Orbital Syndromes

M. Tariq Bhatti, M.D.1

ABSTRACT

The orbit is a complex anatomical structure with unique properties not observed
in other regions of the body. Composed of seven bones, the orbit is filled by the eye, optic
nerve, lacrimal gland, extraocular muscles, peripheral motor and sensory nerves, fat,
arteries, and veins. All these structures are intimately related to one another within an
intricate framework of connective tissue. A variety of traumatic, vascular, inflammatory,
infectious, and neoplastic processes can affect the orbit and its structures. Aside from the
many primary orbital diseases, systemic disorders and pathological processes from neigh-

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boring structures (eye, ocular adnexa, oral cavity, paranasal sinuses, and intracranial cavity)
can involve the orbit. A careful history and complete physical examination, with special
attention to the orbit and ocular adnexa, are required to identify subtle orbital abnormal-
ities that otherwise could be overlooked or mistakenly contributed to a nonorbital process.
This article reviews the pertinent orbital anatomy, discusses the clinical evaluation and
manifestations of orbital syndromes, and highlights several important orbital syndromes
germane to the neurologist, including thyroid-associated orbitopathy, nonspecific orbital
inflammation (also known as inflammatory orbital pseudotumor), perineural orbital
invasion of cutaneous squamous cell carcinoma, rhino-orbital-cerebral mucormycosis,
and carotid-cavernous sinus fistula.

KEYWORDS: orbit, proptosis, thyroid-associated orbitopathy, Graves’ disease,

perineural tumor spread, cutaneous squamous cell carcinoma, mucormycosis,
carotid-cavernous sinus fistula

O rbital disease is not frequently referred to or
encountered in a general neurology practice, but that is
not to say that orbital syndromes are not seen in such a
setting. A variety of disease processes can affect the orbit.
Although it is beyond the scope of this review article to
discuss each category of disease in detail, it is the
intention of this introductory section to familiarize the
reader with the frequency, distribution, and spectrum of
orbital syndromes. Several articles have been published
from centers devoted to the treatment of orbital diseases,
which have documented the enormous spectrum of
orbital syndromes that can be encountered in clinical
practice (Table 1).1 The age, distribution, and frequency
of diseases documented in these series provide a general
overview of orbital syndromes, but specific conclusions
on the precise epidemiology of orbital lesions cannot be
made from these observations for several reasons. First,
some of the series do not include major categories of
orbital disease (for example, trauma is not included in
the Shields et al series). Second, the method and
materials of the collected data vary amongst the different
series (only orbital syndromes with pathological speci-
mens were reviewed in the series by Shields et al and
Wilson and Grossniklaus). Third, the time period in
which each series was published differs. Therefore, the
frequency of lesions detected in a particular series may

1
Departments of Ophthalmology and Medicine, Division of Neurol-
ogy, Duke University Eye Center, Duke University Medical Center,
Durham, North Carolina.
Address for correspondence and reprint requests: M. Tariq Bhatti,
M.D., Departments of Ophthalmology and Medicine, Division of
Neurology, Duke University Eye Center, 2351 Erwin Road, DUMC
3802, Durham, NC 27710-3802 (e-mail: tariq.bhatti@duke.edu).
Neuro-Ophthalmology; Guest Editor, Valérie Biousse, M.D.
Semin Neurol 2007;27:269–287. Copyright # 2007 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2007-979685. ISSN 0271-8235.
269
270 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007

Table 1 Summary of Frequency of Orbital Lesions from Five Published Retrospective Series
Shields* (%) Kennedyy (%) Hendersonz (%) Rootman§ (%) Wilsonk (%) Total (%)

Systemic — 54 (6.6) 52 (3.8) 682 (49.0) 10 (3.2) 798 (17.5)

Inflammatory 132 (20.5) 142 (17.3) 61 (4.4) 129 (9.2) 45 (14.5) 509 (11.1)
Trauma — 107 (3.0) — 76 (5.4) 13 (4.2) 196 (4.3)
Congenital 194 (30.1) 69 (8.4) 39 (2.8) 101 (7.2) 23 (7.4) 426 (9.3)
Primary neoplasia
Epithelial 21 (3.3) 18 (2.2) 68 (4.9) 15 (1.1) 5 (1.2) 127 (2.8)
Fibrous 11 (1.7) 2 (0.24) 20 (1.5) 13 (0.92) 2 (0.64) 48 (1.1)
Fibro-osseous 8 (1.2) 28 (3.4) 31 (2.3) 21 (1.5) 3 (0.96) 91 (2.0)
Cartilaginous 2 (0.31) 1 (0.12) 7 (5.1) 2 (0.14) — 12 (0.26)
Adipose 2 (0.31) — 7 (5.1) — 3 (0.96) 12 (0.26)
Vascular 38 (5.9) 51 (6.2) 125 (9.1) 56 (4.0) 16 (5.1) 286 (6.3)
Neural 23 (3.6) 67 (8.2) 225 (16.4) 71 (5.0) 16 (5.1) 402 (8.8)
Striated muscle 8 (1.2) 8 (0.97) 38 (2.8) 5 (0.35) 12 (3.8) 71 (1.6)
Lymphocytic/leukemic 73 (11.3) 107 (13.0) 126 (9.2) 55 (3.9) 16 (5.1) 377 (8.3)
Langerhans cell 1 (0.16) 3 (0.37) 11 (8.0) 4 (0.28) 3 (0.96) 22 (0.48)
Other 2 (0.31) — 4 (2.9) 2 (0.14) — 8 (0.18)
Secondary neoplasia 70 (10.9) 51 (6.2) 269 (19.5) 44 (3.1) 90 (28.8) 524 (11.5)

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Metastases 16 (2.5) 27 (3.3) 111 (8.1) 38 (2.7) 15 (4.8) 207 (4.5)
Vascular 4 (0.62) 26 (2.2) 65 (4.7) 40 (1.8) 7 (0.32) 142 (3.1)
Other 22 (3.4) 56 (6.8) 119 (8.6) 57 (4.0) 34 (10.9) 288 (6.3)
Total 645 821 1376 1409 312 4563
*Shields JA, Bakewell B, Augsburger JJ, et al. Classification and incidence of space-occupying lesions of the orbit: a survey of 645 biopsies.
Arch Ophthalmol 1984;102:1606–1611.
y
Kennedy RE. An evaluation of 820 orbital cases. Trans Am Ophthalmol Soc 1984;82:134–157.
z
Henderson J. Orbital Tumors. 3rd ed. New York: Brian C. Decker; 1994:43–51.
§
Rootman J. Diseases of the Orbit. Philadelphia: JB Lippincott; 1988:119–139.
k
Wilson MW, Buggage RR, Grossniklaus HE. Orbital lesions in the Southeastern United States. Orbit 1996;15:17–24.
Reprinted from Wilson MW, Grossniklaus HE. Orbital disease in North America. Ophthalmol Clin North Am 1996;9:539–547, with permission
from Elsevier.

reflect a bias based on the ability of orbital lesions to be
identified by the neuroimaging technology of that era.
Lastly, each series was compiled from a tertiary care or
academic center, which carries with it the inherent bias
of the referral pattern in that geographic location.
Despite these limitations, several general obser-
vations or trends can be inferred from the collective data
sets, as was done by Wilson and Grossniklaus,1 who
divided the various orbital syndromes into three broad
categories: neoplastic (50%), inflammatory (25%), and
others (25%). The frequency of a particular orbital
syndrome is more prevalent in a certain age group.
Rootman2 found that neoplastic lesions (capillary he-
mangioma) and structural lesions (congenital cysts) were
very common in infants and children younger than
2 years. In older children and adolescents, 2 to 16 years
of age, structural lesions (orbital trauma, dermoid and
epidermoid cysts), neoplastic lesions, inflammations
(mainly due to infection), and vascular lesions were the
most common diseases. In young and older adults, 17 to
64 years of age, thyroid-associated orbitopathy (TAO)
was by far the most common cause of an orbital syn-
drome. In those older than 65 years, TAO and neoplastic
lesions were the most frequent causes of an orbital
syndrome.
REGIONAL ORBITAL ANATOMY
As is true in many other areas of the body that are
afflicted by abnormal pathology, to appreciate the clin-
ical signs and symptoms of an orbital syndrome requires
a fundamental knowledge of the regional anatomy as
well as an understanding of the underlying disease
pathophysiology. This section is intended to introduce
the reader to the subject of orbital anatomy. Interested
readers are encouraged to refer to more comprehensive
anatomy textbooks or articles on the subject.3–6
The paired bony orbits are composed of seven
bones joined together to form four walls (Fig. 1A).
Shaped like a pyramid, the base of the orbit is the
anterior opening of the face and is defined by the orbital
rim or margin. The medial walls of the orbit run parallel
to one another, in contrast to the lateral orbital walls,
which form right angles to one another. The total
volume of the orbit is 30 cm3 with the eye filling only
7 cm3. The bony orbit is covered by the periorbita, or
periosteum, which is continuous with the dura of the
optic nerve posteriorly and the periosteum of the orbital
margin anteriorly. In part, the orbit is surrounded by the
paranasal sinuses and the intracranial cavity (Fig. 1B).
There are several fossae, notches, foramens, and
fissures of the orbit that transmit or contain important

Figure 1 Orbital anatomy. (A) The seven bones of the orbit. (B) Relationship of the bony orbit and orbital contents to the paranasal
sinuses. (C) Orbital apex. (D) Extraocular muscles. (E) Arterial (top) and venous (bottom) supply of the orbit. (Courtesy of David Peace,
medical illustrator.)
anatomical and neurovascular structures. Located within
the supraorbital rim, the supraorbital notch contains the
supraorbital nerve and artery. Medial to the supraorbital
notch is the supratrochlear notch, which contains a
cartilaginous ring known as the trochlea that supports
the tendon of the superior oblique muscle. Within the
medial orbital wall, along the frontoethmoidal suture
line, are the anterior and posterior ethmoid foramina
that allow the passage of the anterior and posterior
ethmoidal arteries, respectively, from the orbit to the
nasal cavity. These two foramina also serve as a reference
point for the location of the cribriform plate. Along
the floor of the orbit is the infraorbital groove that carries
the intraorbital artery, vein, and a branch of the second
division of the trigeminal nerve from the inferior orbital
fissure to the infraorbital foramen. Along the antero-
lateral portion of the orbital roof is the lacrimal fossa, the
resting place of the lacrimal gland. Whitnall’s tubercle
or lateral orbital tubercle is located at the lateral orbital
ORBITAL SYNDROMES/BHATTI 271
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rim and represents the attachment area of the lateral
canthal tendon and suspensory ligament of the eyeball
(Lockwood’s ligament).
The tip of the orbit ‘‘pyramid’’ is known as the
orbital apex and contains three openings—inferior orbi-
tal fissure, superior orbital fissure, and optic foramen—
that allow the transmission of major neurovascular
structures into and out of the orbit (Fig. 1C). The floor
of the orbit contains the inferior orbital fissure, which is
bordered by the greater wing of the sphenoid, maxillary,
and palatine bones. The inferior orbital fissure commu-
nicates with the pterygopalatine and infratemporal fos-
sae and contains the infraorbital nerve, intraorbital
artery, infraorbital vein, zygomatic nerve, branch of the
inferior ophthalmic vein, and parasympathetic nerves to
the lacrimal gland. The superior orbital fissure is
bounded by the lesser and greater wings of the sphenoid
bone and separates the posterior lateral orbital wall
from the orbital roof. Within the superior orbital fissure
272 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007
lie the three ocular motor cranial nerves (oculomotor
nerve, trochlear nerve, and abducens nerve), three sen-
sory nerves (lacrimal nerve, frontal nerve, nasociliary
nerve), two arteries (orbital branch of middle meningeal
artery and recurrent branch of lacrimal artery), and two
veins (superior orbital vein and superior ophthalmic
vein). The optic foramen opens to the optic canal. It is
enclosed within the lesser wing of the sphenoid bone and
transmits the optic nerve, the ophthalmic artery, and
sympathetic nerves to the pupil. The optic canal is 5 to
6 mm in diameter and 10 to 12 mm in length and
connects the middle cranial fossa to the orbit. The
frontal lobe sits on top of the roof of the optic canal,
and the medial portion of the canal is in contact with the
posterior ethmoid and sphenoid sinuses.
Within the orbit is a complex and intricate con-
nective tissue framework that is critical to the functions
of the eye. The orbital fat, extraocular muscles, and
periorbita are separated, and in many ways compartmen-
talized, by numerous fibrovascular septa. This compart-
mentalization is much more apparent in the anterior
orbit. The eye is covered by Tenon’s capsule, a thin
fascial layer that inserts just posterior to the cornea and is
continuous with the dura of the optic nerve. Clinically
and radiologically, disease processes within the orbit can
be divided as intraconal or extraconal; however, based on
anatomical studies, such a division does not truly exist
(discussed in the following paragraph).
Five of the six extraocular muscles (superior
rectus, inferior rectus, lateral rectus, medial rectus, and
superior oblique) originate from the orbital apex
(Fig. 1D). The inferior oblique muscle originates from
the maxillary process of the orbital floor. The four recti
muscles originate from a tendinous ring at the orbital
apex known as the annulus of Zinn. The annulus of Zinn
surrounds the superior orbital fissure and optic foramen.
Each recti muscle, as it approaches and inserts onto the
eye, is covered by a muscular sheath that extends to the
periorbita. However, a common muscle sheath does not
exist between the four recti muscles; therefore, a true
anatomical division within the orbit dividing it into an
intraconal and extraconal space does not exist.
The arterial vascular supply of the orbit and the
eye is primarily from the ophthalmic artery, the first
intracranial branch of the internal carotid artery
(Fig. 1E). The ophthalmic artery enters the orbit
through the optic canal inferolateral to the optic nerve.
In 85% of cases, the artery courses above the optic nerve,
headed toward the medial orbital wall. The major
arterial branches of the ophthalmic artery in the orbit
are: central retinal artery, lacrimal artery, muscular artery
branches, ciliary arteries, supraorbital artery, posterior
ethmoidal artery, anterior ethmoidal artery, nasofrontal
artery, supratrochlear artery, and dorsonasal artery.
There is a well-established anastomoses system between
the internal and external carotid arteries.
The venous system of the orbit is highly variable
amongst individuals and does not run in parallel with the
arterial system. The main draining vein of the orbit is the
superior ophthalmic vein, which is formed in most cases
by the supraorbital and angular veins. The inferior
orbital venous system has been difficult to anatomically
define and has been described by some as a venous plexus
or network.7
The sensory innervation of the eye, orbit, ocular
adnexa, forehead, side of the nose, and ethmoid sinuses
is from the first division of the trigeminal nerve (oph-
thalmic nerve). The ophthalmic nerve has three main
branches: lacrimal nerve, frontal nerve, and nasociliary
nerve (Fig. 2).
The optic nerve enters the orbit from the middle
cranial fossa through the optic canal. The intraorbital
length of the optic nerve is
30 mm compared with the
20 mm distance between the optic foramen and the eye.
This discrepancy of distances allows for the normal
tortuous course of the optic nerve within the orbit and
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some redundancy of the optic nerve, which accommo-
dates pathological lengthening between the eye and the
orbital apex, as can be seen with proptosis, without
resultant visual dysfunction. The orbital portion of the
optic nerve is covered by pia, arachnoid, and dura mater
(optic nerve sheath).
The paired cavernous sinuses are located on the
lateral aspects of the sphenoid bone, bordered anteriorly
by the superior orbital fissure and posteriorly by the
petrous apex (Fig. 3). It serves as the main draining point
of the cerebral venous system. The main veins that drain
into the cavernous sinuses are anteriorly the superior
and inferior ophthalmic veins, posterosuperiorly the
superior petrosal sinus, posteroinferiorly the inferior
petrosal sinus, and posteriorly the basilar plexus. Each
Figure 2 Drawing of the anatomy of trigeminal nerve. (Cour-
tesy of David Peace, medical illustrator.)

Figure 3 Drawing of the anatomy of the cavernous sinus, lateral view. (Courtesy of David Peace, medical illustrator.)
cavernous sinus communicates with the other through
an intercavernous plexus. Within the cavernous sinus is
the carotid siphon of the internal carotid artery. The
lateral wall of the cavernous sinus, which is composed of
a fold of dura, contains the oculomotor nerve, trochlear
nerve, and the ophthalmic and maxillary divisions of the
trigeminal nerve. The abducent nerve is found within the
cavernous sinus.
CLINICAL EVALUATION AND
MANIFESTATIONS OF ORBITAL
SYNDROMES
History
The recognition and accurate interpretation of the
clinical manifestations of an orbital syndrome requires
a certain level of clinical suspicion and awareness of the
various orbital pathologies. The clinical assessment of a
patient suspected of harboring an orbital syndrome
begins by performing a detailed and thorough medical
history. Specific questions should be addressed to
determine the time course, progression, and overall
nature of the disease process. A prior history of ocu-
lar/orbital surgery or trauma should be documented. It
is helpful in some situations to review old photographs
to determine if the abnormality noted by the patient is a
newly recognized chronic process or of a truly acute
onset. Inquiring about the presence of a palpable or
visible structural abnormality, change in external ap-
pearance, pain, discharge, visual loss, and double vision
can provide valuable information on the possible cause
and anatomical site of the lesion. The subjective com-
plaint of transient visual loss in a particular gaze (gaze-
evoked amaurosis) may be a symptom of an orbital
mass.8
ORBITAL SYNDROMES/BHATTI 273
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Clinical Evaluation
A detailed ocular and orbital examination is best per-
formed by an ophthalmologist or a neurologist familiar
with the specialized equipment and specific examina-
tion techniques. However, general neurologists can
perform many of the basic components of the exami-
nation with a few simple tools (penlight, red-colored
object, near visual acuity card, and direct ophthalmo-
scope). Assessment of the anterior and posterior visual
pathways is performed by measuring central visual
acuity; examining the peripheral visual field by con-
frontation, kinetic, or static perimetry; and assessing
color vision. A swinging flashlight test will determine
the presence of a relative afferent pupillary defect, a
strong indication that an optic neuropathy is present.
Ocular motility is evaluated by determining the extent
and velocity of the extraocular movements. Limitation
of eye movements can occur from either a paretic or
restrictive process, which can be clinically discerned by
performing a forced duction test (manual movement of
the eye with forceps in the direction of the gaze
limitation). Misalignment of the eyes can be quantified
by the prism alternating cover test in various positions
of gaze. In this test, the ocular deviation is measured by
prisms, which neutralize the horizontal and vertical
shifts of the eyes. Slit-lamp biomicroscopy is necessary
to detect abnormalities of the eye’s anterior structures
and internal chambers. Intraocular pressure is measured
in primary and up gazes. Intraocular pressure may be
elevated in some cases of orbital syndromes, and a rise in
intraocular pressure on attempted upgaze is an indica-
tion of TAO. The function of the trigeminal nerve is
examined based on its three divisions (ophthalmic,
maxillary, and mandibular). Visual inspection, palpa-
tion, and auscultation are three important steps of the
ocular adnexal and orbital examination. The position of
274 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007

Figure 4 Clinical manifestations of orbital syndromes. (A) Proptosis. (B) Enophthalmos. (C) Orbital bone destruction with globe
dystopia. (D) Optic neuropathy. (E) Ocular motor cranial neuropathy. (F) Vascular congestion. (Courtesy of John Richardson, medical
illustrator.)

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the eyelids can be assessed by simple visual observation
and more precisely by measuring the distance between the
upper and lower palpebral fissures or the upper eyelid
margin to the pupillary light reflex. The general nature,
location, and extent of an orbital lesion can be determined
by digital palpation. Any horizontal, vertical, or axial
displacement of the globe should be noted. Axial
proptosis is quantified by a Hertel exophthalmometer
(Richmond Products, Inc., Albuquerque, NM). A vol-
untary Valsalva maneuver may cause forward displace-
ment of the globe, indicating a vascular orbital lesion (i.e.,
orbital varix). Resistance to digital pressure applied
against the globe with the eyelids closed is an indication
of orbital congestion or a retrobulbar mass. Complete
funduscopic examination with pharmacological dilation
of the pupil and indirect ophthalmoscopy allows visual-
ization of the posterior pole, optic nerve, peripheral
retina, and retinal vasculature.
Clinical Manifestations
A variety of clinical manifestations are associated with
orbital syndromes (Fig. 4). The hallmark sign of many of
the orbital syndromes, especially in the context of orbital
tumors, is proptosis (Fig. 5). Depending on the location
and nature of the orbital lesion, the globe can be
displaced horizontally, vertically, axially, or in any com-
bination thereof. A large retrobulbar mass cannot only
displace the eye anteriorly but may distort the wall of the
eye posteriorly, resulting in a hyperopic refractive error
shift or retinal-choroidal folds (Fig. 6). Enophthalmos
or posterior displacement of the eye can occur in the
setting of increased orbital cavity volume, decreased
orbital tissue volume, or orbital cicatricial changes (i.e.,
traction from metastatic breast cancer).9,10 Spontaneous
eye pulsations suggest several entities including congen-
ital, traumatic, or iatrogenic absence of an orbital
bone; carotid-cavernous sinus fistula; or a cranio-orbital

Figure 5 A 78-year-old woman with sudden onset proptosis of the left eye associated with eye pain. Final diagnosis—vascular
(cavernous) malformation. (A) External photographs show left eye proptosis. (B) T1-weighted magnetic resonance image, axial and
coronal views, shows large vascular mass in the left orbit.
 ORBITAL SYNDROMES/BHATTI 275

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Figure 6 A 47-year-old woman with 10-day history of headaches and swelling of the right upper eyelid. Final diagnosis—adenoid
cystic carcinoma of the lacrimal gland. (A) External photograph shows fullness of the right upper eyelid. (B) Fundus photograph shows
retinal-choroidal folds of the posterior pole from the orbital mass. (C) Computed tomography scan shows a large mass with calcification.
(D) T1-weighted, postcontrast, fat-saturation magnetic resonance image, coronal view, shows a mass within the right lacrimal fossa
with mixed-signal characteristics.

arteriovenous malformation. The presence of an orbital
bruit is a sign of orbital congestion either due to
increased arterial inflow or decreased venous outflow of
the orbit, as is frequently encountered from a carotid-
cavernous sinus fistula. An orbital bruit has also been
reported to be heard in the setting of atherosclerosis of
the carotid artery siphon, congenital agenesis of the
sphenoid wing, and TAO.11,12
Orbital syndromes may be accompanied by
malposition of the eyelids. Upper eyelid retraction is
classically associated with TAO, but may occur in the
presence of proptosis from an orbital mass, chronic
contact lens wear, myasthenia gravis, Parinaud’s syn-
drome (dorsal midbrain syndrome), globe prominence,
previous eyelid or extraocular muscle surgery, and
midbrain lesions affecting the oculomotor nuclear
complex.13,14 Orbital syndromes causing ptosis may
be the result of mechanical interference or infiltration
of the levator palpebrae muscle, dysfunction of the
oculomotor cranial nerve, or concomitant myasthenia
gravis. It should be kept in mind that ipsilateral
enophthalmos or contralateral proptosis and/or lid
retraction could be incorrectly interpreted as ptosis in
some patients.
Visual loss from an orbital syndrome can occur
from abnormalities at different anatomical ocular
sites. Exposure keratitis, retinal dysfunction, and optic
neuropathy can all result in decreased vision. The
mechanism of the optic neuropathy, depending on
the syndrome, can be due to compression, infiltration,
or ischemia. Clinically, the optic nerve may be swol-
len or initially appear normal if the pathology is in
the posterior orbit with subsequent development of
optic nerve pallor in 4 to 6 weeks. The presence of
optociliary shunt vessels, which are collateral vessels
between the choroidal and retinal circulations, has
been traditionally associated with an optic nerve
sheath meningioma but can be seen from any intrin-
sic optic nerve lesion as well as from chronic papil-
ledema, end-stage glaucoma, and central retinal vein
occlusion.
Ocular dysmotility in the setting of an orbital
syndrome can be due to either a restrictive or paretic
process. Mechanical compression or infiltration of the
extraocular muscles will result in a restrictive ocular
motility problem. In contrast, compression or infiltra-
tion of an ocular motor cranial nerve will cause a palsy
(Fig. 7). These two different pathological processes
can be differentiated by the forced duction test. (A
positive forced duction test is defined as resistance to
manual movement of the eye due to a restrictive
ocular motility disorder.) The pattern of ocular mo-
tility dysfunction and the ‘‘company with which it
keeps’’ can be very helpful in localizing the site of the
lesion. For example, an optic neuropathy associated
with external ophthalmoplegia suggests a lesion in the
orbital apex (orbital apex syndrome), whereas multiple
ocular motor cranial neuropathies without visual loss
276 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007

Figure 7 A 61-year-old man with 1-year history of slowly progressive visual loss in the right eye followed by ptosis and external
ophthalmoplegia. Final diagnosis—orbital meningioma. (A) External photograph shows complete external ophthalmoplegia due to
multiple ocular motor cranial neuropathies. The right eyelid is manually elevated in the presence of ptosis. Pupils are pharmacologically

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dilated. (B) Computed tomography scan, axial view, shows large right orbital mass.

and trigeminal dysfunction suggest a lesion of the therefore, the appropriate neuroimaging is required
superior orbital fissure or cavernous sinus (Fig. 8).15 It to confirm the precise location and extent of the
should be kept in mind that suspected orbital syn- pathological process (discussed in the following sec-
dromes can be mimicked by intracranial lesions; tion).

Figure 8 A 57-year-old man with several-month history of left upper eyelid ptosis, external ophthalmoplegia, visual loss, and
numbness in the left V1 distribution. Final diagnosis—orbital apex syndrome due to poorly differentiated carcinoma. (A) Nine positions of
gaze show complete external ophthalmoplegia with a dilated and fixed left pupil. (B) T1-weighted, postcontrast magnetic resonance
image, coronal view, shows abnormal enhancement within the left orbital apex. (C) Histopathological specimen of orbital apex lesion
shows undifferentiated carcinoma.

Radiological Evaluation
Technological advancements and refinements in the
radiological evaluation of the orbit has been a major
contributor in not only improving the ability to detect
orbital lesions, but in understanding the pathological
processes of many of the orbital syndromes.16 Radio-
logically, orbital lesions can be categorized as subper-
iosteal, intraconal, or extraconal.17
Physicians evaluating a patient suspected of har-
boring an orbital syndrome can choose from a variety of
imaging techniques: computed tomography (CT), mag-
netic resonance imaging (MRI), orbital ultrasonography,
and conventional catheter angiography. It is beyond the
scope of this article to discuss in detail the indications,
advantages, disadvantages, and limitations of these imag-
ing modalities.18,19 In general, CT is best suited for cases
that require quick image acquisitioning and detailed
study of the bony anatomy. In contrast, MRI is an
excellent option for evaluating soft tissue abnormalities
with multiplanar views. The use of orbital fat suppression
techniques has substantially improved the sensitivity of
detecting abnormalities within the orbit that would
otherwise be obscured by the high signal of the orbital
fat.20,21 Orbital ultrasonography is an in-office, relatively
inexpensive, fast, dynamic, and noninvasive method of
evaluating orbital lesions that are predominately anterior
in the orbit, and cystic or inflammatory in nature.2 The
addition of color Doppler flow imaging with orbital
ultrasonography is helpful in determining the blood
flow and velocity of vascular structures and lesions within
the orbit.22 In most cases, CT angiography (CTA) and
magnetic resonance angiography (MRA) have been re-
placed by conventional catheter angiography in the initial
evaluation of patients suspected of harboring an intra-
cranial vascular lesion. However, catheter angiography is
still an important diagnostic tool in the management of
patients with carotid-cavernous sinus fistula and in pa-
tients with an orbital arteriovenous malformation.2,23
ORBITAL SYNDROMES
This section discusses five important orbital syndromes
that neurologists may encounter in clinical practice.
Generally speaking, in some cases the diagnosis of an
orbital syndrome is relatively straightforward based on
the clinical findings, requiring few paraclinical tests.
However, in other more complex and unique cases an
extensive investigation may be required, including an
orbital tissue biopsy. The necessary and appropriate
ancillary testing should be determined on a case-by-
case basis and guided by the differential diagnosis.
Thyroid-Associated Orbitopathy (TAO)
TAO is the most common cause of unilateral or bilateral
proptosis in adults.12 TAO is an inflammatory-mediated
ORBITAL SYNDROMES/BHATTI 277
autoimmune disorder associated with Graves’ disease
and, in a small percentage of cases, with Hashimoto’s
thyroiditis (2%). Twenty-five to 50% of patients with
Graves’ disease will manifest ophthalmic findings, usu-
ally within 18 months from the onset of the hyper-
thyroidism.24 The eye findings can proceed or follow the
thyroid dysfunction, but most often they occur after the
diagnosis of Graves’ disease has been established.25 The
majority of patients are hyperthyroid, but hypothyroid-
ism and euthyroidism (10% of cases) can also be asso-
ciated with TAO. A variety of classification schemes
have been developed to categorize the spectrum of
clinical manifestations associated with TAO. In general,
the severity of TAO can be divided into mild, moderate,
or severe depending on the degree of proptosis, the
presence of an optic neuropathy, and the extent of
extraocular muscle dysfunction.26 Fortunately, only 5%
of patients develop severe TAO and in most cases the
duration of the active phase of disease is 1 to 5 years.12,27
The pathological basis for the clinical manifestations of
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TAO is an increase in orbital tissue volume from the
accumulation of glycosaminoglycans, inflammatory cells,
and edema within the orbital fat and connective tissue of
the extraocular muscles. Impaired venous outflow and
optic nerve compression from the expansion of orbital
tissues results in orbital congestion and visual loss.28
Clinically, TAO is manifested by many eye signs
and symptoms.2,12 In some cases there may not be
clinically apparent eye involvement, and only with radio-
logical testing (orbital ultrasonography, CT, or MRI)
will there be evidence of occult disease.26,29 Upper eyelid
retraction, or Dalrymple’s sign, is the most common sign
associated with TAO and can be seen in isolation or in
the presence of proptosis (Fig. 9). Another common
eyelid finding associated with TAO is upper eyelid lag
during downgaze (von Graefe’s sign). Patients with
TAO may complain of tearing, foreign body sensation,
photophobia, orbital discomfort or pressure, and peri-
orbital fullness or edema. Most of these symptoms can be
attributed to corneal exposure from lid retraction, poor
eyelid closure (lagophthalmos), or proptosis. Periorbital
fullness may be caused by edema, increased orbital fat or
prolapsed orbital fat. Proptosis is present in 60% of
patients with Graves’ disease.30 The proptosis is often
bilateral and symmetric, a result of increased tissue
volume of the orbital fat and extraocular muscles.31
Conjunctival edema (chemosis) and injection overlying
the insertion of the horizontal extraocular muscles may
be present. Elevated intraocular pressure, particularly on
attempted upgaze, is a common finding in patients with
TAO. Transient or constant diplopia occurs from orbital
congestion and infiltration of the extraocular muscles.
The inferior rectus and medial rectus muscles are most
frequently involved, leading to a limitation of elevation
and abduction, respectively. A devastating complication
of TAO is visual loss due to optic neuropathy from
278 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007
Figure 9 A 49-year-old woman with Graves’ disease with several-month history of double vision and bilateral periorbital swelling and
proptosis. Final diagnosis—thyroid-associated orbitopathy. (A) External photograph shows significant restriction of abduction of both
eyes on attempted lateral gazes. Note the bilateral lid retraction and proptosis. (B) Computed tomography, axial and coronal views,
shows enlargement of all the extraocular muscles with crowding within the orbital apex. The tendons of the extraocular muscles are
spared.
orbital congestion and tissue crowding at the orbital
apex.2
The diagnosis of TAO is established by recogniz-
ing the clinical manifestations and obtaining the appro-
priate endocrine evaluation if the patient has not already
been diagnosed with Graves’ disease. In subtle cases of
TAO, orbital ultrasonography, CT, or MRI can be
helpful in detecting enlargement of the extraocular
muscles with sparing of the tendons.29
The medical or surgical treatment of the endocrine
dysfunction in Graves’ disease has not been shown to affect
the disease course of TAO.12 The treatment of TAO is
based on the severity and progression of disease. Mild cases
can be treated with supportive care using artificial tears and
elevating the head of the bed during sleep to decrease
periorbital edema. Eyelid retraction and ocular motility
dysfunction can be treated by a variety of surgical proce-
dures. In cases of diplopia it is advisable that surgery
be performed only after the patient has demonstrated a
6-month period of stability. Patients with more severe
disease, particularly those with significant orbital conges-
tion, ocular motility dysfunction, and optic neuropathy,
may require treatment with systemic corticosteroids,
orbital radiation, or orbital decompression.32
Nonspecific Orbital Inflammatory Syndrome
(Inflammatory Orbital Pseudotumor)
First introduced as a distinct histopathological entity in
1930 by Birch-Hirschfeld, nonspecific orbital inflamma-
tion (NSOI), or inflammatory orbital pseudotumor, is an
idiopathic, noninfectious, inflammatory orbital syn-
drome associated with a wide variety of clinical and
pathological features.33,34 It is the third most common
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orbital syndrome encountered in clinical practice, behind
only TAO and orbital lymphoproliferative disease.35
Nonspecific orbital inflammatory syndrome does not
appear to have a sex predilection and is often seen in
middle-age patients, with
6 to 16% of cases presenting
in the pediatric age group.34 Frequently unilateral on
presentation, it can be bilateral, especially in the NSOI
subtype known as myositis.33 Nonspecific orbital inflam-
matory syndrome is usually confined to the orbit, but in
some cases the disease process can extend into the cranial
cavity or paranasal sinuses.36 Considered a self-limiting
disease, some patients with NSOI may be resistant to
traditional treatment with systemic corticosteroids or
demonstrate recurrent disease during tapering or dis-
continuation of corticosteroid therapy.33,37
NSOI can be classified according to the time
course of presentation, the anatomical structures in-
volved, or the histopathological subtype.2 It can present
as an acute (hours-days), subacute (weeks), or chronic
(months) condition. Clinically and radiologically NSOI
can be seen as a localized (anterior or posterior) or diffuse
process. Depending on the anatomical structure in-
volved, NSOI can be classified as periscleritis (sclera/
Tenon’s space), myositis (extraocular muscle), trochleitis
(trochlea of the superior oblique tendon), dacryoadenitis
(lacrimal gland), perioptic neuritis (optic nerve), or
Tolosa-Hunt syndrome (cavernous sinus, superior orbi-
tal fissure, or orbital apex).34,38,39 According to the
pattern of clinical involvement and radiological findings
of 17 patients presenting with acute NSOI, Rootman
and Nugent40 divided their patients into five categories:
anterior, diffuse, posterior, lacrimal, and myositic.
A variety of histopathological features have been
described with NSOI based on the inflammatory cell
 ORBITAL SYNDROMES/BHATTI 279

profile, degree of inflammation, and fibrovascular re-
sponse.33,34 The inflammatory cellular components of
NSOI include mature T lymphocytes, plasma cells,
neutrophils, eosinophil granulocytes, histiocytes, and
macrophages. Edema, fibrosis, sclerosis, and hyaliniza-
tion changes can be seen in the orbital connective tissue.
The fibrosis or sclerosis present in some cases of NSOI
may be the late stage sequelae of chronic, recurrent, or
severe inflammation or represent a distinct subtype of
NSOI, termed sclerosing orbital pseudotumor.33,41
The clinical manifestations of NSOI are variable
and based on the anatomical structure(s) involved and
the extent and type of histopathological features of the
inflammatory infiltrate (Fig. 10). Pain is a frequent
symptom of NSOI, is often localized to the eye or orbit,
and has been described as a constant ‘‘gnawing’’ or
‘‘boring’’ pain.38 The eyelids are frequently edematous
and erythematous. Lacrimal gland involvement will
result in fullness of the superotemporal quadrant of the
orbit with an S-shaped upper eyelid abnormality. There
choroidal detachment, exudative retinal detachment,
and macular edema.34 Angle closure glaucoma may
develop in rare cases because of anterior displacement
of the lens-iris diaphragm due to anterior choroidal
detachment.42 Diplopia from ocular dysmotility can
result from involvement of one or more of the extra-
ocular muscles. Visual loss due to optic nerve dysfunction
is evidence of optic nerve sheath involvement (perioptic
neuritis).43
Magnetic resonance imaging and CT are the two
most commonly used radiological modalities in the
evaluation and management of patients with NSOI.35
As is the case with the clinical manifestations, the
radiological findings associated with NSOI are diverse
and correlate with the anatomic structures involved and
histopathological features of the disease. On MRI,
NSOI will appear dark (low signal intensity) on the
T1- and T2-weighted sequences with significant en-
hancement after the administration of contrast. Com-
puted tomography will show an ill-defined, isointense

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may be conjunctival injection with chemosis. Intraocular (to the extraocular muscles), infiltrative lesion with a
inflammation (uveitis) may be seen in patients with acute variable enhancement pattern. Lacrimal gland and ex-
anterior NSOI. Posterior eye involvement can demon- traocular muscle involvement is indicated by diffuse
strate abnormalities on funduscopic examination, such as enlargement and enhancement on CT and MRI. The

Figure 10 A 77-year-old woman with a 5-day history of swelling, erythema and pain of the right orbit. Final diagnosis—nonspecific
orbital inflammation. (A) External photograph shows significant erythema, edema, and chemosis involving the right orbit. There is global
limitation of movement of the right eye. The right pupil is pharmacologically dilated. (B) After 3 days of intravenous corticosteroid
treatment, substantial clinical improvement of the right orbit occurred, with only mild injection of the conjunctiva. (C) T1-weighted,
postcontrast magnetic resonance image, axial and coronal views, shows diffuse and nonspecific enhancement of the right orbit and
enlargement of all the extraocular muscles.
280 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007
Figure 11 Algorithm for decision pathways in the diagnosis
and treatment of idiopathic orbital inflammation. CBC, complete
blood count; CT, computed tomography; ACE, angiotensin-con-
verting enzyme; ANCA, antineutrophil cytoplasmic antibody;
MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-
inflammatory drugs. (Reproduced with permission from Yuen SJ,
Rubin PA. Idiopathic orbital inflammation: distribution, clinical
features, and treatment outcome. Arch Ophthalmol 2003;121:
491–499. Copyright # 2003, American Medical Association. All
rights reserved.)
enlargement of the extraocular muscle(s) will involve the
tendon, unlike TAO in which the tendon is spared.
NSOI is a diagnosis of exclusion, requiring para-
clinical testing and a diagnostic trial of systemic cortico-
steroids (Fig. 11).39 Other primary and systemic orbital
syndromes must be considered in the diagnostic possi-
bilities of NSOI such as sarcoidosis, Wegener’s granu-
lomatosis, giant cell arteritis, Erdheim-Chester disease,
lymphoproliferative diseases, and metastatic neo-
plasms.39,44–46 In particular, TAO and infectious orbital
cellulitis can be initially confused with NSOI.34 Orbital
biopsy should be reserved for patients that have chronic
disease, do not respond to corticosteroid therapy, or have
a mass with extraorbital or bony involvement.34
Although the exact dose and route of adminis-
tration is not known, the initial treatment of patients
suspected of having NSOI is systemic corticosteroids.
Some experts advocate the initial use of nonsteroidal
anti-inflammatory medications, particularly in mild
cases of NSOI.39 Patients who have a contraindication
to, are resistant to, or develop a recurrence of symptoms
during tapering or discontinuation of corticosteroid
therapy can be offered the option of immunosuppressive
drugs such as methotrexate, cyclosporine, cyclophospha-
mide, infliximab, or orbital radiation (total dose of 0.1 to
0.3 Gy).34,37,47–49
Perineural Orbital Invasion of Cutaneous
Squamous Cell Carcinoma
Skin cancer can spread by direct extension, hematoge-
nous metastasis or lymphatic dissemination.50,51 A less
frequent mode of cutaneous neoplastic extension is by
perineural spread (PNS) or neurotropism, which was
first described by Cruveilhier in 1842.52 Perineural
tumor spread is defined as invasion of neoplastic cells
within the spaces of the perineurium or endoneu-
rium.51,53,54 Although a variety of neoplasms can dem-
onstrate PNS, the most common are head and neck
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squamous cell carcinomas and major and minor salivary
gland adenoid cystic carcinomas.50,55–57 PNS most com-
monly travels in a centripetal direction (toward the
central nervous system), but in some cases it can be
centrifugal at branching points of nerves.57 Cutaneous
squamous cell carcinoma has a relatively low rate of
PNS, ranging from 2.5 to 14%.56,58
Cutaneous squamous cell carcinoma is the second
most common form of nonmelanoma skin cancer.50,59 A
variety of risk factors have been associated with cutaneous
squamous cell carcinoma, but the most relevant appears
to be solar radiation (ultraviolet B light).50,59 Immuno-
suppressed patients, in particular organ transplantation
patients, are 65 times more likely to develop cutaneous
squamous cell carcinoma.50,59 Most cases of cutaneous
squamous cell carcinoma are cured with surgical excision.
The recurrence rate and metastatic rate of squamous cell
carcinoma are 3 to 18% and 2 to 3%, respectively.60
Several factors have been associated with higher risks of
recurrent or metastatic disease. The presence of PNS
carries a 5 times greater risk of recurrent or metastatic
disease and is associated with poor survival.59
The signs and symptoms of PNS can be attributed
to the spread of tumor cells along branches of the motor
and sensory nerves of the face, head, and neck.55,57
Spreading of the head and neck cancers occurs most
often through the maxillary and mandibular divisions of
the trigeminal nerve and the peripheral branches of the
seventh nerve. When branches of the ophthalmic divi-
sion of the trigeminal nerve are involved, the orbit,
orbital apex, superior orbital fissure, and cavernous sinus
may become affected (the inferior orbit and cavernous
sinus can also become involved via the maxillary division
of the trigeminal nerve).57 The most common primary
skin site associated with perineural orbital invasion of
cutaneous squamous cell carcinoma is the forehead.61–63
 ORBITAL SYNDROMES/BHATTI 281

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Figure 12 A 41-year-old-woman with history of cutaneous squamous cell carcinoma of the forehead removed by Mohs’ surgery
1 year before presentation. She complained of anesthesia and paresthesia in the right forehead region, double vision, and a mass above
the right eye. Final diagnosis—perineural orbital invasion of cutaneous squamous cell carcinoma. (A) Nine positions of gaze show the
superior orbital mass causing inferior displacement of the eye (central panel). Note limited elevation of the right eye (top, center panel).
(B) Computed tomography scan shows large right superior orbital mass with destruction of bone. (C) Histopathology of biopsy specimen
demonstrates an infiltrating, moderately differentiated squamous cell carcinoma.

The clinical manifestations of PNS are the result
of the tumor cells causing neural tissue ischemia or
axonal or myelin degeneration.64 As many as 40% of
patients with PNS may be asymptomatic.65 The two
most frequent ophthalmic manifestations of PNS are
facial or ocular pain and sensory symptoms (numbness,
tingling, burning or formication) in the distribution of
the ophthalmic division of the trigeminal nerve.61 Facial
weakness may also be present. In some cases, single or
multiple ocular motor cranial nerve dysfunctions may
develop from superior orbital fissure or cavernous sinus
involvement.66 An orbital mass may develop because of
tumor cell breakthrough from the perineurium of an
orbital peripheral nerve (Fig. 12).56 Central nervous
system involvement can result in hemiparesis and neo-
plastic meningitis.56
Establishing the diagnosis of perineural orbital
invasion of cutaneous squamous cell carcinoma requires
maintaining a high clinical suspicion of the disease in the
appropriate clinical setting and correctly interpreting the
radiological findings. Reasons for a delay in diagnosis
include vague symptomatology, similarity to other more
recognized diagnostic entities, an incomplete medical
history of a previous skin lesion, the absence of a primary
skin lesion, and the long time interval between the initial
presentation of the skin lesion and clinical manifesta-
tions.55,57,67,68 The radiological findings can be initially
negative in nearly 50% of patients.69 MRI is the techni-
que of choice in the evaluation of patients suspected of
having PNS.70 A wide range of neuroimaging features
have been described in patients with PNS57,65,70 includ-
ing enlargement or destruction of the nerve foramen,
enlargement or abnormal enhancement of the nerve, and
loss of the normal fat planes around the nerve.
The diagnosis of perineural orbital invasion of
cutaneous squamous cell carcinoma can be empirically
made in patients with a history, physical examination,
and radiological findings consistent with the diagnosis.
In most cases, tissue biopsy of either the orbital mass or
supraorbital nerve will establish the diagnosis.71 The
prognosis of patients with perineural orbital invasion of
cutaneous squamous cell carcinoma is dismal, with a
5-year survival rate of
30%.54 Orbital exenteration,
radiation therapy, and chemotherapy can be offered to
patients.62
Rhino-orbital-cerebral Mucormycosis
Mucormycosis refers to a life-threatening fungus infec-
tion caused by the order of fungi known as Mucorales
282 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007
(Fig. 13).72 Modifications in fungi taxonomy have led to
a more general and accepted term for infections within
the class of Zygomycetes called zygomycosis.73 This
article maintains the term mucormycosis, but the reader
should be aware that fungal infections of this clinical
type can be caused by several species within the orders of
Mucorales and Entomophthorales.
Mucormycosis can be caused by a variety of
species, but the most common organism is Rhizopusor-
yzae (also called Rhizopusarrhizus).72 It is a relatively rare
infection with
500 new cases developing every year.72
Patients with metabolic and immunological disturbances
are at high risk of developing mucormycosis. Diabetic
ketoacidosis, renal disease (renal failure or renal trans-
plantation), deferoxamine therapy, and leukemia are
some of the common underlying disorders.74 Mucormy-
cosis can be divided into six clinical presentations: rhino-
orbital-cerebral (ROCM), pulmonary, cutaneous, gas-
trointestinal, disseminated, and miscellaneous.72 Of
these six, ROCM is the most common presentation
with nearly 70% of patients having diabetes mellitus.
Susceptible patients are inoculated by inhaling spores
onto the oral and nasal mucosa. The disease process then
spreads to the paranasal sinuses extending into the orbit
through the ethmoid and maxillary sinuses. The infec-
tion can continue to travel into the cranial cavity by way
of the cribriform plate, orbital apex, orbital vessels (peri-
or intravascular) or orbital nerves (perineural).72–74 In
other cases, the inoculation can occur through the skin.73
The diagnosis of ROCM requires maintaining a
high degree of suspicion in the appropriate clinical
situation and appreciating the signs and symptoms of
the disease. The clinical manifestations are most often
unilateral and begin in one of the paranasal cavities.
Commonly, the presentation is acute in onset, but a
slowly progressive process has been described.75 Several
case series have identified sinusitis, perinasal anesthesia,
perinasal cellulitis, rhinorrhea, facial swelling, and fever
as important initial presenting signs and symptoms of
mucormycosis.74,76–80 The presence of black eschar is a
helpful sign of mucormycosis, but it cannot be relied on
Figure 13 Taxonomy of Zygomycetes.
during the initial evaluation of a patient because often it
may not be present.78
The findings on CT and MRI are nonspecific for
mucormycosis but are helpful in determining the extent
of disease and response of disease to treatment (Fig. 14).
In some cases the CT results can be normal on the initial
presentation.81 There is often paranasal sinus mucosa
thickening, and late in the disease there will be bone
destruction. Infiltration of orbital tissue with enlargement
of the extraocular muscles will be seen on MRI.74,80
The ophthalmological findings of mucormycosis
are the result of direct fungal infiltration and ischemic
infarction, and in many cases may be the initial presen-
tation of the disease.74,77,78,82 Complete or partial ex-
ternal ophthalmoplegia, visual loss, proptosis, and
periorbital edema are frequent ocular manifestations of
mucormycosis. The external ophthalmoplegia may be in
a pattern consistent with an ocular motor cranial neuro-
pathy. Visual loss can occur from either a central retinal
artery occlusion or an optic neuropathy. Mucormycosis
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can result in an orbital apex or cavernous sinus syndrome.
Central nervous system involvement can result in inter-
nal carotid artery occlusion, cavernous sinus thrombosis,
hemiparesis, meningitis, or brain abscess.74
Histopathological demonstration of large,
branching, aseptate hyphae in tissue specimens obtained
by biopsy are critical in confirming the diagnosis of
mucormycosis.78 In a substantial number of cases, cul-
tures may be negative and therefore should not be relied
on for establishing the diagnosis.80 The mortality rate of
patients with mucormycosis has ranged from 6 to 73%.83
A multitude of factors have been associated with poor
survival in patients with mucormycosis, including im-
munosuppressive therapy, orbital involvement, diabetes
mellitus with ketoacidosis, delay in diagnosis (> 6 days),
mental status changes, hemiplegia, cavernous sinus
thrombosis, and periorbital necrosis.74,80,83
The treatment of mucormycosis requires a multi-
disciplinary team approach. Antifungal therapy with
amphotericin B, surgical débridement of diseased tissue,
and hyperbaric oxygen therapy have all been shown to
 ORBITAL SYNDROMES/BHATTI 283

Figure 14 A 24-year-old man suffered head, face, and neck burn injuries. After being in the intensive care burn unit for several days he
developed explosive bilateral proptosis. Final diagnosis—mucormycosis (Rhizopus species). (A) T1-weighted, postcontrast magnetic
resonance image, axial view, shows diffuse enhancement of both orbits with tenting of the eyes. Note the paranasal sinus disease. (B)
Orbital biopsy reveals large aseptate hyphae (arrows).

benefit and improve the survival rate of patients with carotid artery system (Fig. 15). A CCSF can be cate-

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mucormycosis.74,83 There appears to be a role for orbital
exenteration in patients with mucormycosis, but the
precise indication and timing of surgery is not known.84
Carotid-Cavernous Sinus Fistula
Carotid-cavernous sinus fistula (CCSF) is an abnormal
communication between the cavernous sinus and the
gorized based on its etiopathogenesis, hemodynamic
properties, or angiographic anatomy. Based on the
angiographic findings, Barrow et al. classified CCSFs
into four types: type A (direct fistulas), type B (arterial
supply via the meningeal branch of internal carotid
artery), type C (arterial supply via the meningeal branch
of external carotid artery), and type D (arterial supply
via the meningeal branches of internal and external

Figure 15 Artist’s drawing of a direct carotid-cavernous sinus fistula resulting in vascular orbital congestion. (Courtesy of David
Peace, medical illustrator.)
284 SEMINARS IN NEUROLOGY/VOLUME 27, NUMBER 3 2007
Figure 16 A 67-year-old man with left eye conjunctival injection, chemosis, ptosis, and glaucoma. Final diagnosis—dural carotid-
cavernous sinus fistula. (A) External photograph shows ‘‘arterialization’’ of the conjunctival vessels. (B) Cerebral angiogram shows left
internal carotid injection, early phase. Arrowhead is pointing to internal carotid artery. Arrow indicates filling of the cavernous sinus. (C)
Cerebral angiogram shows left internal carotid injection, late phase. Arrows indicate dilated superior ophthalmic vein.
carotid arteries).85 Types B, C, and D are also known as
indirect, low-flow, or dural CCSFs. Type A, or direct
CCSF, is the most common type, occurring in nearly
90% of cases.86
The clinical manifestations of CCSF depend on
the type, flow, duration, and venous drainage pattern of
the fistula. Direct (type A) CCSFs often present within
several days of the initial injury. In contrast, indirect and
dural CCSFs present with progressive symptoms that
may begin with a red eye and subtle orbital congestion
findings that, if not specifically examined for, may be
overlooked. Carotid-cavernous sinus fistula is an impor-
tant diagnostic entity to consider when evaluating a
patient with a chronic red eye that does not respond to
topical antibacterial or antiallergic medications.87
Ophthalmic signs and symptoms are the most
frequent clinical manifestations of CCSF and are the
result of vascular congestion. The clinical manifestations
are more severe in direct CCSFs than indirect CCSFs.88
Clinical findings include pulsatile proptosis; head, ocu-
lar, or facial pain; chemosis; periorbital edema; and
conjunctival injection. Detailed inspection of the red
eye in a patient with CCSF will reveal ‘‘arterialization’’ of
the conjunctival blood vessels (Fig. 16). The presence of
an orbital bruit, to either the examiner or the patient, is
very often present in type A CCSFs. Double vision is
very common in patients with CCSFs, and can occur
from either an ocular motor cranial neuropathy (often a
sixth nerve palsy) or extraocular muscle restriction from
orbital congestion.88 Glaucoma can occur in up to 50%
of patients, often due to raised episcleral venous pres-
sure.86 Visual loss can occur because of retinal or optic
nerve dysfunction. Sudden worsening of the eye findings
in some patients is the result of thrombosis of the
superior ophthalmic vein.89 Nonocular manifestations
of CCSF include epistaxis, intracerebral hemorrhage,
and subarachnoid hemorrhage.
The gold standard diagnostic test for establishing
the diagnosis of a CCSF is catheter angiography. How-
ever, CT and MRI may reveal enlargement of the
extraocular muscle and/or the superior ophthalmic
vein. Some patients may not require treatment of their
CCSF. Dural CCSFs can spontaneously close in 20 to
50% of patients.88 Most CCSFs can be closed by
endovascular embolization therapy.90
CONCLUSION
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The orbital syndromes are composed of a diverse group
of diseases that can be both diagnostic and therapeutic
challenges. Familiarity with the orbital anatomy and the
spectrum of orbital diseases is important in the clinical
recognition of orbital syndromes. Thyroid-associated
orbitopathy is the most common orbital syndrome.
NSOI is a diagnosis of exclusion that requires a trial of
systemic corticosteroids. Perineural orbital invasion of
cutaneous squamous cell carcinoma should be considered
in all patients with a history of cutaneous squamous cell
carcinoma of the head and face with sensory and motor
findings. Rhino-orbital-cerebral mucormycosis is a life-
threatening infection often seen in patients with diabetes
mellitus in ketoacidosis. A chronic red eye can be the
manifestation of a carotid-cavernous sinus fistula.
ACKNOWLEDGMENTS
This article is greatly enhanced by the work of two of the
most talented medical illustrators in the business: Dave
Peace, M.S., University of Florida Brain Institute,
Gainesville, FL; and John Richardson, Malcolm Randall
Veterans Administration Medical Center, Gainesville,
FL; and by the excellent editorial support of Mabel
Wilson. The author would also like to thank all his
patients who so graciously consented to allow their
images to be published.
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