.7­13
While the
pathophysiology is not precisely
understood, there is debate over
whether the disease is a primary RPE
disorder or a choroidal vascular dis-
ease.4
Angiography has demonstrated
a profound delay in choroidal filling
time, along with the discovery of
extensive areas of choroidal nonperfusion
in its acute stages.3,4
Recovery of
choroidal blood flow following clinical
resolution is a hallmark of the
entity.4
These findings demonstrate
that APMPPE is a primary choroidal
vascular disease.1­14
The vasculitis associated with
APMPPE may affect the long and
short posterior ciliary vessels that
supply the optic disk.13
This may
result in neural axoplasmic stasis and
compression of the central retinal
vein, leading to optic neuropathy and
central retinal vein occlusion.14
The perinuclear pattern antineutrophilic
cytoplasmic antibody
(pANCA), myeloperoxidase (MPOANCA)
is often associated with systemic
vasculitis, producing systemic
and ocular effects.12
This particular
marker is known to be an identifier in
the disease process of APMPPE.7­13
The most frequent systemic manifestation
associated with APMPPE is
glomerulonephritis.6
However, inflammation
in other tissues of the body
(along with those detected in ocular
structures) is possible.8
A paraneoplastic
disorder has been described in
patients who have combined optic
neuritis and retinitis.8
This syndrome
is defined serologically by the presence
of a paraneoplastic IgG autoantibody
CRMP-5-IgG.8
These patients
may present with an inflammatory
vitritis similar to those seen with
APMPPE.8
The disease has also been
identified as potentially producing
neurological sequellae.10
One study
reported that three patients with
APMPPE developed neurological dis-
ease.10
All three presented with
marked visual disturbances and
headaches.10
One patient developed
recurrent strokes involving different
vascular territories of the brain, and
two patients had cerebrospinal fluid
pleocytosis in the setting of persistent
headaches.10
Management
While APMPPE tends to be selflimiting,
there is evidence suggesting
that systemic corticosteroids may
have a benefit in its management.9
Unfortunately, other studies demonstrate
that oral steroids have no effect
on recovery.5,15
Treatment options
should be explained but left in the
hands of the treating retinal specialist.
These experts, by default of their clinical
experiences, will possess a philosophy
favoring one choice over the
other. Most individuals enjoy a full
recovery of function with little residual
deficit.1,2,5,15
However, some
researchers have discovered that the
long-term visual outcome following
an episode may not always be favor-
able.15
Older age of onset and initial
foveal involvement appear to be associated
with worse visual outcomes.15
Since an association with the antineutrophilic
cytoplasmic antibody
(ANCA) marker has been established,
testing using both pANCA and cytoplasmic
patterns might help establish
a systemic diagnosis in patients who
present with eye manifestations such
as scleritis, retinal vein occlusion,
optic neuropathy or APMPPE who are
otherwise determined to be in good
health.7­13
Clinical pearls
* The association of a uveitis with
an acute or chronic meningoencephalitis
may suggest an infectious
etiology or even a specific organism
known to possess a relationship with
the meningeal syndromes.
* Wegener granulomatosis, sarcoidosis,
Behçeťs disease and VogtKoyanagi-Harada
syndrome are other
notable uveomeningeal disorders.
* The disease has also been categorized
as a "white dot" syndrome
because of its classic appearance.
Other white dot syndromes requiring
consideration include multiple
evanescent white dot syndrome
(MEWDS), birdshot chorioretinopathy,
serpiginous choroiditis, punctate
inner choroidopathy (PIC disease)
and acute retinal pigment epitheliitis
(Krill disease).
VITREOUSANDRETINA
As seen here,APMPPE is typically bilateral
and affects otherwise healthy young adults.
PhotocourtesyJeromeSherman,OD,FAAO.
44A REVIEW OF OPTOMETRY APRIL 15, 2008
* Disruption of Bruch's membrane
seems to occur far less frequently in
this condition as compared to others
such as age-related macular degeneration,
making the formation of
choroidal neovascularization a rarity.
* One should consider the diagnosis
of primary ocular-CNS lymphoma
in patients with unilateral or bilateral
vitritis and intermediate uveitis with
or without neurological findings.
1. Hedges TR, Sinclair SH, Gragoudas ES. Evidence for vasculitis
in acute posterior multifocal placoid pigment epitheliopathy.Ann
Ophthalmol 1979;11(4):539­42.
2. Spaide RF, Yannuzzi LA, Slakter J. Choroidal vasculitis in
acute posterior multifocal placoid pigment epitheliopathy. Br
J Ophthalmol 1991;75(11):685­7.
3. Howe LJ,Woon H, Graham EM, et al. Choroidal hypoperfusion
in acute posterior multifocal placoid pigment
epitheliopathy. An indocyanine green angiography study.
Ophthalmol 1995;102(5):790­8.
4. Dhaliwal RS, Maguire AM, Flower RW, et al. Acute posterior
multifocal placoid pigment epitheliopathy. An indocyanine
green angiographic study. Retina
1993;13(4):317­25.
5. Moorthy RS, Jampol LM. Posterior uveitis of unknown
cause. In: Yanoff M, Duker JS, Ophthalmology (2nd ed.),
Philadelphia: Mosby, 2004, pp. 1219­28.
6. Quillen DA, Davis JB, Gottlieb JL, et al. The white dot
syndromes. Am J Ophthalmol 2004;137(3):538­50.
7. Matsuo T. Eye manifestations in patients with perinuclear
antineutrophil cytoplasmic antibody­associated vasculitis:
Case series and literature review. Jpn J Ophthalmol
2007;51(2):131­8.
8. Brazis PW, Stewart M, Lee AG. The uveo-meningeal
syndromes. Neurologist 2004;10(4):171­84.
9. Vedantham V, Ramasamy K. Atypical manifestations of
acute posterior multifocal placoid pigment epitheliopathy.
Indian J Ophthalmol 2006;54(1):49­52.
10. Comu S, Verstraeten T, Rinkoff JS, et al. Neurological
manifestations of acute posterior multifocal placoid pigment
epitheliopathy. Stroke 1996;27(5):996­1001.
11. Jones BE, Jampol LM,Yannuzzi LA, et al. Relentless placoid
chorioretinitis: A new entity or an unusual variant of
serpiginous chorioretinitis? Arch Ophthalmol
2000;118(7):931­8.
12. Matsuo T, Horikoshi T, Nagai C. Acute posterior multifocal
placoid pigment epitheliopathy and scleritis in a
patient with pANCA-positive systemic vasculitis. Am J
Ophthalmol 2002;133(4):566­8.
13. Matsuo T. Eye manifestations in patients with perinuclear
antineutrophil cytoplasmic antibody-associated vasculitis:
Case series and literature review. Jpn J Ophthalmol
2007;51(2):131­8.
14. Allee SD, Marks SJ. Acute posterior multifocal placoid
pigment epitheliopathy with bilateral central retinal vein
occlusion. Am J Ophthalmol 1998;126(2):309­12.
15. Roberts TV, Mitchell P. Acute posterior multifocal placoid
pigment epitheliopathy: A long-term study. Aust NZ J
Ophthalmol 1997;25(4):277­81.
BIRDSHOT
RETINOCHOROIDOPATHY
Signs and symptoms
Birdshot retinochoroidopathy (BRC),
sometimes referred to as vitiliginous
chorioretinitis, is a rare ocular disorder
named and delineated as a separate
clinical entity by Ryan and Maumenee
in 1980.1,2
Known to be a bilateral, progressive,
retinal-choroidal vascular
inflammatory disease with a strong
association to middle-aged white individuals
of Northern European decent,
BRC produces a diffuse posterior
choroidopathy with an associated anterior
segment reaction, vitritis and retinal
vasculitis.1­9
The typical age of
presentation is the fourth to fifth
decades of life, with a slight female
predominance.6
As the disease progresses,
profuse retinal-vascular leakage
ensues, with resultant retinal,
macular and disk edema develop-
ing.1­9
The fundus lesions are often
described as creamy, small (less than
1 disc diameter) and scattered
throughout the entire fundus.1­8
As the
retina and disc swell and cystoid macular
edema (CME) advances, visual
acuity is affected variably.1­5
Individuals presenting with a duration
longer than 30 months have a higher
likelihood of visual acuities reduced
to 20/50 or worse than those presenting
with shorter durations.8
Visual
loss can progress to levels as poor as
20/200.10
The fundus exhibits a characteristic
patterned distribution of depigmented
spots with an absence of adjacent
hyperpigmentation reaction.2
Traditionally,
no pathologic alterations are
evident on the optic disc (peripapillary
atrophy), even when the optic
disc itself succumbs to the effects of
the disease process (disc swelling
ensues).4
Early complications of the
disease may include the inability to
see in the dark, visual field deficits,
epiretinal membranes (with the potential
for macular hole development),
venous sheathing, retinal neovascularization
with or without recurrent vitreous
hemorrhage and subretinal neovascular
membranes occurring in the
juxtapapillary and perimacular
regions. At the end stage is optic atrophy
and changes that mimic retinitis
pigmentosa, despite the absence of
typical findings.
The diagnosis of BRC is made classically
upon its appearance and ocular
findings.5
The fluorescein angiography
appearance demonstrates mild
hyperfluorescent patches that correlate
with the areas of hypopigmentation.
There is often mild vascular leakage,
late optic disc staining and petalloid
appearance classic of CME.5
Pathophysiology
The specific etiology of BRC
remains unknown.1­15
The majority of
patients possess autoimmune human
leukocyte antigen disease (HLA), in
which the body fails to distinguish
self from nonself.1­5
The HLA-A29
marker is a specific identifier for this
condition.1,4,5
Lymphocyte reactivity to
the retinal S antigen also points to an
autoimmune etiology.4
The distribution
and appearance of the lesions
map them to the major choroidal
veins.4
The preponderance of evidence
suggests that this is a single,
unique disease rather than a conglomeration
of concomitantly occurring
disorders, because in each case there
is core similarity in the ophthalmologic
appearance, clinical course and
Birdshot retinochoroidopathy.
PhotocourtesyJeromeSherman,OD,FAAO.
APRIL 15, 2008 REVIEW OF OPTOMETRY 45A
association with HLA-A29 marker.4
Under the influence of released
inflammatory cytokines, retinal vessels
(capillaries and retinal arterioles)
become more permeable, creating an
environment conducive to the formation
of CME.1­5
CME is the predominant
cause of lost visual function.1­14
Defects in the visual field can be correlated
to the areas of choroidal
depigmentation.1­16
Management
Treatment for BRC is not always
required. In instances in which there
is no threat to macular integrity and
no loss of function, careful photodocumentation
and monitoring will suffice.
When vision is threatened or
macular edema evolves, intervention
should be considered. Periocular and
systemic steroids are the mainstay of
treating the disease.5,9,11,12
Here, the
goal is to slow or arrest the inflammatory
process, decreasing vascular
leakage and preserving function by
limiting impingement on macular
structures.5­14
Azathioprine, a commonly used
immunosuppressive agent, is designed
to be deployed in cases in which
inflammation is unsuccessfully controlled
with oral or intravenous
steroids.11
Given the inflammatory vasculopathic
nature of BRC, the agent is
suitable for augmenting disease control
along with steroids. It also provides an
option in cases of steroid-related com-
plications.11
The principal indication
for azathioprine with respect to BRC is
uncontrolled disease with maximum
systemic steroid therapy.5,11,12
The medication,
typically prescribed for one
year or longer, demonstrates an ability
for decreasing relapse rate and reducing
total steroid dosage.11
Improvement
or maintenance of visual acuity is the
rule more than the exception.11
Other
medications in the same class with a
similar mechanism of action are
methotrexate and cyclosporine.5,11­14
Interestingly, cyclosporine reduction
appears possible with adjunctive ketoconazole
usage.12
The regimen appears
safe and efficacious.12
The combination
of systemic corticosteroids and
immunomodulating agents is sometimes
referred to in the literature as corticosteroid-sparing
systemic immunomodulatory
therapy (IMT).13
Without
question, this particular strategy has
gained momentum as the current standard,
with prompt induction clearly
able to preserve tissue structure, architecture
and function.12 ­14
Since some patients may be apprehensive
about the effects of an intricate
medicinal cocktail, another
viable option is intraocular corticosteroid
injection.15
Intravitreal triamcinolone
injection has demonstrated
reasonable efficacy as a therapy for
BRC.15
Its advantages include a swift,
stabilizing effect that also reduces the
potential for systemic side effects that
are often produced by the intravenous
and oral preparations.13
Of course, the
inherent complications of this class of
medicine remain and include cataract
formation and increased intraocular
pressure.15
Intravenous polyclonal immunoglobulin
(IVIg) has been successfully
administered for treating numerous
autoimmune conditions.16
Investigators
have used this modality in BRC
as an alternative to traditional therapy,
with some success.16
While laser photocoagulation for
the exuding lesions and the uveiticbased
CME is not specifically recommended,
even in advancing cases, oral
acetozolamide therapy can be
attempted in an effort to reverse the
progression of macular leakage.17
As a
last resort, if all other standard and
current modalities have failed to
resolve CME, pars plana vitrectomy
(PPV) with intravitreal triamcinolone
application has recently shown promise
as a procedure that at the least may
temporarily stabilize the condition.17
Frequent complications, however,
include premature cataract formation
and ocular hypertension.17
Fluorescein angiography, optical
coherence tomography, indocyanine
videoangiography and other instruments
that measure or image retinal
thickness and retinal structures, along
with electrodiagnostic testing, can
help monitor the disease and its rate of
progression.5,18
Quantified measurements
can assess treatment efficacy.5,18
Clinical pearls
* The long-term prognosis of BRC
is guarded.
* End-stage disease can result in
sensory retinal and optic nerve atrophy,
with resultant permanent visual
consequences.
* The amount of visual loss with
BRC is typically proportional to the
chronicity and extent of the cystoid
macular edema.
1. Fich M, Rosenberg T. Birdshot retinochoroidopathy in
monozygotic twins. Acta Ophthalmol (Copenh)
1992;70(5):693­7.
2. Ryan SJ, Maumenee AE. Birdshot retinochoroidopathy.
Am J Ophthalmol 1980;89(1):31­45.
3. Kaplan HJ,AabergTM. Birdshot retinochoroidopathy.Am
J Ophthalmol 1980;90(6):773­82.
4. Priem HA, Oosterhuis JA. Birdshot chorioretinopathy:
Clinical characteristics and evolution. Br J Ophthalmol
1988;72(9):646­59.
5. Moorthy RS, Jampol LM. Posterior uveitis of unknown
cause. In: Yanoff M, Duker JS, Ophthalmology (2nd ed.),
Philadelphia: Mosby, 2004, pp. 1219­28.
6. Shah KH, Levinson RD, Yu F, et al. Birdshot chorioretinopathy.
Surv Ophthalmol 2005;50(6):519­41.
7. Willermain F, Greiner K, Forrester JV. Atypical end-stage
birdshot retinochoroidopathy. Ocul Immunol Inflamm
2003;11(4):305­7.
8. Herbort CP, Probst K, Cimino L, et al. Differential inflammatory
involvement in retina and choroid in birdshot chorioretinopathy.
Klin Monatsbl Augenheilkd 2004;221(5):351­6.
9. Nenciu A, Stefan C. Birdshot retinochoroidopathy.
Oftalmologia 2003;58(3):13­20.
10. Thorne JE, Jabs DA, Peters GB, et al. Birdshot
retinochoroidopathy: Ocular complications and visual
impairment.Am J Ophthalmol 2005;140(1):45­51.
11. Greenwood AJ, Stanford MR, Graham EM.The role of
azathioprine in the management of retinal vasculitis. Eye
1998;12(Pt. 5):783­8.
12. Silverstein BE, Wong IG. Reduction of cyclosporine
dosage with ketoconazole in a patient with birdshot
retinochoroidopathy.Am J Ophthalmol 1998;125(1):106­8.
13. Kiss S,Ahmed M, Letko E, et al. Long-term follow-up of
patients with birdshot retinochoroidopathy treated with
corticosteroid-sparing systemic immunomodulatory therapy.
Ophthalmol 2005;112(6):1066­71.
14. Becker MD, Wertheim MS, Smith JR, et al. Long-term
follow-up of patients with birdshot retinochoroidopathy
treated with systemic immunosuppression. Ocul Immunol
Inflamm 2005;13(4):289­93.
15. Shah A, Branley M. Use of intravitreal triamcinolone in
the management of birdshot retinochoroidopathy associated
with cystoid macular oedema:A case study over a three-year
VITREOUSANDRETINA
46A REVIEW OF OPTOMETRY APRIL 15, 2008
period. Clin Experiment Ophthalmol 2005;33(4):442­4.
16. LeHoang P, Cassoux N, George F, et al. Intravenous
immunoglobulin (IVIg) for the treatment of birdshot
retinochoroidopathy. Ocul Immunol Inflamm
2000;8(1):49­57.
17. Gutfleisch M, Spital G, Mingels A, et al. Pars plana vitrectomy
with intravitreal triamcinolone:Effect on uveitic cystoid
macular oedema and treatment limitations. Br J Ophthalmol
2007;91(3):345­8.
18. De Geronimo F, Glacet-Bernard A, Coscas G, et al.
Birdshot retinochoroidopathy: Measurement of the posterior
fundus spots and macular edema using a retinal thickness
analyzer, before and after treatment. Eur J Ophthalmol
2000;10(4):338­40.
MYELINATED NERVE FIBERS
Signs and symptoms
Occasionally, myelinated nerve
fibers will be discovered upon consultation
for reduced visual acuity, strabismus
or leukocoria, though in the
vast majority of cases it is discovered
upon routine ophthalmic examina-
tion.1
One report noted a greater incidence
among women.2
Myelinated
nerve fibers may be unilateral or
bilateral.1,2
The prevalence of myelinated
nerve fibers in the general population
approaches 1%.1
There may be
multiple patches within an eye.1­3
Funduscopically, myelinated nerve
fibers are white to gray patch densities
that follow the pattern and architecture
of the retinal nerve fiber layer.
The concentration is greatest at the
origin of the myelinated nerve fibers
and "feathers out" at the edges. This
classic pattern helps to identify myelinated
nerve fibers and differentiate
the condition from cotton wool spots.
Depending on the density of myelinated
fibers, retinal vessels and
choroidal detail may be obscured.
Lesion size may range from less than
one-half disc diameter to several disc
diameters. Myelinated nerve fibers
may be contiguous with the optic disc
or may appear distant in the fundus
with normal retina between the lesion
and the optic disc.
Visual acuity is typically unaffected.
Visual field defects can occur and,
due to the fact that myelinated nerve
fibers involve the nerve fiber layer,
they can produce visual field defects
that mimic those seen in
glaucoma. However, in
most instances, visual
field defects tend to be
mild and are smaller
than would be expected
given the extent of the
lesion--indicating that
light penetrates to the
photoreceptor level.1,4
While typically a
benign finding in itself,
multiple associated
complicating factors
have been reported to
occur with myelinated
nerve fibers, including
cilioretinal artery occlusion, retinal
neovascularization, juxtapapillary
hemorrhage, branch vein occlusion,
vitreous hemorrhage, telangiectasis
and branch artery occlusion.1,5­9
Additionally, myelinated nerve fibers
appear to present more frequently in
patients with Down's syndrome, neurofibromatosis
and craniofacial
dysostosis.4
It has long been thought that myelinated
nerve fibers represented a congenital
anomaly, and in the vast
majority of cases, that is likely correct.
However, it has also been documented
that myelination of retinal
nerve fibers can be acquired later in
life and may actually advance over
time, although this seems uncom-
mon.10­13
Further, atrophy and regression of
myelinated nerve fibers have been
documented to occur as a result of
glaucoma, optic neuritis and multiple
sclerosis, anterior ischemic optic neuropathy,
Behçeťs related papillitis and
following vitrectomy.14­18
There appears to be a well-documented
but as-of-yet unnamed syndrome
consisting of (aniso)myopia
and anisometropic amblyopia in association
with myelinated nerve
fibers.19­26
This syndrome appears distinct
from simple unilateral myopia
with amblyopia and from myelinated
nerve fibers without myopia or
amblyopia.24
Macular changes, including
irregular pigmentation and loss of
foveal reflex, are often present in
association in these cases, and these
may contribute significantly to vision
loss beyond amblyopia.20­24
Pathophysiology
During normal development, retinal
ganglion cell myelination begins
in the lateral geniculate nucleus and
proceeds anteriorly to the optic nerve,
stopping at the lamina cribrosa in
most cases. This process is completed
shortly after birth.1,4
Normally, the retina is not myelinated
because oligodendroglia, the cells
responsible for myelination in the central
nervous system, are absent in the
retina. An anomalous distribution of
oligodendroglia is thought to be the
etiology of myelinated nerve fibers,
rather than myelination simply continuing
beyond the lamina cribrosa.
While myelinated nerve fibers
themselves are typically benign, they
may be associated with other causes
of vision reduction. Visual deprivation
imparted by myelination is insufficient
to cause any significant degree
of visual loss or deprivational amblyopia.
However, in cases in which unilateral
myelination occurs in association
with high myopia, profound
anisometropic amblyopia often
occurs. It has been suggested that
Myelinated nerve fibers may be focal or diffuse, as seen here.
APRIL 15, 2008 REVIEW OF OPTOMETRY 47A
myelination may cause myopia development,
though the cause is truly
unknown.25
At this time, it is not clear
whether high myopia contributes to
the development of myelination or
vice-versa. Peripapillary myelinated
nerve fibers in an eye with myopia
may be secondary to an imbalance
between the process of myelination
and the formation of the lamina
cribrosa.21
Management
There is no intervention for myelinated
nerve fibers. The most important
facet of management involves
correct identification. In that myelinated
nerve fibers can superficially
resemble cotton wool spots, careful
differentiation must be performed to
avoid unnecessary medical testing.
Because glaucoma-like visual field
defects can arise from myelinated
nerve fibers, it is important to examine
for these lesions before therapeutic
management, especially if the optic
disc and other features do not suggest
glaucoma. Of note, scanning laser
polarimetry measurements of patients
with myelinated nerve fibers demonstrate
increased retardation.27
Thus,
GDx analysis may assist in the differential
diagnosis of these lesions.
Patients with myelinated nerve
fibers in association with unilateral
high myopia develop what many
describe as anisometric amblyopia.
However, such vision loss in association
with myelinated nerve fibers
tends to be refractory to standard
amblyopia therapy.19­26
Although there
has been limited success in the amblyopic
management of these patients,
there appears to be a subset who have
associated macular abnormalities that
do not respond to standard management
strategies. Thus it can be said
that many of these patients with
extensive myelination, monocular
high myopia and amblyopia have
vision loss that has developed from
more than one source. Anisometropia
imparts an amblyogenic factor, while
subtle macular abnormalities, which
may somehow result from extensive
myelination, additionally contribute
to vision loss that is unresponsive to
amblyopia therapy. Nevertheless, in
patients with myelinated nerve fibers,
anisometropia and vision loss, aggressive
amblyopic therapy must be instituted,
with the understanding that the
outcome may be poor because of conditions
other than the amblyogenic
anisometropia.
Clinical pearls
* Myelinated nerve fibers can be
confused with cotton wool spots. The
edges of myelinated nerve fibers
appear feathery and follow the architecture
of the nerve fiber layer, however,
while cotton wool spots do not.
If uncertainty persists, photograph the
lesion and reappoint the patient for reevaluation.
Cotton wool spots fade
over several weeks, whereas myelinated
nerve fibers do not.
1. Straatsma BR, Foos RY, Heckenlively JR, et al. Myelinated
retinal nerve fibers.Am J Ophthalmol 1981;91(1):25­38.
2. Kodama T, Hayasaka S, Setogawa T. Myelinated retinal
nerve fibers: Prevalence, location and effect on visual acuity.
Ophthalmologica 1990;200(2):77­83.
3. Velasque L, Mortemousque B. Myelinated retinal nerve
fibers. Review of the literature. J Fr Ophtalmol
2000;23(9):892­6.
4. Ruttum MS, Poll J. Unilateral retinal nerve fiber myelination
with contralateral amblyopia. Arch Ophthalmol
2006;124:128­30.
5. Munteanu M, Zolog I, Giuri S. Myelinated nerve fibers
associated with juxtapapillary haemorrhages. Oftalmologia
2001;53(3):13­6.
6. Silvestri G, Sehmi K, Hamilton P. Retinal vascular abnormalities.
A rare complication of myelinated nerve fibers?
Retina 1996;16(3):214­8.
7. Minning CA, Davidorf FH. Neovascularization associated
with myelinated nerve fibers: A case report. Ann
Ophthalmol 1983;15(12):1142­4.
8. Leys AM, Leys MJ, Hooymans JM, et al.. Myelinated nerve
fibers and retinal vascular abnormalities. Retina
1996;16(2):89­96.
9. Munteanu M, Munteanu G, Giuri S. Myelinated nerve
fibers associated with cilioretinal artery occlusion. J Fr
Ophtalmol 2001;24(7):744­7.
10. Ali BH, Logani S, Kozlov KL, et al. Progression of retinal
nerve fiber myelination in childhood. Am J Ophthalmol
1994118(4):515­7.
11. Jean-Louis G, Katz BJ, Digre KB, et al.Acquired and progressive
retinal nerve fiber layer myelination in an adolescent.Am
J Ophthalmol 2000;130(3):361­2.
12. Rosen B, Barry C, Constable IJ. Progression of myelinated
retinal nerve fibers.Am J Ophthalmol 1999;127(4):471­3.
13. Gottfried JL, Katz BJ, Digre KB, et al. Acquired and progressive
retinal nerve fiber layer myelination in an adolescent.Am
J Ophthalmol 2000; 130(3):361­2.
14. Schachat AP, Miller NR. Atrophy of myelinated retinal
nerve fibers after acute optic neuropathy.Am J Ophthalmol
1981;92(6):854­6.
15. Williams AJ, Fekrat S. Disappearance of myelinated retinal
nerve fibers after pars plana vitrectomy. Am J
Ophthalmol 2006;142(3):521­3.
16. Sharpe JA, Sanders MD. Atrophy of myelinated nerve
fibres in the retina in optic neuritis. Br J Ophthalmol
1975;59(4):229­32.
17. Katz SE,Weber PA. Photographic documentation of the
loss of medullated nerve fibers of the retina in uncontrolled
primary open angle glaucoma. J Glaucoma 1996;5(6):406­9.
18. Chavis PS, Tabbara KF. Demyelination of retinal myelinated
nerve fibers in Behçeťs disease. Doc Ophthalmol
1998;95(2):157­64.
19. Kee C, Hwang JM.Visual prognosis of amblyopia associated
with myelinated retinal nerve fibers. Am J Ophthalmol
2005;139(2):259­65.
20. Munteanu M, Zolog I, Giuri S, et al. Unilateral myelinated
nerve fibers associated with myopia or amblyopia.
Oftalmologia 2002;53(2):61­6.
21. Lee MS, Gonzalez C. Unilateral peripapillary myelinated
retinal nerve fibers associated with strabismus, amblyopia,
and myopia.Am J Ophthalmol 1998;125(4):554­6.
22. Summers CG, Romig L, Lavoie JD. Unexpected good
results after therapy for anisometropic amblyopia associated
with unilateral peripapillary myelinated nerve fibers. J Pediatr
Ophthalmol Strabis 1991;28(3):134­6.
23. Laghmari M,Boutimzine N,Karim A,.et al.Extensive peripapillary
myelinated nerve fibers, high ipsilateral myopia and
refractory amblyopia. J Fr Ophtalmol 2004;27(2):188­90.
24. Hittner HM,Antoszyk JH. Unilateral peripapillary myelinated
nerve fibers with myopia and/or amblyopia. Arch
Ophthalmol 1987;105(7):943­8.
25. Schmidt D, Meyer JH, Brandi-Dohrn J. Widespread
myelinated nerve fibers of the optic disc: Do they influence
the development of myopia? Int Ophthalmol
1996­97;20(5):263­8.
26. Höh H, Käsmann-Kellner B, Ruprecht KW.Anisomyopia
and myelinated nerve fibers--a syndrome. Klin Monatsbl
Augenheilkd 1999;214(1):31­6.
27. Tóth M, Holló G. Influence of myelinated retinal nerve
fibers on scanning laser polarimetry using variable and
enhanced corneal compensation methods.Ophthalmic Surg
Lasers Imaging 2006;37(4):336­40.
CONGENITAL HYPERTROPHY OF
THE RETINAL PIGMENT
EPITHELIUM
Signs and symptoms
Congenital hypertrophy of the retinal
pigment epithelium (CHRPE) is
typically an incidental finding discovered
during routine dilated fundus
examination. Patients are almost
invariably asymptomatic, with 3%
reporting visual photopsiae (i.e.,
flashes and floaters), diminished acuity
or visual field defects.1
Clinically,
there are three recognized presentations:
solitary, grouped, and multiple.2
VITREOUSANDRETINA
48A REVIEW OF OPTOMETRY APRIL 15, 2008
Solitary CHRPEs are classically
unilateral and appear as flat, welldemarcated,
darkly pigmented lesions
of the ocular fundus. They may appear
gray, brown or black and are often
surrounded by a white ring or halo.
Less commonly, CHRPE may be nonpigmented
centrally and display a
dark border. Solitary CHRPEs are
typically round or oval. Approximately
13% assume a more amorphous
geographic configuration.1
These lesions are usually located in
the retinal periphery, but may sometimes
be found in the macula or peripapillary
area.3,4
Size varies tremendously:
Solitary CHRPE may range
from 0.2­13 mm in basal diameter.1
Lacunae, which appear as focal round
areas devoid of pigment, are often
observed within larger lesions; choroidal
vessels may be visible at the
lacunar base. Other variations in solitary
CHRPE can include overlying
vascular sheathing, adjacent areas of
white without pressure and, rarely,
development of a focal elevated nodule
within the lesion.1
Grouped CHRPE describes a presentation
of sectorially oriented hyperpigmented
spots in one or more quadrants
of the fundus.2
These lesions are
also flat and well-delineated, but are
on average smaller than solitary
CHRPE.2
The ophthalmoscopic
appearance often resembles a cluster
of animal footprints; hence the condition
is colloquially referred to by
many clinicians as "bear track
retinopathy." Grouped CHRPE is
commonly found near or contiguous
with the optic nerve, and it also tends
to be unilateral in presentation.2
Multiple CHRPE is the most significant
of the three presentations
because it carries an association with
familial adenomatous polyposis
(FAP), a potentially life-threatening
hereditary form of colon cancer.
Multiple CHRPE is marked by the
presence of numerous scattered
lesions averaging six per eye.5
The
hallmark of this condition is bilaterality,
which occurs in
86% of patients.6
Multiple CHRPE
seems to have a
slight predilection
for the retinal
periphery, although
it may also be found
in the posterior
pole. The size of the
lesions tends to be
small, with most
being less than onehalf
of a disc diameter
(0.75 mm).7
There is a fair
amount of variability
in ophthalmoscopic
appearance. As with solitary
CHRPE, the lesions may differ in pigmentation
(gray to black or amelanotic),
shape (round, oval, tear-shaped,
bean-shaped or linear) and the presence
or absence of a surrounding
halo.5­7
When multiple CHRPEs are
discovered with a concurrent diagnosis
of FAP, the condition is referred to
as Gardner's syndrome.
Pathophysiology
Histologic evaluation of solitary
CHRPE lesions reveals cellular
hypertrophy of the retinal pigment
epithelium (RPE) with associated
accumulation of macromelanosomes;
in other words, the RPE cells are larger
and contain more pigment than
usual, but they are not otherwise
abnormal. The RPE basement membrane
is somewhat thickened locally,
and there is evidence of progressive
photoreceptor loss in the outer retina,
although the underlying choriocapillaris
remains unaltered.4,8
Lacunae,
more common in solitary CHRPE
than in other varieties, represent focal
depigmentation and atrophy of RPE
cells with concurrent thickening of
Bruch's membrane.10
In contrast to solitary CHRPE, the
RPE cells in grouped CHPRE appear to
be normal-sized, but contain increased
amounts of large pigment granules as
well as a thickened basement mem-
brane.11
The multiple CHRPEs of
Gardner's syndrome show distinct histological
differences from the other two
presentations; notably, these lesions are
often multilayered and extend throughout
the sensory retina, with evidence of
associated RPE hyperplasia.7,11
Multiple
CHRPE has been frequently described
as a hamartoma of the RPE.5­7,11
CHRPEs are often evident in newborns,
and they have even been
observed in prematurely born infants.9
They are present throughout life, and
until recently they were thought to
remain invariably stable. However,
evidence now suggests that most solitary
CHRPEs show progressive
enlargement over time. The mechanisms
of RPE growth may involve
horizontal expansion, development of
additional lacunae and/or broadening
of existing lacunae.1
A small percentage
of solitary CHRPEs exhibit
intralesional nodules, and these may
display enlargement as well.1
At least
three published reports have demonstrated
malignant growth associated
with solitary CHRPEs.12­14
Grouped
CHRPE and multiple CHRPE are not
believed to demonstrate any significant
growth in number or size.7
Management
Solitary and grouped CHRPE rarely
A circumpapillary CHRPE; such presentations are often mistaken
for other forms of pathology.
APRIL 15, 2008 REVIEW OF OPTOMETRY 49A
require any significant intervention.
The most important consideration is
differentiating these lesions from other,
more ominous conditions, particularly
choroidal melanoma. Typically, the
diagnosis is straightforward and made
by ophthalmoscopic examination
alone, but ambiguous cases may benefit
from additional diagnostic testing.
Ultrasonography can be helpful in
demonstrating a flat lesion without
acoustic hollowing, choroidal excavation
or orbital shadowing. Fluorescein
angiography of CHRPEs shows a characteristic
hypofluorescence within the
pigmented area and hyperfluorescence
associated with lacunae and halo; there
is no evidence of vascular filling or
leakage, as is typical with melanoma.
Solitary CHRPEs should be carefully
documented using detailed drawings,
fundus photography or both, and monitored
periodically for changes in size or
elevation.
Multiple CHRPE, because of its
close association with FAP, must be
evaluated and managed with great
care. One study suggested that the
presence of at least four lesions
(regardless of size), or at least two
lesions, one of which is large, carries
high sensitivity and maximal specificity
for Gardner's syndrome.6
All
patients who meet this criteria or those
who display atypical bilateral CHRPEs
should be evaluated for the possibility
of polyposis; this is particularly important
in those with a positive family history
of colon polyps or cancer.15
Appropriate referral for these individuals
is to a gastroenterologist for sigmoidoscopy
or colonoscopy. In addition,
genetic testing is available to
identify the specific mutation in the
APC gene that has been associated
with FAP.6
This test can also be used to
identify FAP carriers within the immediate
family.
Clinical pearls:
* Historically, CHRPE was sometimes
called a "halo nevus," referring
to the nearly pathognomonic depigmented
border associated with these
lesions.16
While descriptive, this term
was also quite misleading; nevi are
histologically distinct from CHRPE,
and are localized to the choroid rather
than the retina.
* The red-free (green) filter on the
ophthalmoscope or slitlamp can be
helpful in differentiating ambiguous
CHRPE from choroidal nevi or
melanoma. With the filter in place,
choroidal pigmentation becomes
almost imperceptible, while retinal
pigmentation remains visible.
* Generally, when CHRPE is
encountered unilaterally and/or fewer
than three pigmented lesions are evident,
there is little risk of Gardner's syndrome.
These patients need only to be
followed for associated changes in the
size or elevation of the lesions, which
are typically minimal and benign.
* A rare variant of grouped CHRPE
is the presentation of white variably
sized spots in a clustered pattern of the
posterior fundus. It has been referred to
in the literature as "polar bear tracks."17
This condition may be unilateral or
bilateral. The lesions are relatively stable
and considered to be of no functional
significance.18
Visual acuity,
fields, color vision and electrophysiologic
testing are all normal, and fluorescein
angiography reveals hyperfluorescence
throughout the various phases.18
1. Shields CL, Mashayekhi A, Ho T, et al. Solitary congenital
hypertrophy of the retinal pigment epithelium: Clinical features
and frequency of enlargement in 330 patients.
Ophthalmol 2003;110(10):1968­76.
2. Meyer CH, Rodrigues EB, Mennel S, et al. Grouped congenital
hypertrophy of the retinal pigment epithelium follows
developmental patterns of pigmentary mosaicism.
Ophthalmol 2005;112(5):841­7.
3. Apte RS, Bressler NM. Foveal congenital hypertrophy of
the retinal pigment epithelium in the setting of geographic
atrophy from age-related macular degeneration. Am J
Ophthalmol 2003;135(1):120­1.
4. Arroyo JG, Bula D. Congenital hypertrophy of the retinal
pigment epithelium inhibits drusen formation. Retina
2005;25(5):669­71.
5. Tiret A, Parc C. Fundus lesions of adenomatous polyposis.
Curr Opin Ophthalmol 1999;10(3):168­72.
6. Tiret A, Sartral-Taiel M, Tiret E, Laroche L. Diagnostic
value of fundus examination in familial adenomatous polyposis.
Br J Ophthalmol 1997;81(9):755­8.
7. Traboulsi EI. Ocular manifestations of familial adenomatous
polyposis (Gardner syndrome). Ophthalmol Clin
North Am 2005;18(1):163­6.
8. Shields CL, Materin MA, Walker C, et al. Photoreceptor
loss overlying congenital hypertrophy of the retinal pigment
epithelium by optical coherence tomography. Ophthalmol
2006;113(4):661­5.
9. Aiello LP, Traboulsi EI. Pigmented fundus lesions in a
preterm infant with familial adenomatous polyposis. Arch
Ophthalmol 1993;111(3):302­3.
10. Parsons MA, Rennie IG, Rundle PA, et al. Congenital
hypertrophy of retinal pigment epithelium: A clinico-pathological
case report. Br J Ophthalmol 2005;89(7):920­1.
11. Regillo CD, Eagle RC Jr, Shields JA, et al. Histopathologic
findings in congenital grouped pigmentation of the retina.
Ophthalmol 1993;100(3):400­5.
12. Fan JT, Robertson DM, Campbell RJ. Clinicopathologic
correlation of a case of adenocarcinoma of the retinal pigment
epithelium.Am J Ophthalmol 1995;119(2):243­5.
13. Shields JA, Shields CL, Eagle RC Jr, Singh AD.
Adenocarcinoma arising from congenital hypertrophy of
retinal pigment epithelium. Arch Ophthalmol
2001;119(4):597­602.
14. Trichopoulos N, Augsburger JJ, Schneider S.
Adenocarcinoma arising from congenital hypertrophy of the
retinal pigment epithelium. Graefes Arch Clin Exp
Ophthalmol 2006;244(1):125­8.
15. Holmes RL, Ambasht SK, Kelley PS. Index case of familial
adenomatous polyposis revealed by congenital hypertrophy
of the retinal pigment epithelium. Ann Intern Med
2005;143(8):618­9.
16. Alexander LJ. Primary Care of the Posterior Segment.
East Norwalk, CT:Appleton & Lange, 1989.
17. Karacorlu SA, Karacorlu M, Ozdemir H, Sanisoglu H.
Indocyanine green angiographic findings in congenital
grouped albinotic spots. Retina 2006;26(4):470­2.
18. Fuhrman C, Bopp S, Laqua H. Congenital grouped
albinotic spots:A rare anomaly of the retinal pigment epithelium.
Ger J Ophthalmol 1992;1(2):103­4.
CAVERNOUS HEMANGIOMA OF
THE RETINA
Signs and symptoms
Cavernous hemangioma of the retina
(CHR) and optic disc are rare
lesions. They were noted by Gass in
1971 as deserving their own separate
classifications as unique entities.1­3
They represent asymptomatic congenital
malformations of the retinal blood
vasculature that are typically non-progressive
and usually unilateral, with a
propensity for increased frequency in
women.4
CHR appears most commonly
as a solitary vascular lesion of limited
size (1 or 2 disc diameters) in the
midperipheral or peripheral retina,
posterior pole or optic nerve head.4
CHR can be seen in all ethnicities.3
Since they produce no dysfunction
unless they occur in the macula (causing
decreased acuity) or hemorrhage
(with patients reporting the symptom
VITREOUSANDRETINA
50A REVIEW OF OPTOMETRY APRIL 15, 2008
of floating spots), they often
remain undiscovered until
they are observed during a
routine dilated fundus
examination. However,
CHR rarely are a source of
intraocular hemorrhage.1­4
When they do produce
spontaneous vitreous bleeding,
the episodes are often
recurrent and significant.3
CHR are easily recognized
by their characteristic saccular
"grape-like" appear-
ance.1,3,4
Most individuals have a
single lesion (consisting of
multiple saccular components)
in one eye with no
other ocular or systemic anomalies.3
However, on occasion the disturbance
can be found demonstrating multiple
lesions in one retina with abnormal
vascular lesions of the skin and central
nervous system (CNS).3
While the
tumors are generally considered static
and incapable of growth, the literature
documents two cases of cavernous
hemangioma of the optic nerve which
demonstrated an increase in size.1
The
literature has also documented a case
in which a cavernous hemangioma
interfered with oculomotor nerve
function, causing ophthalmoparesis,
ptosis and visual impairment via a
compressive etiology.5
Cavernous hemangioma of the retina,
optic nerve or choroid may serve as the
ocular component of the neuro-oculocutaneous
phacomatosis sometimes
referred to as cavernoma multiplex.6
Pathophysiology
CHR are considered hamartomas
(from the Greek meaning a benign
overgrowth of mature cells normally
found in the affected area) with an
autosomal dominant inheritance pat-
tern.2,7,8
The lesions themselves consist
of clustered, large, thin-walled
intraretinal vessels lined with normal,
healthy, vascular endothelium that
have taken the shape of round sac-
cules.3
As the tumor evolves, it displaces
and replaces the sensory retina
in that zone.3
There is no recognized
malignant potential.1­7
The fluorescein angiographic features
include a normal arterial and
venous supply, extraordinarily slowed
venous drainage, no arteriovenous
shunting, no disturbances of vascular
permeability, no secondary retinal
exudation and the unique formation of
isolated clusters of vascular globules,
with plasma/erythrocyte sedimentation
surrounding the main body of the
malformation.4
Management
These lesions rarely require therapeutic
intervention over the patienťs
lifetime.1­7
They do not necessitate
any restriction of activity and they
typically remain stable and
unchanged over time.1­5
However,
because of their vascular nature and
potential to serve as markers for additional
lesions in alternate locations,
there is always some risk of other
lesions developing that may not be as
benign.1­7
Unfortunately, these unusual
formations may also exist in the
brain.6
While rare, the possibility of
intracranial hemorrhage must be
viewed as a life-threatening sequela.6
For these reasons, individuals with
cavernous hemangioma of
the retina should be referred
for neurological consultation
and possibly for neu-
roimaging.2­7
Family members
should be advised to be
properly evaluated for these
vascular lesions.2,7
Clinical pearls
* CHR are considered stable
intraretinal lesions.
However, the same tumor
occurring on the optic disc
has the potential for growth
and causing vitreous hemorrhage
and therefore should
be closely monitored.
* The presence either of
CHR or choroidal hemangioma
should alert the clinician to search for
features suggestive of systemic and
familial involvement.
* The principle differential diagnoses
include exudative retinal telangiectasias
and Coaťs disease, the vascular
Von Hipple Lindau tumor and the
arteriovenous malformation (Racemose
hemangioma/Wyburn Mason
syndrome).
1. Kushner MS, Jampol LM, Haller JA. Cavernous hemangioma
of the optic nerve. Retina 1994;14(4):359­61.
2. Weberg AM, Magnus D. Cavernous hemangioma of the
retina:A neuro-oculocutaneous phakomatosis. J Am Optom
Assoc 1988;59(7):564­6.
3. Augsberger JJ,Bornfeld N,Correa ZMS.Hemangiomas of
the retina. In:Yanoff M, Duker JS, Ophthalmology (2nd ed.),
Philadelphia: Mosby, 2004, pp. 1089­92.
4. Lewis RA, Cohen MH, Wise GN. Cavernous haemangioma
of the retina and optic disc. A report of three cases
and a review of the literature. Br J Ophthalmol
1975;59(8):422­34.
5. Mirzayan MJ, Capelle HH, Stan AC, et al. Cavernous
hemangioma of the cavernous sinus, skin, and retina:
Hemodynamic changes after treatment: Case report.
Neurosurg 2007;60(5):E952.
6. Sarraf D, Payne AM, Kitchen ND, et al. Familial cavernous
hemangioma: An expanding ocular spectrum. Arch
Ophthalmol 2000;118(7):969­73.
7. Pancurak J, Goldberg MF, Frenkel M, et al. Cavernous
hemangioma of the retina. Genetic and central nervous system
involvement. Retina 1985;5(4):215­20.
8. Friel JP. Hamartoma. In: Friel JP, Dorlanďs Illustrated
Medical Dictionary (26th ed.) Philadelphia: W. B. Saunders
Co., 1981, p. 579.
A cavernous hemangioma of the retina with its characteristic saccular
"grape-like" appearance.
APRIL 15, 2008 REVIEW OF OPTOMETRY 51A
NEURORETINITIS
Signs and symptoms
While neuroretinitis can present in
any age group due to several potential
causative etiologies, patients are typically
young. It is common for neuroretinitis
to affect children. In fact, the
majority of patients are younger than
20 years.1­13
There is no gender
predilection.
Neuroretinitis typically presents as a
unilateral, acute, painless loss of
vision. Rarely, it presents bilaterally.
It can also present without symptoms.
Alternatively, vision may be
decreased to the finger-counting
level.1­13
The typical visual field loss
is a central or cecocentral sco-
toma.2,14
A relative afferent pupil
defect (RAPD) will be present if the
condition is unilateral or markedly
asymmetric. Interestingly, the magnitude
of the RAPD will be small
relative to what one would expect
given the profound degree of vision
loss. In fact, in many unilateral
cases, no detectable RAPD is evident
despite profound vision loss in the
affected eye.2,14
Ophthalmoscopically, there will be a
markedly edematous disc. There may
also be peripapillary hemorrhages due
to venous stagnation. Occasionally a
mild vitritis will be evident overlying
the disc. Initially, there will be a serous
retinal detachment extending from the
disc to the macula. The key diagnostic
feature in well-developed neuroretinitis
is the presence of macular exudates
in the form of a florid macular star.1­13
However, this finding may not occur
for up to several weeks after onset, and
the diagnosis may not be apparent
early in the course of the disease. It is
not uncommon to have a serous retinal
detachment within the posterior pole
occur early on in association with the
advent of disc edema. This is highly
suspicious for early neuroretinitis, with
the macular exudates ensuing later.2,13
Numerous conditions have been
shown to be associated with neuroretinitis,
including toxoplasmosis, toxocariasis,
measles, syphilis, Lyme disease,
herpes simplex and zoster viruses,
mumps, tuberculosis, malignant
hypertension, ischemic optic neuropathy
and leptospirosis.15­25
However, the
most common cause by far is
Bartonella henselae, the organism
responsible for cat scratch disease.26­36
Occasionally, cat scratch disease will
be caused by B. quintana.37
In cat
scratch disease neuroretinitis, the
patient may have an antecedent history
of fever, malaise and/or lymphadenopathy
occurring several weeks
preceding the visual loss. There may
also be an antecedent history of a cat
scratch or flea bite.26­37
Pathophysiology
Neuroretinitis was initially identified
by Leber in 1916 as a retinopathy
associated with unilateral vision loss
and disc edema. Later, upon the discovery
that the foci of dysfunction was
the optic nerve rather than the retina,
the condition was renamed Leber's
idiopathic stellate neuroretinitis.38
Neuroretinitis, like most optic neuropathies,
has many proposed mechanisms,
although the exact pathophysiologic
pathway has not been identified.
In that the majority of cases are the
result of infectious etiologies, it is
plausible that cell invasion with proinflammatory
activation and suppression
of apoptosis may occur.39
Visual loss results predominately
from the retinal edema rather than
from optic nerve dysfunction. This is
evidenced by the fact that the visual
field defects reflect a retinal cause as
well as the relative mild degree (or
absence) of afferent pupil defect in the
face of profound vision loss.2,14
While
the macular exudates are characteristic
of this condition, it may not be present
upon early presentation and may take
several weeks (typically two) before
developing.2,40
After development of
disc and retinal edema, there will be
spontaneous resolution and fluid
resorption. The aqueous phase of the
edema resolves most quickly, leaving
the accumulated lipid exudates
within the outer plexiform layer
forming the characteristic macular
star.
Management
When encountering neuroretinitis,
it is important to medically consider
and evaluate patients for all
possible causes. A history should be
elicited for exposure to cats, flea or
tick bites, travel to Lyme-endemic
areas, exposure to sexually transmitted
disease, lymphadenopathy,
skin rashes, malaise, myalgia and
fever. Tests that should be ordered (as
dictated by the history) include Lyme
titer, toxoplasmosis titer, toxocariasis
titer, purified protein derivative skin
testing and chest X-ray for tuberculosis.
However, because the most common
cause is infection by B. henselae
or B. quintana from a cat scratch, one
must carefully examine for these entities.
Cat scratch disease can be identified
by immunoassay antibody testing
for B. henselae and B. quintana.5,14,41
Prognosis for visual recovery in
neuroretinitis is generally excellent,
especially if the cause is cat scratch
disease. Most patients will return to
normal or near-normal vision without
treatment.2,14,30
While neuroretinitis
from cat scratch disease is typically a
self-limiting condition with an excellent
prognosis, antimicrobial therapy
may be used to hasten recovery.
Successful agents include rifampin,
ciprofloxacin, doxycycline, sulfamethoxazole
and trimethop-
rim.2,3,14,28,29
A commonly used therapy
Neuroretinitis associated with cat scratch disease.
NEURO-OPHTHALMIC DISEASE
NEURO-OPHTHALMICDISEASE
52A REVIEW OF OPTOMETRY APRIL 15, 2008
is doxycycline 100 mg PO BID for one
month.2,3,14,28,29
In neuroretinitis, the disc edema will
resolve in approximately eight weeks.
The macular exudates will resolve over
several months. However, a residual
macular pigmentary atrophy or optic
atrophy may remain. Occasionally, this
will lead to a poor visual outcome.2,3,26
Clinical pearls
* Neuroretinitis should be suspected
in cases of disc edema with profuse
adjacent retinal edema and painless
vision loss with a relatively mild afferent
pupil defect.A confirmatory sign is
the appearance of a macular star within
10­14 days.
* Very few entities will mimic neuroretinitis
with its characteristic macular
star. Mimicking entities include
malignant hypertension and anterior
ischemic optic neuropathy.
* The afferent pupil defect will be
remarkably mild (or even absent)
despite severe vision loss. This is a
prominent diagnostic feature of neu-
roretinitis.
* The absence of pain on eye movements
greatly helps differentiate neuroretinitis
from demyelinating optic
neuropathy. Patients with neuroretinitis
need not have the same concerns for
the development of multiple sclerosis.
* Fleas may be the vectors of the
Bartonella organisms and hence neuroretinitis.
However, history of a cat
scratch or bite is not always necessary
to make this diagnosis.
* While antibiotics are frequently
used for cat scratch disease neuroretinitis,
there are no controlled clinical
trials that indicate a better clinical outcome
from this therapy.
1. Reddy AK, Morriss MC, Ostrow GI, et al. Utility of MR
imaging in cat-scratch neuroretinitis. Pediatr Radiol
2007;37(8):840­3.
2. Wade NK, Levi L, Jones MR, et al. Optic disk edema
associated with peripapillary serous retinal detachment:An
early sign of systemic Bartonella henselae infection. Am J
Ophthalmol 2000;130(3):327­34.
3. Ghauri RR, Lee AG. Optic disk edema with a macular
star. Surv Ophthalmol 1998;43(3):270­4.
4. Labalette P, Bermond D, Dedes V, et al. Cat-scratch disease
neuroretinitis diagnosed by a polymerase chain reaction
approach. Am J Ophthalmol 2001;132(4):575­6.
5. Sander A, Berner R, Ruess M. Serodiagnosis of cat
scratch disease: Response to Bartonella henselae in children
and a review of diagnostic methods. Eur J Clin
Microbiol Infect Dis 2001;20(6):392­401.
6. Lombardo J. Cat-scratch neuroretinitis. J Am Optom
Assoc 1999;70(8):525­30.
7. Donnio A, Buestel C, Ventura E, et al. Cat-scratch disease
neuroretinitis. J Fr Ophtalmol 2004;27(3):285­90.
8. Ulrich GG,Waecker NJ, Meister SJ, et al. Cat scratch disease
associated with neuroretinitis in a 6-year-old girl.
Ophthalmol 1992;99(2):246­9.
9. Depeyre C, Mancel E, Besson-Leaud L, et al. Abrupt
visual loss in children. Three case studies of ocular bartonellosis.
J Fr Ophtalmol 2005;28(9):968­75.
10. Shoari M, Katz BJ. Recurrent neuroretinitis in an adolescent
with ulcerative colitis. J Neuroophthalmol
2005;25(4):286­8.
11. Weiss AH, Beck RW. Neuroretinitis in childhood. J
Pediatr Ophthalmol Strabis 1989;26(4):198­203.
12. Besson-Leaud L, Mancel E, Missotte I, et al. Sudden
sight impairment revealing a cat-scratch disease: Report of
three cases. Arch Pediatr 2004;11(10):1209­11.
13. Saatci AO, Oner FH, Kargi A. Unilateral neuroretinitis
and periparillary serous retinal detachment in cat-scratch
disease. Korean J Ophthalmol 2002;16(1):43­6.
14. Suhler EB, Lauer AK, Rosenbaum JT. Prevalence of
serologic evidence of cat scratch disease in patients with
neuroretinitis. Ophthalmol 2000;107(5):871­6.
15. Moreno RJ, Weisman J, Waller S. Neuroretinitis: An
unusual presentation of ocular toxoplasmosis.
Ophthalmologie 1980;215:53­8.
16. Arruga J, Valentines J, Mauri F, et al. Neuroretinitis in
acquired syphilis. Doc Ophthalmol 1986;64:23­9.
17. Karma A, StenborgT, Summanen P, et al. Long-term follow-up
of chronic Lyme neuroretinitis. Retina
1996;16:505­9.
18. Margo CE, Sedwick LA, Rubin ML. Neuroretinitis in
presumed visceral larva migrans. Retina 1986(6);95­8.
19. Neppert B. Measles retinitis in an immunocompetent
child. Klin Monatsbl Augenheilkd 1994;205:156­60.
20. Foster RE, Lowder CY, Meisler DM, et al. Mumps neuroretinitis
in an adolescent. Am J Ophthalmol
1990;110:91­3.
21. Stechschulte SU, Kim RY, Cunningham ET Jr.
Tuberculous neuroretinitis. J Neuro-Ophthalmol
1999;19:201­4.
22. Jensen J. A case of herpes zoster ophthalmicus complicated
with neuroretinitis. Acta Ophthalmol
1948;26:551­5.
23. Johnson BL, Wisotzkey HM. Neuroretinitis associated
with herpes simplex encephalitis in an adult. Am J
Ophthalmol 1977;83;481­9.
24. Scott IU, Flynn HW,Al-Attar L, et al. Bilateral optic disc
edema in patients with severe systemic arterial hypertension:
Clinical features and visual acuity outcomes. Ophthal
Surg Lasers Imaging. 2005;36(5):374­80.
25. Lee AG, Beaver HA. Acute bilateral optic disk edema
with a macular star figure in a 12-year-old girl. Surv
Ophthalmol 2002;47(1):42­9.
26. Brazis PW, Stokes HR, Ervin FR. Optic neuritis in cat
scratch disease. J Clin Neuroophthalmol 1986;6(3):172­4.
27. Chrousos GA, Drack AV,Young M, et al. Neuroretinitis
in cat scratch disease. J Clin Neuroophthalmol
1990;10(2):92­4.
28. Matsuo T, Kato M. Submacular exudates with serous
retinal detachment caused by cat scratch disease. Ocul
Immunol Inflamm 2002;10(2):147­50.
29. KodamaT, Masuda H, Ohira A. Neuroretinitis associated
with cat-scratch disease in Japanese patients. Acta
Ophthalmol Scand 2003;81(6):653­7.
30. Rosen B. Management of B. henselae neuroretinitis in
cat-scratch disease. Ophthalmol 1999;106(1):1­2.
31. Besada E, Woods A, Caputo M. An uncommon presentation
of Bartonella-associated neuroretinitis. Optom Vis
Sci 2002;79(8):479­88.
32. Rosen BS, Barry CJ, Nicoll AM, et al. Conservative
management of documented neuroretinitis in cat scratch
disease associated with Bartonella henselae infection. Aust
NZ J Ophthalmol 1999;27(2):153­6.
33. De Schryver I, Stevens AM, Vereecke G, et al. Cat
scratch disease (CSD) in patients with stellate neuroretinitis:
3 cases. Bull Soc Belge Ophtalmol 2002;(286):41­6.
34. Ziemssen F, Bartz-Schmidt KU, Gelisken F. Secondary
unilateral glaucoma and neuroretinitis: Atypical manifestation
of cat-scratch disease. Jpn J Ophthalmol
2006;50(2):177­9.
35. Veselinoviç D. Bartonella henselae as a cause of optical
nerve neuritis.Vojnosanit Pregl 2006;63(11):971­4.
36. Chai Y,Yamamoto S, Hirayama A, et al. Pattern visual
evoked potentials in eyes with disc swelling due to cat
scratch disease­associated neuroretinitis. Doc Ophthalmol
2005;110(2­3):271­5.
37. George JG, Bradley JC, Kimbrough RC, et al. Bartonella
quintana associated neuroretinitis. Scand J Infect Dis
2006;38(2):127­8.
38. Dreyer RF, Hopen G, Gass JDM, Smith JL. Leber's idiopathic
stellate neuroretinitis. Arch Ophthalmol
1984;102:1140­5.
39. Dehio C. Molecular and cellular basis of Bartonella
pathogenesis. Annu Rev Microbiol 2004;58:365­90.
40. Brazis PW, Lee AG. Optic disk edema with a macular
star. Mayo Clin Proc 1996;71(12):1162­6.
41. Flexman JP, Chen SC, Dickeson DJ, et al. Detection of
antibodies to Bartonella henselae in clinically diagnosed cat
scratch disease. Med J Aust 1997;166(10):532­5.
TILTED DISC SYNDROME
Signs and symptoms
Tilted disc syndrome (TDS) is a
unilateral or bilateral congenital optic
disc anomaly that can be discovered in
patients of any age, with an incidence
of 2% in the general population.1
There is neither gender predilection
nor an identifiable hereditary pattern.1
The opthalmoscopic appearance is
variable.2
In TDS, the disc appears to
be rotated about its axis, with the long
axis of the disc approaching the horizontal
meridian in extreme cases.
Instead of a vertically oriented disc,
the nerve fibers appear shifted so that
the superior portion of the disc
appears to be positioned in the superior
nasal quadrant, giving the disc a Dshaped
appearance.3,4
In many cases,
the major retinal vessels emerge from
the disc, immediately run nasally, then
abruptly turn and course temporally in
the traditional vascular branching pattern.
This vascular anomaly is termed
situs inversus.3,5,6
Despite the varied appearances,
APRIL 15, 2008 REVIEW OF OPTOMETRY 53A
NEURO-OPHTHALMICDISEASE
there are some consistent findings.
The most consistently encountered
finding is a conus in the inferior and
inferior nasal aspect of the peripapillary
retina contiguous with the optic
disc. In some cases, the conus can
involve the inferior aspect of the disc
with apparent rim thinning or obliteration
with a pseudoglaucomatous
appearance. This inferiorly located
conus is associated with significant
ectasia as well as staphylomatous formation
within this localized area.1,3,7,8
The inferiorly located conus has been
referred to as Fuchs' coloboma. The
colobomatous formation may extend
inferiorly outward from the disc and
manifest as hypoplasia of the retina,
retinal pigment epithelium (RPE), and
choroid.1­5
This appears as a very lightly
pigmented fundus. Other findings
encountered with TDS include myelinated
nerve fibers, lacquer cracks,
choroidal folds, foveal retinal detachment
and retinoschisis and peripapillary
choroidal neovascular membranes
with subretinal hemorrhages.1,9,10­13
Visual acuity is unaffected in TDS;
however, visual field loss is common.
The most commonly encountered visual
field defect is a superior temporal
scotoma.1,14­18
In cases in which TDS is
bilateral, this can appear as superior
bitemporal scotomas suggestive of chiasmal
compression. However, in TDS
the visual field defect is unchanging
and does not respect the vertical hemianopic
line as it would in a chiasmal
compressive mass, thus helping to distinguish
the two conditions.14­18
Other
potential visual field defects include
arcuate scotoma, nasal contraction and
an enlarged blind spot.16
The most commonly encountered
refractive error in patients with TDS is
myopic astigmatism at an oblique
axis.1,6,16
There has been conjecture that
the refractive error results from fundus
alterations seen in TDS.5
However, it
has been seen more recently that clinically
significant lenticular astigmatism
is present in TDS patients.19
Another report showed that in the
majority of TDS cases, astigmatism
was mainly corneal, and it suggested
that morphogenetic factors in the
development of the tilted disc might
possibly influence the corneal development
in such a way as to result in
corneal astigmatism.20
It has also been
recently reported that color vision
abnormalities consisting of red-green,
blue and mixed defects were found in
eyes with TDS.21
Pathophysiology
Contrary to popular belief, there is
no actual tilting or rotation of the disc
in TDS, even though the disc may
appear to have rotated by as much as
90° about its axis. Actually, TDS represents
a congenital coloboma due to
incomplete closure of the embryonic
fetal fissure at six weeks' gestation.22
During development, the eye first
appears in the form of the optic sulci
in the fourth week of gestation. The
optic vesicle forms from growth of the
optic sulci towards the surface ectoderm.
As the optic vesicle reaches the
surface ectoderm, it invaginates to
form a goblet-shaped optic cup. If
there is incomplete closure upon
invagination, a coloboma potentially
involving the disc, retina and RPE
results.2,22
The inferior aspect of the disc (and
adjacent fundus) therefore has a
congenital absence of tissue.3,4,8,23
Automated perimetry has disclosed
reduced mean deviations in this and
other areas of the visual field as well,
leading to the theory that TDS is a
variant of optic nerve hypoplasia.24
The colobomatous formation affects
the shape of the chorioscleral canal
due to a deficiency in the choroid,
neural retina and RPE. As such, the
nerve fibers will be concentrated in
the superior and superior temporal
aspect of the disc and the inferior and
inferior nasal section will be deficient
in axons.3,4,8,23
This gives the nerve a Dshape,
with the flat edge along the area
of the conus. The congenital absence
of tissue in the inferior nasal aspect of
the nerve may be significant enough
that the patient will have a corresponding
superior temporal visual field
defect that does not respect the vertical
hemianopic line.14­18
Theoretically, the staphylomatous
and ectatic formations caused by the
incomplete fetal-fissure closure producing
the conus also stretch the tissues,
permitting secondary lacquer
crack formation. These breaks in
Bruch's membranes form a nidus for
the development of choroidal neovascular
membranes with subsequent
subretinal hemorrhages.2,7,9
Management
Because TDS is a congenital anomaly,
there is no management for the
finding itself. In cases in which
choroidal neovascular membranes
form as a result of TDS, the visual outcomes
tend to be quite good in that the
membranes are very responsive to
photocoagulation or demonstrate no
progression or even involution without
treatment.9
The most important factor in managing
TDS is proper diagnosis. The
heaped-up axons in the superior aspect
of the nerve in TDS frequently have
been misdiagnosed either as disc
edema or papilledema. Also, the inferior
nasal conus and possibly colobomatous
extension into the disc has
been frequently misdiagnosed and
treated as normal tension glaucoma.
Further, the superior temporal defect
Tilted disc syndrome.
54A REVIEW OF OPTOMETRY APRIL 15, 2008
in TDS has been confused with chiasmal
compressive disease, especially
when TDS is bilateral.
Clinical pearls
* TDS has a varied ophthalmoscopic
appearance. However, the most
diagnostic feature is the inferiorly
located conus. This is invariably present
in TDS and must be present for the
clinician to make this diagnosis.
* The main differentiating factors
between the visual field defect in TDS
and chiasmal compressive disease is
that the field defects in TDS are nonprogressive
and do not respect the
vertical hemianopic midline.
* TDS is sometimes misdiagnosed
as disc edema, papilledema, normal
tension glaucoma and pituitary tumor.
1. Apple DJ, Rabb MF,Walsh PM. Congenital anomalies of
the optic disc. Surv Ophthamol 1982;27:3­41.
2. Sowka J, Aoun P. Tilted disc syndrome. Optom Vis Sci
1999;76(9):618­23.
3. Dorrell D. The tilted disc. Br J Ophthalmol
1978;62:16­20.
4. Giuffre G. Hypothesis on the pathogenesis of the papillary
dysversion syndrome. J Fr Ophthalmol
1985;8:565­72.
5. Young SE,Walsh FB, Knox DL.The tilted disk syndrome.
Am J Ophthalmol 1976;82:16­23.
6. Guiffre G. Chorioretinal degenerative changes in the
tilted disc syndrome. Int Ophthalmol 1991;15:1­7.
7. Bottoni FG, Eggink CA, Cruysberg JR, et al. Dominant
inherited tilted disc syndrome and lacquer cracks. Eye
1990;4:504­9.
8. Prost M. Clinical studies of the tilted disc syndrome. Klin
Oczma 1991;93:121­3.
9. Khairallah M, Chatti T, Messaoud R, et al. Peripapillary
subretinal neovascularization associated with tilted disc
syndrome. Retina 1996;16:449­51/
10. Toussaint P,Turut P, Milazzo S, et al. Aspects of the tilted
disc syndrome. Bull Soc Ophthalmol Fr
1989;89:267­8,71­2.
11. Cockburn DM. Tilted discs and medullated nerve
fibers. Am J Optom Physiol Opt 1982;59:760­1.
12. Miura G, Yamamoto S, Tojo N, et al. Foveal retinal
detachment and retinoschisis without macular hole associated
with tilted disc syndrome. Jpn J Ophthalmol
2006;50(6):566­7.
13. Cohen SY, Quentel G. Chorioretinal folds as a consequence
of inferior staphyloma associated with tilted disc
syndrome. Graefes Arch Clin Exp Ophthalmol
2006;244(11):1536­8.
14. Manor RS.Temporal field defects due to nasal tilting of
discs. Ophthalmologica 1974;168:269­81.
15. Berry H. Bitemporal depression of the visual fields due
to an ocular cause. Br J Ophthalmol 1963;47:441­4.
16. Guiffre G. The spectrum of the visual field defects in
the tilted disc syndrome. Clinical study and review. NeuroOphthalmol
1986;6:239­46.
17. Rucker CW. Bitemporal defects in the visual fields due
to anomalies of the optic discs. Arch Ophthalmol
1946;35:546­54.
18. Graham MV, Wakefield GJ. Bitemporal visual field
defects associated with anomalies of the optic discs. Br J
Ophthalmol 1973;57:307­14.
19. Gündüz A, Evereklioglu C, Er H, et al. Lenticular astigmatism
in tilted disc syndrome. J Cataract Refract Surg
2002;28(10):1836­40.
20. Bozkurt B, Irkec M, Gedik S, et al.Topographical analysis
of corneal astigmatism in patients with tilted-disc syndrome.
Cornea 2002;21(5):458­62.
21. Vuori ML, Mäntyjärvi M. Tilted disc syndrome and
colour vision. Acta Ophthalmol Scand 2007 Apr 2 [Epub
ahead of print].
22. LarsenWJ. Development of the eyes. In: LarsenWJ, ed.
Human Embryology (2nd ed.), New York: Churchill
Livingstone, 1997, pp. 375­84.
23. Gürlü VP, Al˘mg˘l ML. Retinal nerve fiber analysis and
tomography of the optic disc in eyes with tilted disc syndrome.
Ophthalmic Surg Lasers Imaging
2005;36(6):494­502.
24. Brazitikos PD, Safran AB, Simona F, et al. Threshold
perimetry in tilted disc syndrome. Arch Ophthalmol
1990;108:1698­700.
MORNING GLORY SYNDROME
Signs and symptoms
Morning glory syndrome is a rare
congenital optic disc anomaly that can
be discovered at any age, although
most patients are usually made aware
of the condition with their first eye
examination. The incidence is
unknown. It occurs equally in
males and females.1,2
Morning
glory syndrome can be either bilateral
or unilateral.2­8
When morning
glory syndrome is bilateral, visual
acuity is typically quite good.4,9
However, most patients with unilateral
morning glory syndrome
have markedly reduced visual acuity,
often to the level of hand
motion vision.4,10
While reports are
often contradictory regarding the
level of visual function, it can safely
be stated that morning glory
syndrome has a spectrum of severity,
with most patients retaining
useful vision.11
There will be a markedly
enlarged anomalous disc and peripapillary
retina. The nerve will appear
larger than the fellow eye in unilateral
cases. The condition gets its name
from its resemblance to a tropical
flower of the same name. It is characterized
by a funnel-shaped excavated
and enlarged dysplasic optic disk, with
white tissue surrounded by an elevated
pigmented peripapillary annulus.
White glial tissue is present at the bottom
of the cup and represents an
important diagnostic criterion. The
retinal vessels arise from the periphery
of the disc anomaly and run an abnormally
straight, radial course over the
peripapillary retina. The origin of the
vessels is obscured by the central tuft
of glial tissue. This can give the morning
glory disc a pseudoglaucomatous
appearance.1,6,12­14
There appear to be
an excessive number of retinal vessels;
however, this is simply because glial
tissue obscures the branching of the
vessels within the optic cup. In a number
of cases, a retinal detachment may
be present or may develop during the
clinical course.15­21
Strabismus is frequently
encountered in patients with
morning glory syndrome.22
Many ocular conditions have
appeared in association with morning
glory syndrome, including microophthalmos,
cataracts, myopia, ciliary
body cysts, Bergmeister's papilla and
hypertelorism.12,23
Numerous systemic
abnormalities have also been identified
as being associated with morning glory
syndrome, including Goldenhar's syndrome;
sphenoidal encephalocele;
porencephaly and hydronephrosis;
renal failure; cerebral malformation;
frontonasal dysplasia; endocrine irregularities;
neurofibromatosis Type 2;
Morning glory syndrome.
PhotocourtesyofDianaShechtman,OD,FAAO.
APRIL 15, 2008 REVIEW OF OPTOMETRY 55A
NEURO-OPHTHALMICDISEASE
midline craniofacial defects such as
basal encephalocele, cleft lip and
palate; and agenesis of the corpus cal-
losum.3,5,6,10,15,24,25
However, despite
numerous reported associations, these
comorbidities seem to be mostly anecdotal
cases and morning glory syndrome
is considered an isolated ocular
abnormality. Further, in the absence of
consistent systemic associations, perhaps
the term "syndrome" truly does
not apply to this condition.
Pathophysiology
Morning glory syndrome is a nonprogressive
congenital optic nerve
anomaly. This condition has been
shown to be limited to the eye, with no
involvement of the retrobulbar nerve
and brain.2,15,23
It has long been considered
a variant of optic nerve colobo-
ma;23
however, this may not be true.
The central glial tissue, vascular anomalies,
scleral defects and adipose and
smooth muscle tissue within the peripapillary
sclera is more consistent with
a mesenchymal abnormality.24,26
An
alternate theory suggests that abnormal
enlargement of the distal optic
stalk during development allows formation
of the characteristic excavation
seen in morning glory syndrome.24
The only potential active pathology
that occurs in association with morning
glory syndrome is rhegmatogenous
retinal detachment. The etiology
was unclear until the development of
more sophisticated imaging techniques,
namely optical coherence
tomography (OCT). OCT has demonstrated
slit-like retinal breaks within or
at the edge of the excavation within
morning glory syndrome. These slitlike
retinal breaks provide a direct
communication between the subretinal
space and the vitreous cavity, permitting
the fluid movement that leads to
the evolution of tissue separation.16­21
Management
Management of morning glory syndrome
typically does not extend
beyond proper diagnosis. While the
appearance can be quite dramatic,
extensive neurological evaluation
must be avoided, as this is a nonprogressive
disc anomaly and not
acquired disc pathology. While many
systemic abnormalities have been
associated with the condition, there is
not enough consistency to consider
these comorbidities anything but coincidental,
making extensive evaluation
unwarranted. Similarly, glaucoma
treatment based solely upon the disc
appearance in patients with morning
glory syndrome should be avoided. In
unilateral cases, protective eyewear
should be recommended to protect the
better-seeing eye.
The patient must be monitored and
educated about the signs and symptoms
of retinal detachment. Management
of this unique type of rhegmatogenous
retinal detachment often
includes pars plana vitrectomy with
posterior hyaloid removal, fluid-air
exchange, endolaser in the area of the
retinal break, and long-acting gas bubble
injection.17,18
Clinical pearls
* The neuroretinal rim of the morning
glory disc is recessed and not truly
readily visible. This appearance has
been mistakenly identified as acquired
thinning of the rim, as seen in glaucoma.
Morning glory syndrome has frequently
been misdiagnosed and mistreated
as normal tension glaucoma.
Always rule out morning glory syndrome
in cases of suspected normal
tension glaucoma. Avoid impulsive
diagnoses.
* In cases where there is reduced
visual acuity, morning glory syndrome
has been misdiagnosed as amblyopia.
* While dramatic in appearance,
morning glory syndrome has very little
future impact and virtually no management
options for patients. If clinicians
can recognize the accompanying
images in this manuscript as morning
glory syndrome, then referral and special
testing can be obviated.
1. Auber AE, O'Hara M. Morning glory syndrome. MR
imaging. Clin Imaging 1999;23(3):152­8.
2. Murphy BL, Griffin JF. Optic nerve coloboma (morning
glory syndrome): CT findings. Radiol 1994;191(1):59­61.
3. Chaudhuri Z, Grover AK, Bageja S, et al. Morning glory
anomaly with bilateral choroidal colobomas in a patient
with Goldenhar's syndrome. J Pediatr Ophthalmol Strabis
2007;44(3):187­9.
4. Beyer WB, Quencer RM, Osher RH. Morning glory syndrome.A
functional analysis including fluorescein angiography,
ultrasonography, and computerized tomography.
Ophthalmol 1982;89(12):1362­7.
5. Merlob P, Horev G, Kremer I, et al. Morning glory fundus
anomaly, coloboma of the optic nerve, porencephaly
and hydronephrosis in a newborn infant: MCPH entity. Clin
Dysmorphol 1995;4(4):313­8.
6. Schneider C, Cayrol D, Arnaud B, et al. Clinically isolated
morning glory syndrome. J Fr Ophtalmol
2002;25(2):178­81.
7. Nagy V, Kettesy B, Toth K, et al. Morning glory syndrome--a
clinical study of two cases. Klin Monatsbl
Augenheilkd 2002;219(11):801­5.
8. De Laey JJ, Ryckaert S, Leys A.The "morning glory" syndrome.
Ophthalmic Paediatr Genet 1985;5(1­2):117­24.
9. Singh SV, Parmar IP, Rajan C. Preserved vision in a case
of morning glory syndrome: Some pertinent questions.
Acta Ophthalmol (Copenh) 1988;66(5):582­4.
10. Dureau P, Attie-Bitach T, Salomon R, et al. Renal
coloboma syndrome. Ophthalmol 2001;108(10):1912­6.
11. Harasymowycz P, Chevrette L, Décarie JC, et al.
Morning glory syndrome: Clinical, computerized tomographic,
and ultrasonographic findings. J Pediatr
Ophthalmol Strabis 2005;42(5):290­5.
12. Steinkuller PG.The morning glory disk anomaly: Case
report and literature review. J Pediatr Ophthalmol Strabis
1980;17(2):81­7.
13. Pau H. Handmann's optic nerve anomaly and "morning
glory" syndrome. Klin Monatsbl Augenheilkd
1980;176(5):745­51.
14. Pierre-Filho PdeT, Limeira-Soares PH, Marcondes AM.
Morning glory syndrome associated with posterior pituitary
ectopia and hypopituitarism. Acta Ophthalmol Scand
2004;82(1):89­92.
15. Jackson WE, Freed S. Ocular and systemic abnormalities
associated with morning glory syndrome. Ophthalmic
Paediatr Genet 1985;5(1­2):111­5.
16. Coll GE, Chang S, Flynn TE, et al. Communication
between the subretinal space and the vitreous cavity in the
morning glory syndrome. Graefes Arch Clin Exp
Ophthalmol 1995;233(7):441­3.
17. Ho TC, Tsai PC, Chen MS, et al. Optical coherence
tomography in the detection of retinal break and management
of retinal detachment in morning glory syndrome.
Acta Ophthalmol Scand 2006;84(2):225­7.
18. Yamakiri K, Uemura A, SakamotoT. Retinal detachment
caused by a slitlike break within the excavated disc in
morning glory syndrome. Retina 2004;24(4):652­3.
19. Matsumoto H, Enaida H, Hisatomi T, et al. Retinal
detachment in morning glory syndrome treated by triamcinolone
acetonide-assisted pars plana vitrectomy. Retina
2003;23(4):569­72.
20. Ho CL,Wei LC. Rhegmatogenous retinal detachment
in morning glory syndrome pathogenesis and treatment.
Int Ophthalmol 2001;24(1):21­4.
21. Bartz-Schmidt KU, Heimann K. Pathogenesis of retinal
detachment associated with morning glory disc. Int
Ophthalmol 1995;19(1):35­8.
22. Chan RT, Chan HH, Collin HB. Morning glory syndrome.
Clin Exp Optom 2002;85(6):383­8.
23. Mafee MF, Jampol LM, Langer BG, et al. Computed
tomography of optic nerve colobomas, morning glory
anomaly, and colobomatous cyst. Radiol Clin North Am
1987;25(4):693­9.
24. Razeghinejad MR, Masoumpour M. Chiari type I malformation
associated with morning glory disc anomaly. J
56A REVIEW OF OPTOMETRY APRIL 15, 2008
Neuroophthalmol 2006;26(4):279­81.
25. Chen CS, David D, Hanieh A. Morning glory syndrome
and basal encephalocele. Childs Nerv Syst
2004;20(2):87­90.
26. Dutton GN. Congenital disorders of the optic nerve:
Excavations and hypoplasia. Eye 2004;18(11):1038­48.
FACIAL NERVE PALSY
Signs and symptoms
The seventh cranial nerve (CN VII,
facial nerve) is responsible for the voluntary
motor innervation to the muscles
of facial expression and the
stapedius muscle of the inner ear, and
for sensory innervation to the anterior
two thirds of the tongue.1­7
The orbicularis
oculi is responsible for eyelid closure,
and is under the control of CN
VII.1­6
Consequently, damage to one of
the CN VII nuclei, damage to one of
the CN VII fascicles or interruption to
its peripheral course will produce
characteristic clinical findings that
include weakness or paralysis of one
side of the face with an inability to
voluntarily close the ipsilateral eye.
Additional findings on the affected
side include flattening of the nasolabial
fold, drooping of the corner of the
mouth, ectropion, lagophthalmos,
decreased tear production, conjunctival
injection, corneal compromise,
decreased taste sensation and hyperacusis
(supersensitivity to sound).1­5
Facial nerve palsy shows no gender
preference; men and women are affected
equally. Risk factors include diabetes,
pregnancy and family history.2,6
Facial
nerve palsy can be marked or subtle. In
cases of suspected involvement, the clinician
must selectively test the involved
muscles of the face, looking for asymmetry
between the right and left sides.
Specifically, patients should be instructed
to look up and wrinkle the forehead
(moving the frontalis and corrugator
muscles), purse the lips and whistle
(orbicularis oris muscle), smile and/or
puff out the cheeks (buccinators muscle)
and squeeze the eyes tightly closed
(orbicularis oculi).
Pathophysiology
Supranuclear motor neurons connecting
cortical areas 4 and 6 with the
facial nuclei descend as fascicles of
the corticobulbar (cortex-to-cranial
nerve nuclei) tract through the internal
capsule to the level of the lower pons
by way of the cerebral peduncles.2,3
The portion of each facial nucleus that
controls the muscles of the upper face
(frontalis, orbicularis oculi and corrugator)
receives corticobulbar stimulation
from the right and left (crossed
and uncrossed) precentral motor cortices.
The supranuclear innervations
supporting the muscles of facial
expression in the lower face is crossed
only.2,3,5
The muscles that close the
eyes and wrinkle the forehead are
bilaterally innervated; therefore a
lesion in the cortex or supranuclear
pathway on one side spares eyelid closure
and forehead wrinkling but
results in contralateral paralysis of the
lower face.2,3
Since the area of the cortex
associated with facial muscle function
lies near the motor representation
of the hand and tongue, weakness of
the thumb, fingers and tongue ipsilateral
to the facial palsy is not uncom-
mon.2­5
Lastly, because supranuclear
lesions are upper motor neuron lesions
(sometimes referred to as central
lesions), they produce spastic rather
than flaccid paralysis. This allows the
amount of flattening to the nasolabial
fold and mouth-corner-droop to often
be significantly less than its lower
motor neuron counterpart.2,3
The facial motor nuclei are located
in the lower pontine tegmentum and
possess an intimate relationship with
the trigeminal nerve (CN V), abducens
nuclei (CN VI), cochlear nuclei (CN
VIII), medial longitudinal fasciculus
(MLF), paramedian pontine reticular
formation (PPRF), descending corticospinal
fibers and descending sympathetic
fibers. The facial nucleus
contains four separate cell groups,
which innervate specific muscle
groups. Motor axons exit the nucleus
dorsally, loop around the CN VI nuclei
and emerge into the subarachnoid
space from the lateral aspect of the
pons.2,3,5
Fibers from the superior salivatory
and lacrimal nuclei (parasympathetic
preganglionic fibers supplying
the sublingual, submandibular and
lacrimal glands) join the facial nerve
as the nervus intermedius at the cerebellopontine
angle. CN VIII is present
here as well. Lesions at this level
include temporal bone fractures and
infections, schwannomas, neuromas
(cerebellopontine angle tumors) and
vascular compressions, producing
deficits in hearing, balance, tear production
and salivatory flow.2,3,5
The facial and the vestibuloacoustic
(CN VIII) nerves enter the internal
auditory meatus together.1­3
The facial
nerve then departs from the acoustic
nerve to enter the fallopian (facial)
canal, which courses 30 mm through
the temporal bone and incorporates
the geniculate ganglion.2
Lesions that
involve the ganglion include geniculate
ganglionitis. Lesions such as
acoustic neuroma, which involve cranial
nerve VIII, can impair hearing and
facial nerve function and produce
corneal hypoesthesia. Lesions that
begin within the nucleus or along the
fascicles are said to involve the final
common pathway of neural transmission
and are known as lower motor
neuron or peripheral lesions.
The first major branch of CN VII,
the greater superficial petrosal nerve,
traverses the geniculate ganglion, proceeds
forward, traverses the dura
A left facial nerve palsy in a young man,
the result of trauma.
APRIL 15, 2008 REVIEW OF OPTOMETRY 57A
mater of the middle cranial fossa and
synapses in the sphenopalatine ganglion.
The sphenopalatine ganglion
gives rise to postganglionic fibers,
which join the zygomatic and lacrimal
nerves of CN V to innervate the
lacrimal gland. Lesions here impair
reflex tear secretion. It is important to
note that when defective tear production
accompanies CN V (muscles of
mastication) or CN VI palsy, middle
cranial fossa disease is indicated.2,3,5
The stapedius branch of CN VII
arises from the distal segment of the
facial nerve.2,3
Lesions here disable
the ability to dampen sound, producing
hyperacusis. As the facial nerve
continues downward in the facial
canal, the chorda tympani branch arises
from it. The chorda tympani contains
sensory afferent fibers, which
transmit taste sensation from the anterior
two-thirds of the tongue. It also
contains autonomic (parasympathetic
preganglionic) nerve fibers, which
innervate the submandibular and sublingual
salivary glands.2,3
Lesions anywhere
along this pathway cause an
interruption in salivatory flow and the
ability to sense taste from the anterior
two-thirds of the tongue.2,3
Lesions of
the parotid gland must also be investigated
as part of the workup. Sensory
afferents from the external auditory
meatus and a small area of skin
behind the ear transmit pain, temperature
and touch information.2,3
The most common etiology (53%)
of unilateral facial weakness is idio-
pathic.2
The term "Belľs palsy" is
often used to describe idiopathic CN
VII dysfunction, though this remains a
diagnosis of exclusion.1­11
Belľs palsy
may be related to idiopathic inflammation
or may be secondary to viral
infection or vascular compression of
CN VII. Other common causes of
peripheral CN VII palsy include trauma
(21%), cerebellopontine angle
tumor (7%), otitis media, herpes
zoster oticus (Ramsay-Hunt syndrome),
Lyme disease, sarcoidosis,
Guillain-Barré syndrome, EpsteinBarr
virus, parotid neoplasm, syphilis,
diabetes mellitus, herpes simplex
infection, pregnancy and HIV.1­11
Management
The optometric management of a
patient who presents with CN VII
palsy begins with a detailed history
and a cursory evaluation of the 12 cranial
nerves. Close attention should be
given to the affected eyeliďs posture,
corneal wetting (tear break up time),
blink posture, tear quality (sodium fluorescein
staining) and tear quantity
(Schirmer tear testing).
Exposure keratopathy associated
with facial nerve palsy can be managed
with ocular lubricating drops and
ointments. Moisture chamber shields
can be attached to spectacle temples to
create a moist ocular environment and
lessen tear evaporation. Temporary
external eyelid weights may also be of
benefit as a temporary measure in
cases that are likely to resolve or as a
stopgap measure prior to surgical
intervention.7
Since idiopathic facial nerve palsy
is a diagnosis of exclusion, laboratory
testing (Lyme titer, rheumatoid factor,
erythrocyte sedimentation rate, antinuclear
antibody, fluorescent treponemal
antibody absorption test, HIV
titer), echocardiogram, chest X-ray,
lumbar puncture (in patients with suspected
neoplasm), neuroradiologic
studies (computed tomography and
magnetic resonance imaging) and
appropriate referrals (otolaryngology,
neurology, neurosurgery) should be
obtained.1­6
Treatment for peripheral facial
weakness depends upon the etiology
and is usually relegated to the special-
ist.4
For example, treatment of
Ramsay-Hunt syndrome consists of
800 mg acyclovir Q5H, PO for 7­10
days; Lyme disease: 100 mg doxycycline
TID PO for 7­10 days; sarcoidosis:
20­80mg prednisone, PO.
According to Salinas and colleagues,
most of the available evidence from
randomized controlled trials demonstrates
no significant or clear benefit
to treating Belľs palsy with systemic
corticosteroids.9
Allen and Dunn
assert the same position for oral antivi-
rals.10
However, because using these
agents rarely creates complications,
their use in cases of Belľs palsy
remains controversial.
Clinical pearls
* Patients with idiopathic facial
nerve paralysis (Belľs Palsy) typically
complain of acute (24­48 hours) unilateral
facial weakness with a widening
of the palpebral fissure and
impaired ability to close the eye.
* Chronic, slowly progressive
facial nerve palsy suggests a neoplastic
etiology.
* Mobius syndrome is a rare, nonprogressive,
congenital neuromuscular
disorder that presents with multiple
dental and medical complications,
including congenital, bilateral or unilateral
palsies of the sixth, seventh and
eighth cranial nerves.8
* The number-one concern of the
eyecare practitioner is corneal protection
via tears, punctal plugs, moisture
chambers, internal or external weights
or complete or partial tarsorrhaphy.
* Occasionally after injury, some
fibers of CN VII regenerate to erroneously
innervate adjacent structures.
This phenomenon is known as aberrant
regeneration. The result is simultaneous
movements of muscles or
synkinesis (e.g., the corner of the
mouth contracts on attempted eyelid
closure) or the stimulation of glands
supplied by the redistributed branches
of CN VII when the nerve is activated
(e.g., excessive lacrimation upon eating,
known as crocodile tearing or gustolacrimal
tearing).2­5
1. Gurwood AS. The eyelid and neuro-ocular disease. In:
Blaustein BH (ed.) Ocular Manifestations of Neurologic
Disease, Philadelphia: Mosby, 1996, pp. 127­51.
2. Gurwood AS, Tasca JM, Kulback E. A review of cranial
nerve VII palsy with emphasis on Belľs palsy. South J
Optom 1996;14(3):13­17.
3. May M, Galetta S.The facial nerve and related disorders
of the face. In: Glaser JS (ed.), Neurophthalmology (2nd
ed.), Philadelphia: J. B. Lippincott Co., 1990, pp. 239­77.
4. Savino PJ, Sergot RC. Neuroophthalmology: Isolated
seventh nerve palsy. In: Rhee DJ, Pyfer MF, The Wills Eye
Manual (3rd ed.), Philadelphia: Lippincott Williams &
Wilkins 1999, pp. 290­4.
NEURO-OPHTHALMICDISEASE
58A REVIEW OF OPTOMETRY APRIL 15, 2008
5. Bajandas FJ, Kline LB. Seven Syndrome of the Seventh
(Facial) Nerve. In: Bajandas FJ, Kline LB (eds.), Neuro-ophthalmology
Review Manual (3rd ed.), Thorofare, NJ: Slack,
1988:151­6.
6. Danielides V, Skevas A, van-Cauwenberge P, et al. Facial
nerve palsy during pregnancy. Acta Otolaryngol Belg
1996;50(2):131­5.
7. Zwick OM, Seiff SR. Supportive care of facial nerve
palsy with temporary external eyelid weights. Optom
2006;77(7):340­2.
8. Sensat ML. Mobius syndrome: A dental hygiene case
study and review of the literature. Int J Dent Hyg
2003;1(1):62­7.
9. Salinas RA, Alvarez G, Ferreira J. Corticosteroids for
Belľs palsy (idiopathic facial paralysis). Cochrane Database
Syst Rev 2004;18(4):CD001942.
10. Allen D, Dunn L.Aciclovir or valaciclovir for Belľs palsy
(idiopathic facial paralysis). Cochrane Database Syst Rev
2004;1(3):CD001869.
11. Gilbert SC. Belľs palsy and herpesviruses. Herpes
2002;9(3):70­3.
HEMIFACIAL SPASM
Signs and symptoms
While patients with hemifacial
spasm (HFS) are aware of facial contracture,
it is typically not painful.
Half of the patienťs face is usually
seen in constant, spastic motion.1,2
The
spasms often start in the upper portion
of the face and progress downward,
increasing in involvement and fre-
quency.1,2
The spasms are usually brief,
only lasting seconds but ongoing and
often persistent during sleep. If it prevents
eyelid opening, symptoms will
include lost functional vision, corresponding
losses of visual field and
stereopsis. Patients are often predominantly
concerned with cosmetic
appearance. HFS frequently affects
middle-aged individuals ages of
40­60.1
In one study of 230 patients
clinically diagnosed with HFS, 6.5%
had young-onset HFS and 21.7% had
old-onset HFS; the remaining patients
in the study were uncategorized
because their acquiring the condition
took place during the classically recognized
time period. In young-onset
HFS, the mean age of onset of symptoms
was 26 years, with a range of
6­30 years. Eighty percent of the
cases occurred in women. Seventyfive
percent of the young-onset cases
demonstrated neurovascular compression
of the root exit zone of the facial
nerve. While the prevalence of hypertension,
diabetes mellitus and other
associated vascular disorders in the
late-onset group was higher than in
young-onset group, the clinical features
and frequency of compression
between the two groups were similar.
Genetic, anatomic or other unidentified
factors are the most likely contributors
to young-onset HFS, and
hypertension may be a risk factor
involved in late-onset HFS.1,2
Pathophysiology
The motor division of the seventh
cranial nerve (CN VII) is responsible
for delivering the voluntary motor
innervations to the muscles of facial
expression and to the stapedius muscle
of the inner ear (helping to dampen
loud sounds).3­8
Irritation by adjacent
or direct infection, infiltration,
inflammation or compression of CN
VII nuclei or its fascicles can produce
involuntary contracture of the affected
region.1,2,9­15
The facial motor nuclei
are located in the lower pontine
tegmentum and possess an intimate
relationship with the trigeminal nerve
(CN V), abducens nuclei (CN VI),
cochlear nuclei (CN VIII), medial
longitudinal fasciculus (MLF), paramedian
pontine reticular formation
(PPRF), descending corticospinal
fibers and descending sympathetic
fibers.4,5
The facial nucleus contains
four separate cell groups that innervate
specific muscle groups. Motor
axons exit the nucleus dorsally, loop
around the CN VI nuclei and emerge
into the subarachnoid space from the
lateral aspect of the pons.4,5
Fibers
from the superior salivatory and
lacrimal nuclei (parasympathetic preganglionic
fibers supplying the sublingual,
submandibular and lacrimal
glands) join the facial nerve as the
nervus intermedius at the cerebellopontine
angle.4,5
CN VIII is present
here as well. Lesions capable of
impinging on the nerve at this level
include temporal bone fractures and
infections, schwannomas, neuromas
(cerebellopontine angle tumors) and
vascular compressions. These injuries
may concomitantly produce deficits
in hearing, balance, tear production
and salivatory flow.4,5
The facial and the vestibuloacoustic
(CN VIII) nerves enter the internal
auditory meatus together.3­5
The facial
nerve then departs from the acoustic
nerve to enter the fallopian (facial)
canal, which courses 30 mm through
the temporal bone and incorporates
the geniculate ganglion.4
Lesions that
may affect the homeostasis here
include geniculate ganglionitis
(Ramsey-Hunt syndrome or herpes
zoster oticus).3­6
The first major
branch of CN VII, the greater superficial
petrosal nerve, traverses the geniculate
ganglion, proceeds across the
dura mater of the middle cranial fossa
and synapses in the sphenopalatine
ganglion.4,5
The sphenopalatine ganglion
gives rise to postganglionic
fibers, which join the zygomatic and
lacrimal nerves of CN V to innervate
the lacrimal gland. Lesions here, in
addition to their effects on the facial
nerve, impair reflex tear secretion.4­6
The portion of the facial nerve containing
the motor fibers that innervate
the muscles of facial expression exits
the stylomastoid foramen and enters
the substance of the parotid gland
before distribution, making lesions of
the parotid gland part of the differential
diagnosis.4,5
There is considerable evidence that
primary hemifacial spasm (HFS) is in
almost all cases related to vascular
compression of the facial nerve at its
root within the exiting region of brainstem
(root exit zone).14
The offending
vessels include the vertebral arteries,
the posterior inferior cerebellar arteries,
the anterior inferior cerebellar arteries
and, in some circumstances, an artery
of uncertain origin.14
Clinical and electrophysiological
features suggest the
presence of mechanical mechanisms at
the level of the neural fibers, demyelinating
pathology and functional
changes in nuclear cells, which cause
them to assume a posture of hyperactivity
within the facial nucleus.9,10,14
Measured lateral spread responses
APRIL 15, 2008 REVIEW OF OPTOMETRY 59A
(LSR) elicited by this excessive stimulation
of the facial-nerve branches testify
to the existence of these electrophysiological
disturbances.9,10
Although
vascular compression is accepted as a
main producer of HFS, facial nucleus
supersensitivity is also deemed to be a
cause of emphatic HFS.14
Management
Treatment of the contractures of
HFS is aimed at treating the underlying
cause. Detailed evaluation is
mandatory in all patients with newly
acquired cases of HFS or with essential
blepharospasm, with or without
apraxia. Magnetic resonance imaging
(MRI) and three-dimensional magnetic
resonance angiography (MRA) are
proven techniques for identifying
causes and predicting the prognosis of
HFS.16,17
When HFS spasm is produced
by abnormal vascular compression
or tumor, the area should be
surgically decompressed by neurosurgical
specialists.2,11­14
Gamma knife
radiosurgery, a relatively new modality,
has been recently used in a patient
with HFS secondary to an intracanalicular
vestibular schwannoma.6
The resolution of the spasm and cessation
of the tumor's growth were
achieved with a single session of
gamma knife radiosurgery.8
Microvascular decompression
(MVD) constitutes a potentially curative
treatment. A sponge or barrier is
placed between a compressing vessel
and the facial nerve.9,10
In one study of
33 patients, LSR disappeared with
vascular decompression in 23 patients,
with no evidence of LSR upon surgical
closure.10
The other 10 patients had
evidence of LSR following the surgical
conclusion. In the study, the
authors considered 20 of the 23 LSRabsent
patients clinically cured at the
three-month follow-up. Three patients
continued to present with mild/moderate
spasm. At the 10-month followup,
two of the remaining LSR-absent
patients were free of spasm, with only
one having recurrence.10
In contradistinction,
seven of the 10 LSR-present
patients exhibited cure at the threemonth
follow-up, with all 10 meeting
the criteria for cure at the 10-month
evaluation. This underscores the
thinking that HFS not only results
from mechanical pulsations of an
elongated artery positioned against
the CN VII root exit zone, but also that
elements of demyelination of the
nerve and acquired neural hyperactivity
are generated by the neurovascular
compression.9,10
In extreme cases, facial nerve
decompression with exposure of the
facial nerve from the brainstem to the
parotid gland can be accomplished
without injury to the nerve, tympanic
membrane, external auditory canal or
other structures.12
The procedure has
had good results for patients with
facial paralysis from Belľs palsy, herpes
zoster oticus, infection, hemifacial
spasm, temporal bone fracture and
tumors. Access occurs through the
mastoid, middle cranial fossa and
retrolabyrinthine fossa.12
For completeness,
myectomy, either surgical
(removal of muscular tissue) or neurochemical
(elimination of axons via
injection of neurotoxin:doxorubicin),
is mentioned in the literature as a
potential remedy.18
Acupuncture has shown some benefit
in these cases. Appropriate
needling can markedly improve the
blood supply to the vertebral basilar
artery, increase the cerebral blood
flow, relax the spasm of the vascular
smooth muscles and create the effects
of resuscitating and tranquilizing the
mind, dredging channels and relieving
spasm and pain.13
Clinical pearls
* Chronic, slowly progressive HFS
with the development of or conversion
to facial nerve palsy suggests a spaceoccupying
lesion.
* The presence or a parotid mass
suggests tumor of the gland.
* When defective tear production
accompanies CN V (muscles of mastication)
or CN VI palsy, middle cranial
fossa disease should be suspected.
* Tardive dyskinesia (late twitching
secondary to exposure to antipsychotic
medications) can produce similar
symptoms.
* Facial synkinesis, abnormal movements
created by aberrant sprouting of
axons following injury (similar to the
"jaw wink" phenomenon) is a separate
entity.
1. Tan EK, Chan LL. Young onset hemifacial spasm. Acta
Neurol Scand 2006;114(1):59­62.
2. Nakamura T, Osawa M, Uchiyama S. Arterial hypertension
in patients with left primary hemifacial spasm is associated
with neurovascular compression of the left rostral
ventrolateral medulla. Eur Neurol 2007;57(3):150­5.
3. Gurwood AS.The eyelid and neuro-ocular disease. In:
Blaustein BH (ed.) Ocular Manifestations of Neurologic
Disease, Philadelphia: Mosby, 1996, pp. 127­51.
4. Gurwood AS, Tasca JM, Kulback E. A review of cranial
nerve VII palsy with emphasis on Belľs palsy. South J
Optom 1996;14(3):13­17.
5. May M, Galetta S.The facial nerve and related disorders
of the face. In: Glaser JS (ed.), Neurophthalmology (2nd
ed.), Philadelphia: J. B. Lippincott Co., 1990, pp. 239­77.
6. Bajandas FJ, Kline LB. Seven Syndrome of the Seventh
(Facial) Nerve. In: Bajandas FJ, Kline LB (eds.), Neuro-ophthalmology
Review Manual (3rd ed.),Thorofare, NJ: Slack,
1988:151­6.
7. Jowi JO, Matende J, Macharia MI, et al. Hemifacial spasm:
Case report. East Afr Med J 2006 ;83(7):401­4.
8. Peker S, Ozduman K, Kiliç T, et.al. Relief of hemifacial
spasm after radiosurgery for intracanalicular vestibular
schwannoma. Min Invas Neurosurg 2004;47(4):235­7.
9. Sindou MP. Microvascular decompression for primary
hemifacial spasm. Importance of intraoperative neurophysiological
monitoring. Acta Neurochir (Wien)
2005;147(10):1019­26.
10. Hatem J, Sindou M,Vial C. Intraoperative monitoring
of facial EMG responses during microvascular decompression
for hemifacial spasm. Prognostic value for long-term
outcome: A study in a 33-patient series. Br J Neurosurg
2001;15(6):496­9.
11. James ML, Husain AM. Brainstem auditory evoked
potential monitoring:When is change in waveV significant?
Neurol 2005;2265(10):1551­5.
12. Pulec JL. Total facial nerve decompression: Technique
to avoid complications. Ear Nose Throat J
1996;75(7):410­5.
13. Liu Z, Fang G. Mind-refreshing acupuncture therapy
for facial spasm, trigeminal neuralgia and stubborn facial
paralysis. J Tradit Chin Med 2004;24(3):191­2.
14. Suthipongchai S, Chawalparit O, Churojana A, et al.
Vascular loop compressing facial nerve in hemifacial
spasm: demonstrated by 3D-phase contrast magnetic resonance
angiography in 101 patients. J Med Assoc Thai
2004;87(3):219­24.
15. Harrison AR. Chemodenervation for facial dystonias
and wrinkles. Curr Opin Ophthalmol 2003;14(5):241­5.
16. Tan EK, Chan LL, Lim SH, et al. Role of magnetic resonance
imaging and magnetic resonance angiography in
patients with hemifacial spasm. Ann Acad Med Singapore
1999;28(2):169­73.
17. Ho SL, Cheng PW,Wong WC, et al.A case-controlled
MRI/MRA study of neurovascular contact in hemifacial
spasm. Neurol 1999;53(9):2132­9.
18. Faucett DC. Essential blepharospam. In: Yanoff M,
Duker JS, Ophthalmology (second ed.), Philadelphia:
Mosby, 2004, pp. 695­7.
NEURO-OPHTHALMICDISEASE
60A REVIEW OF OPTOMETRY APRIL 15, 2008
HERPES ZOSTER
Signs and symptoms
Herpes zoster rash can affect any
dermatome on the body, but it most
commonly resides in the facial and
midthoracic-to-upper lumbar der-
matomes.1,2
The rash appears as erythematous
macules and papules, which
progress into vesicles within 12­24
hours. The rash progresses into pustules
at days three and four, with
crusting of the pustules at seven to
10 days. This rash is often accompanied
by a regional lym-
phadenopathy.1­8
Herpes zoster
patients frequently present with a
prodrome of fever, malaise,
headache and dysesthesia over one
to four days prior to developing any
visible cutaneous involvement.1
In
fact, it may take 48­72 hours after
the onset of pain for any sign of rash
to emerge. Burning pain classically
precedes rash eruption and can persist
for several months after the rash
resolves.1­12
The pain preceding the
systemic form of the rash is often misdiagnosed
as myocardial infarction,
ulcerative appendicitis, herniated intervertebral
disc or temporal arteritis, to
name a few.2
Following resolution of
the crusting pustules, about 9% of all
patients suffer from extreme pain
known as postherpetic neuralgia.1­8
Severe and possibly debilitating pain
remains, despite the absence of active,
visible skin lesions.1­12
The presentation of herpes zoster
ophthalmicus may vary from dermatologic
involvement alone to ocular manifestations
such as lid retraction, keratitis,
scleritis, uveitis, glaucoma, retinitis
(acute retinal necrosis and progressive
outer retinal necrosis), optic neuritis
and panophthalmitis. When ophthalmic
manifestations arise, the condition
is termed herpes zoster ophthalmicus
(HZO) and occurs in 7% of
all zoster patients.2,4
Anecdotally, cases
involving the eye have been observed
to produce adnexal pain over months,
without iritis, uveitis or vesicular
breakout, making the chief complaint a
mystery until the skin manifestations
appear. The lesions of herpes zoster
generally completely resolve within
one to three weeks.6­7
Severe complications
include pneumonia, other collateral
bacterial infections, seizure activity
and encephalopathy.8,9
Pathophysiology
Varicella zoster virus (VZV) causes
chickenpox.1­12
Herpes zoster represents
a separate clinical condition
caused by the same virus.7
Both conditions
are characterized by areas of
intense dermatomal pain followed by a
rash 1 to 3 days later.1
The varicella
zoster virus is a member of the herpes
virus family. Varicella is spread by
direct contact with active skin lesions
or airborne via droplets and is highly
contagious.1­12
The virus has an affinity
for the upper respiratory tract and typically
enters the human system through
the conjunctiva and/or nasal or oral
mucosa, producing the characteristic
pox appearance.1­10
When the hosťs
immunity fails, the dormant virus
leaves the confines of the dorsal route
ganglion where it lies dormant to produce
shingles (the zoster presentation)
upon recurrence.1­12
Chickenpox is usually a mild, selflimiting
disease of childhood. It is
more severe when it develops in
adults.11
One study reported that for
every 100,000 people who contract the
malady, four to nine will die from it,
and most of the deaths are adults.11
Chickenpox infection during pregnancy
can lead to a severe maternal ill-
ness.11
Further, the disease seems to be
more virulent in non-pregnant
women.11
Interestingly, while most
women who contract chickenpox
during pregnancy give birth to
healthy children, some babies are
susceptible to in utero infection.11
Ninety percent of the population
develops serological infection by
adolescence, with nearly 100% of
the population having some evidence
of antibodies to the disease
by age 60.1
Only 20% of patients
suffer reactivation after initial
infection.2
Any condition that
decreases immune status, such as
human immunodeficiency virus
infection, chemotherapy, malignancy
and long-term oral corticosteroid
or other immunosuppressant
use, increases the risk of herpes zoster
activation. A second reactivation is
even more rare and occurs mostly in
immunosuppressed patients such as
organ transplant recipients or those
who suffer from AIDS or neoplasm.1
Management
Herpes zoster is managed using
orally administered antiviral medications
such as acyclovir (800 mg PO 5
times a day), famciclovir (500 mg PO
TID) and valacyclovir (1,000 mg PO
TID) for one week.1,10,12,13
The antiviral
medications seem most effective when
initiated within the first 72 hours of the
onset of the rash, especially for reducing
the degree of post-herpetic neural-
gia.12
Acyclovir has been documented
as effective in preventing disease reactivation;
however, the proper dose,
duration and circumstances of its use
are still controversial.10
Orally administered corticosteroids
are reputed to reduce pain and potentially
the onset of postherpetic neural-
gia.10,12
Since the disease is self-limiting,
most care is palliative, including
The many faces of herpes zoster ophthalmicus.
OCULOSYSTEMIC DISEASE
APRIL 15, 2008 REVIEW OF OPTOMETRY 61A
the use of astringents such as calamine
lotion or aluminum acetate solution
(Domeboro, Bayer) to minimize weeping
and soothe the affected area, and
topical antibiotic creams and ointments
to prevent secondary infection.
Patients with postherpetic neuralgia
may require narcotics for pain con-
trol.12
Tricyclic antidepressants and
anticonvulsants in low dosages are
potential options for unremitting
pain.12
Capsaicin cream (based on the
chemical in chili peppers that makes
them hot), lidocaine patches and
injectable nerve blocks can be used in
the worst cases.12
Antiviral agents can play role in
preventing varicella zoster disease in
immunocompetent and immunosuppressed
patients.10
As with herpes
zoster, acyclovir has been documented
as effective in preventing disease
reactivation, but the proper dose,
duration and circumstance of its uses
are controversial.10
Since VZV-specific cell-mediated
immunity and cell-mediated immunity
in general declines with age, it should
be expected that the incidence of herpes
zoster increases with age. This may
also explain the increased incidence of
zoster in immunocompromised individuals
or those who are undergoing
immunosuppressive therapy.7,8
Therefore, any patient younger than 50
who presents with signs of an acute
zoster infection must be referred to
rule out an immunocompromised state.
Clinical pearls
* Once infection with chickenpox
occurs, it usually confers lifelong protection
against a subsequent attack.
Secondary infections have been
reported, but they usually only occur
when the initial episode was mild.1­10
* The zoster virus has a high affinity
for the first (ophthalmic) division
of the trigeminal nerve. This manifests
as Hutchinson's sign, a series of
skin lesions along the nose (and ending
at the tip of the nose) that respect
the vertical midline.5
* There is evidence suggesting that
varicella can be prevented by vaccination.
Vaccine is about 80­85% effective
against the disease and highly
(more than 95%) effective in preventing
severe disease.10
* A significant issue is postherpetic
neuralgia and decreases the quality
of life for patients experiencing this
condition.
1. Gurwood AS, Savochka J, Sirgany BJ. Herpes zoster ophthalmicus.
Optom 2002;73(5):295­303.
2. McCrary ML,Severson J,Tyring SK.Varicella zoster virus.JAm
Acad Dermatol 1999;41(1):1­14.
3. Ragozzino MW, Melton LJ III, Kurland LT, et al. Populationbased
study of herpes zoster and its sequelae. Medicine 1982;
61:310­6.
4. Karbassi M, Raizman M, Schuman J. Herpes zoster ophthalmicus.
Surv Ophthalmol 1992;36(6):395­08.
5. Cobo M,Foulks GN,LiesegangTJ,et al.Observations on the
natural history of herpes zoster ophthalmicus. Curr Eye Res
1987;6:195­9.
6. Burgoon CF, Burgoon JS, Baldridge GD.The natural history
of herpes zoster. JAMA 1957;164:265­269.
7. Arvin AM. Investigations of the pathogenesis of Varicella
zoster virus infection in the SCIDhu mouse model. Herpes
2006;13(3):75­80.
8. Carreo A, López-Herce J, Verdú A, et al. Varicella
encephalopathy in immunocompetent children.J Paediatr Child
Health 2007;43(3):193­5.
9. Heininger U, Seward JF. Varicella. Lancet
2006;368(9544):1365­76.
10. Boeckh M. Prevention of VZV infection in immunosuppressed
patients using antiviral agents.Herpes 2006;13(3):60­5.
11. No author listed.Chickenpox,pregnancy,and the newborn.
DrugTher Bull. 2005;43(9):69­72.
12. Stankus SJ, Dlugopolski M, Packer D. Management of herpes
zoster (shingles) and postherpetic neuralgia. Am Fam
Physician 2000;61(8):2437­48.
13. Martin JB. Viral encephalitis and prion diseases. In:
Fauci AS, Braunwald E, Isselbacher KJ, et al.,. Harrison's
Principles of Internal Medicine, (14th ed.), New York:
McGraw-Hill, 1998, pp. 1023­31.
GARDNER'S SYNDROME
Signs and symptoms
Gardner's syndrome, a variation
of familial adenomatous
polyposis (FAP), is a multisystem
disorder characterized by a triad
of findings: polyps of the gastrointestinal
(GI) tract, multiple
osteomas (benign tumors of bony
origin) and a variety of soft tissue
tumors.1­4
There may also be a predisposition
to thyroid and periampullary
cancers.2
Patients may present
at any age, from infancy to late in
life, with a variety of symptoms.1
Gardner's syndrome is of interest to
eyecare practitioners due to a high
association with congenital hypertrophy
of the retinal pigment epithelium
(CHRPE). These are typically benign
and asymptomatic fundus lesions, normally
discovered on routine ophthalmoscopy.
CHRPE is present in
approximately 70% of patients with
FAP and can be the initial diagnostic
indication of Gardner's syndrome.4
The characteristic ocular presentation
is bilateral and involves two to 30 pigmented
lesions, averaging about six
per eye.5,6
This unique form of CHRPE
(referred to as multiple CHRPE or
atypical CHRPE) seems to have a
slight predilection for the retinal
periphery. The lesions tend to be
small: most are less than 0.5 disc
diameter (0.75 mm).7
Ophthalmoscopically,
there is a fair amount of
variability; individual lesions may
show differences in pigmentation
(gray to black or amelanotic), shape
(round, oval, tear-shaped, bean-shaped
or linear) and the presence or absence
of a surrounding halo.5­7
GI-related symptoms of Gardner's
syndrome may include episodes of
rectal bleeding and/or mucous discharge,
diarrhea and abdominal pain.
Weight loss, anemia and intestinal
obstruction typically portend the presence
of cancer. As many as 25% of
patients with the syndrome may have
OCULOSYSTEMICDISEASE
Multiple CHRPE with wide variation in size and
shape should be considered suspicious for
Gardner's syndrome, especially if the condition is
bilateral.
62A REVIEW OF OPTOMETRY APRIL 15, 2008
colorectal cancer at the time of initial
diagnosis.2
Non-GI-related symptoms
can be diverse: desmoids (benign but
locally aggressive fibroid tumors of
connective tissue), which can cause
focal swelling, pain or bleeding; dental
abnormalities associated with tooth or
jaw pain; thyroid carcinoma which
presents as a tender neck mass with
hoarseness and symptoms of hypo- or
hyperthyroidism. Since the soft tissue
and bone abnormalities may predate
the development of actual colon
polyps in Gardner's syndrome by as
much as 10 years, patients may report
a history of seemingly unrelated nondescript
symptoms.2,3
Pathophysiology
Gardner's syndrome is considered a
rare hereditary disorder, with an
approximate incidence of 1 in 14,000
live births.2
The condition displays an
autosomal dominant inheritance pattern
with variable penetrance. It is
believed that Gardner's syndrome and
FAP represent variants of the same
disorder, since both conditions display
an association with a genetic
mutation in the adenomatous polyposis
coli (APC) gene.8
Although most
cases show familial clustering, onethird
are believed to result from spontaneous
mutations.1
Precisely what
determines the extent and variability
of the extracolonic manifestations in
Gardner's syndrome is unknown;
however, some have proposed that
environmental factors such as diet,
exercise and smoking play a role in
the disease pathogenesis.1,2,9
Management
Gardner's syndrome represents a
potentially life-threatening disease
that can cause great morbidity to a
variety of organ systems. In cases
where this condition is suspected, the
physician is obligated to initiate
appropriate medical testing. Specific
laboratory studies for Gardner's syndrome
involve genetic testing to identify
the APC gene and its associated
mutation.2,6
Also, these patients must
be evaluated by sigmoidoscopy or
colonoscopy to rule out the presence
of polyps and other associated pathol-
ogy..2,10
Additional testing may include:
complete blood count with differential
and platelets; carcinoembryonic antigen;
liver function (to rule out metastasis);
thyroid function; abdominal CT
or MRI; X-rays of the chest, skull and
teeth (for osteomas) and upper gastrointestinal
endoscopy.11
Treatment options for Gardner's
syndrome are limited. Regular administration
of oral nonsteroidal antiinflammatory
agents (e.g., sulindac,
indomethacin) have demonstrated
some success in diminishing the size
and number of polyps.1,12
Recent clinical
trials with celecoxib (Celebrex,
Pfizer) 400 mg daily have shown that
this drug significantly prevents the
development and growth of colorectal
adenomatous polyps in patients with
FAP; unfortunately, celecoxib also
carries a substantial risk of adverse
cardiovascular events and therefore
cannot be routinely recommended for
this indication.13,14
Tamoxifen or
toremifene may be helpful in managing
unresectable desmoid tumors.1
Despite medical therapy, virtually
all cases of Gardner's syndrome ultimately
require surgery to prevent the
development of colon cancer.
Treatment options include total proctocolectomy
(surgical removal of the
rectum and colon) with permanent terminal
ileostomy or subtotal colectomy
with reconstructive anastomosis sur-
gery.1
Prophylactic colon resection is
recommended even in asymptomatic
family members demonstrating signs
of the disease, and it is typically performed
by the time the patient is 20
years old.1
Clinical pearls
* Multiple CHRPE is one of the
earliest diagnostic features of
Gardner's syndrome and is seen in
more than one-half of patients with
FAP. Patients who display atypical or
bilateral CHRPE should be evaluated
for the possibility of polyposis, especially
if they report a positive family
history of colon polyps or cancer.10
* Gardner's syndrome is a multisystem
disorder, and as such it
requires care by a multidisciplinary
healthcare team. In addition to receiving
ophthalmic examination, individuals
with this condition may warrant
consultative evaluation by specialists
in the following medical areas: colorectal
surgery, dentistry, dermatology,
endocrinology, gastroenterology,
internal medicine, neurology, oncology,
orthopedic surgery and proctology.
* Colon cancer will inevitably
develop in all individuals with
Gardner's syndrome unless prophylactic
surgery is performed. Even
after subtotal colectomy, there is a significant
possibility of recurrence;
hence, these patients need to be monitored
for life.
1. Fotiadis C, Tsekouras DK, Antonakis P, et al. Gardner's
syndrome: A case report and review of the literature.
World J Gastroenterol 2005;11(34):5408­11.
2. Nandakumar G, Morgan JA, Silverberg D, Steinhagen
RM. Familial polyposis coli: Clinical manifestations, evaluation,
management and treatment. Mt Sinai J Med
2004;71(6):384­91.
3. Cruz-Correa M, Giardiello FM. Diagnosis and management
of hereditary colon cancer. Gastroenterol Clin
North Am 2002; 31(2):537­49.
4. Traboulsi EI. Ocular manifestations of familial adenomatous
polyposis (Gardner syndrome). Ophthalmol Clin
North Am 2005;18(1):163­6.
5. Tiret A, Parc C. Fundus lesions of adenomatous polyposis.
Curr Opin Ophthalmol 1999;10(3):168­72.
6. Tiret A, Sartral-Taiel M, Tiret E, Laroche L. Diagnostic
value of fundus examination in familial adenomatous polyposis.
Br J Ophthalmol 1997;81(9):755­8.
7. Traboulsi EI. Ocular manifestations of familial adenomatous
polyposis (Gardner syndrome). Ophthalmol Clin
North Am 2005;18(1):163­6.
8. Nishisho I, Nakamura Y, Miyoshi Y, et al. Mutations of
chromosome 5q21 genes in FAP and colorectal cancer
patients. Science 1991;253(5020):665­9.
9. Baglioni S, Genuardi M. Simple and complex genetics of
colorectal cancer susceptibility. Am J Med Genet C Semin
Med Genet 2004;129(1):35­43.
10. Holmes RL,Ambasht SK, Kelley PS. Index case of familial
adenomatous polyposis revealed by congenital hypertrophy
of the retinal pigment epithelium. Ann Intern Med
2005;143(8):618­9.
11. Tidy C. Familial polyposis of the colon--Gardner's syndrome.
2005. http://www.patient.co.uk/showdoc/40001234.
Accessed 13 October 2007.
12. Giardiello FM,YangVWW, Hylind LM. Primary chemoprevention
of familial adenomatous polyposis with sulindac.
N Engl J Med 2002; 346(14):1054­9.
13. Bertagnolli MM, Eagle CJ, Zauber AG, et al. (APC Study
Investigators). Celecoxib for the prevention of sporadic
colorectal adenomas. N Engl J Med 2006;355(9):873­84.
14. Arber N, Eagle CJ, Spicak J, et al. (PreSAP Trial
Investigators). Celecoxib for the prevention of colorectal
adenomatous polyps. N Engl J Med 2006;355(9):885­95.
ANTIPHOSPHOLIPID ANTIBODY
SYNDROME
Signs and symptoms
Patients with antiphospholipid antibody
syndrome (APAS) are typically
female and young.1­6
Rarely, children
are affected.7
Up to 10% of healthy
individuals have circulating antiphospholipid
antibodies.8
Approximately
50% of patients with antiphospholipid
antibodies also have systemic
lupus erythematosus (SLE) or
other autoimmune diseases.3,8,9
However, in many cases, APAS
exists without associated autoimmune
disease.1,3,5,8
The most common
conditions that result from
APAS that affect the eye and visual
system are arterial or venous
thrombosis with resultant
ischemia. This manifests as central
retinal vein or artery occlusion
(CRVO or CRAO), papillophlebitis,
anterior ischemic optic
neuropathy (AION), migraine,
ophthalmoparesis and diplopia,
amaurosis fugax, isolated retinal hemorrhages
and cotton wool spots, and
retinal neovascularization.9­29
While
these conditions typically occur in elderly
patients, the patient with APAS
experiences them at a younger age,
typically under 50 years.
In addition to ocular manifestations,
thrombi are often present in
other systems. Venous thromboses of
the arms and legs, pulmonary
embolism, sagittal, pelvic, mesenteric,
portal, and axillary thromboses
have all been encountered in APAS.
Transient ischemic attack (TIA) and
cerebrovascular accidents are the
most common occurrences from
thrombosis in the arterial system.
Another systemic finding is thrombocytopenia
(reduced platelet
count).5,6,8,30­37
A common and in many cases
defining event in APAS is recurrent
pregnancy loss that can occur in any
trimester. Preeclampsia and intrauterine
growth retardation have also been
found to be associated with APAS.5,6,8,33
Pathophysiology
Antiphospholipid antibodies are a
group of circulating antibodies that
include anticardiolipin antibody, lupus
anticoagulant, and the Biologic False
Positive Test for Syphilis (BFP-TS).
These antibodies are directed against
phospholipid binding proteins, which
prolong phospholipid-dependent
coagulation assays.8
In this condition,
phospholipids present in cell membranes
are erroneously identified by
the body as foreign; consequently, the
body produces antibodies to them. The
antibodies appear to have an affinity
for the cell membranes found in
platelets, vessel endothelial cells, and
clotting factors.1,5,8,33
APAS is an autoimmune disorder
with two forms: primary and secondary.
Antiphospholipid antibodies (anticardiolipin
antibodies and lupus anticoagulant)
are known to occur
commonly in patients with SLE.3,8,9,37
When these antibodies occur in the
presence of SLE, it is considered a
secondary syndrome.
Not until 1985 did Hughes identify
these antibodies in seemingly normal
patients experiencing thrombotic
events and pregnancy loss in the
absence of SLE.39
This primary form
exists in the absence of clinically or
serologically proven autoimmune disease
and has been termed Primary
Antiphospholipid Antibody Syndrome
and occasionally referred to as Hughes
Syndrome.1,3,33
APAS is diagnosed by
arterial and venous thrombosis, pregnancy
loss and/or thrombocytopenia
in the presence of lupus anticoagulant
and anticardiolipin antibodies.33
The
method of promoting thrombosis by
the antiphospholipid antibodies is
unclear. Thrombosis appears to be the
cause of pregnancy loss.8
Anticardiolipin antibody is
one of the few autoantibodies in
which subtypes can be identified.
These subtypes are IgM, IgG and
IgA.38­44
Cardiolipin, present in
mitochondria, is actually unlikely
to be the offending antigen.
However, because antiphospholipid
antibodies cross-react with
other phospholipids, cardiolipin
serves as a representative antigen.
IgG antibodies are associated
with thrombosis and pregnancy
loss. IgM antibodies are
associated with thrombosis and
hemolytic anemia. Most patients with
APAS have moderate-to-high levels of
IgG anticardiolipin antibody levels.38­44
Lupus anticoagulant, an antiphospholipid
antibody originally discovered
in SLE, is an immunoglobulin
(either IgG or IgM) that agglutinates
phospholipids present in plasma clotting
factors and subsequently prevents
their participation in clotting. Lupus
anticoagulant inhibits conversion of
prothrombin to thrombin, prolonging
in vitro clotting time as measured by
the prothrombin time (PT), partial
thromboplastin time (PTT), Kaolin
clotting time and dilute Russell Viper
Venom time.38­44
Curiously, while this
antibody prolongs clotting time in
vitro, in vivo it appears to promote
thrombosis.43
Lupus anticoagulant
appears to be the antibody most asso-
OCULOSYSTEMICDISEASE
Papillophlebitis/CRVO in a patient with high anticardiolipin
antibodies.
PhotocourtesyofSarahHill,OD.
APRIL 15, 2008 REVIEW OF OPTOMETRY 63A
64A REVIEW OF OPTOMETRY APRIL 15, 2008
ciated with thrombosis.33,38,41,42
The Venereal Disease Research
Laboratory (VDRL) test for syphilis
was the first test to detect an antiphospholipid
antibody. The phospholipid
antigen involved here caused erroneous
reactivity on this test. Patients
with this antigen tested false-positive
for syphilis; consequently, this
antiphospholipid antibody was named
the Biologic False Positive Test for
Syphilis. Patients with autoimmune
disorders frequently will test falsepositive
for syphilis on VDRL test-
ing.8,45
However, those with with BFPTS
do not appear to have a significant
risk for thrombosis, so BFP-TS is not
strongly associated with APAS.8,45
Management
While it appears that rheumatologists
and other primary care physicians
are aware that patients with
APAS can have ocular manifestations,
many ophthalmic practitioners often
don't associate ocular thrombosis with
APAS, and consequently don't test for
these antibodies or suggest its inclusion
as a diagnostic possibility. APAS
must be considered, however, in cases
of retinal vascular occlusion and other
thrombotic conditions in young
patients. It should be especially considered
in unusual thrombotic events
such as recurrent or bilateral artery or
vein occlusion, or with combined artery
and vein occlusion (especially if there is
no history of vascular disease)--particularly
if the patient is young.9­29
Patients
with a history of thrombotic conditions
(retinal vein or artery occlusions, TIA,
amaurosis fugax), thrombocytopenia, or
autoimmune disorders should be
investigated for APAS.
Testing includes a complete blood
count with differential, prothrombin
time (PT), activated partial thromboplastin
time (aPTT), antinuclear antibody
(ANA), ELISA anticardiolipin
antibody assay, Dilute Russell Viper
Venom Time (DRVVT), plasma clot
time or kaolin clot time for the lupus
anticoagulant. The diagnosis of this
condition requires positive serology
either for the lupus anticoagulant or
anticardiolipin antibody (positive anticardiolipin
antibody ELISA) on two
separate occasions at least eight weeks
apart.42
Beyond the positive serology,
there must also be thrombocytopenia,
thrombotic disease (such as retinal
vein occlusion, for example) or (recurrent)
pregnancy loss.5,8,33
In patients with ocular manifestations
of APAS, standard management
is undertaken for each condition.
Patients with thrombotic events arising
from APAS may potentially experience
recurrent thrombosis with
resultant morbidity, including cerebrovascular
accident and even death. It
has been recommended that APAS
should also be managed so as to
improve outcomes as well as to reduce
recurrences. Oral anticoagulants such
as heparin or low-dose aspirin therapy
(80­100mg/day) are typically
employed.1,5,8,40,46,47
In cases in which
antiplatelet therapy is insufficient and
thrombotic events recur, high doses of
oral corticosteroids and possibly other
immunosuppressants such as cyclophosphamide,
are used in conjunction
with low dose aspirin therapy.1,5,8
Clinical pearls
* Primary APAS is a relatively
newly discovered condition. It must
become part of the differential diagnosis
in thrombotic conditions.
* Conditions in which one should
consider APAS as a diagnosis include
amaurosis fugax, migraine, TIA, retinal
hemorrhages and cotton wool
spots, central retinal vein and artery
occlusion, anterior ischemic optic
neuropathy or ophthalmic and cilioretinal
artery occlusions.
* Consider APAS in younger
patients with central retinal vein and
artery occlusion, or in any patient with
bilateral or recurrent CRVO.
* When suspecting APAS in female
patients, inquire about a history of
pregnancy loss.
* APAS can exist independently of
known autoimmune disease, in which
case it is called Primary APAS.
Through serologic testing and appropriate
consultation, the optometrist
may be the physician who diagnoses
this autoimmune condition.
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