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The Journal of Emergency Medicine, Vol. 35, No. 3, pp. 239 –246, 2008
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doi:10.1016/j.jemermed.2007.04.020
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EVALUATION OF THIRD NERVE PALSY IN THE EMERGENCY DEPARTMENT
Michael M. Woodruff,
MD
and Jonathan A. Edlow,
MD
Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Reprint Address: Michael M. Woodruff, MD, Department of Emergency Medicine, Beth Israel Deaconess Medical Center, One
Deaconess Rd., Boston, MA 02215
e Abstract—Third nerve palsy is an uncommon condition
that carries significant risk of serious disease due to both
the variability of its presentation and its association with
intracranial aneurysms. In this article, we review the existing literature on the pathophysiology, diagnosis, and management of third nerve palsy presenting to the Emergency
Department. © 2008 Elsevier Inc.
CASE PRESENTATION
A 59-year-old man with a history of migraines presented
to the Emergency Department (ED) complaining of approximately 5 weeks of progressive double vision and a
mild headache that began gradually 2–3 days prior. On
the day of presentation, the patient had noted left facial
and eye pain that was described as “sharper” in nature,
and unusual. The patient had vomited once before arrival. In the ED, the patient appeared comfortable and
had normal vital signs. There was ptosis of the left
eyelid, with a sluggishly reactive pupil and partial inability to adduct the left eye. In its resting position, the left
eye was deviated laterally and inferiorly. On further
examination, there was no chemosis or proptosis of the
affected eye, and visual acuity was normal. The contralateral eye was completely normal. Cranial nerves II
and IV–XII were normal. Strength, sensation, reflexes,
and cerebellar function were normal.
The neurology team was consulted, and they agreed
that this was a case of isolated partial CN III palsy. A
magnetic resonance imaging (MRI) scan of the brain was
normal, and magnetic resonance angiography (MRA)
showed no evidence of an aneurysm causing the CN III
dysfunction. The emergency physician and the neurologist agreed that the patient had a high pre-test probability
of an aneurysm causing this type of CN III palsy; therefore, the neurosurgeon was consulted, and a traditional
catheter angiogram was performed. A 5-mm saccular
aneurysm was discovered originating from the posterior
e Keywords—third nerve palsy; emergency medicine; cranial neuropathy; dilatated pupil
INTRODUCTION
Of all the cranial nerve palsies, isolated dysfunction of
the third nerve (CN III) is a particularly thorny issue
for the emergency physician. Although rare, it is a
condition that demands thorough and appropriate evaluation due to its frequent association with intracranial
aneurysms (1,2). Furthermore, the clinical presentation of third nerve dysfunction is remarkably varied—
the nerve supplies seven different muscles, and almost
any combination of these can be affected to varying
degrees. Over the past 50 years, a good deal of work
has been done to define the anatomic and pathologic
features of third nerve palsies to enable clinicians to
determine when an aneurysm might be the cause of the
palsy. In this article we review the existing literature
on CN III palsy and offer a straightforward approach
to the problem that is useful to the practicing emergency physician.
RECEIVED: 18 October 2005; FINAL
ACCEPTED: 12 November 2006
SUBMISSION RECEIVED:
27 June 2006;
239
240
M. M. Woodruff and J. A. Edlow
communicating artery. After lengthy discussions, the patient opted for endovascular coiling of the aneurysm,
because the risk of rupture of symptomatic aneurysms is
likely to be higher than that of asymptomatic aneurysms.
QUESTION 1: IS THIS A THIRD NERVE
PALSY?
The presentation of third nerve palsy is extremely varied,
so the clinician must think of this possibility with complaints relating to the eye. A CN III dysfunction can
present with diplopia, ptosis, eye pain, headache, pupillary dilatation, monocular blurry vision, or any combination thereof (3). Unfortunately, the differential diagnosis for these complaints is broad and includes
myasthenia gravis, botulism, orbital infections, orbital
trauma, lens pathology, retinal pathology, migraine, and
dysfunction of cranial nerves III, IV, and VI.
A careful history will quickly narrow the differential.
For example, it must be established whether the diplopia
is monocular (does not resolve with closing one eye) or
binocular (resolves on closing one eye), because the
differential diagnosis for monocular diplopia is generally
limited to refractive or ocular problems. The physician
must search for any associated symptoms, such as facial
or extremity weakness, fevers, or changes in speech, gait,
or coordination that might suggest the presence of intracranial infection, hemorrhage, ischemia, or mass. If any
historical or clinical features suggest spontaneous subarachnoid hemorrhage (e.g., sudden onset of severe
headache, meningismus, photophobia) a non-contrast
head computed tomography (CT) scan should be performed; if CT is non-diagnostic, lumbar puncture should
be performed. Although opthalmoplegic migraine can
cause CN III palsy, the diagnosis of migraine headache
in a patient without a history of such should not be made
without neurologic workup.
To confirm the diagnosis of CN III palsy, the physician must perform a detailed physical examination of the
eye. CN III has a number of motor functions (Table 1).
To examine the pupil, a light is shined directly into
the eye, and note is made of the degree of constriction of
the iris muscle. Bright ambient light may interfere with
this examination by constricting the pupil too much, so
ideally the room lights should be dimmed. The process is
repeated in the opposite eye, and the two responses are
compared. The consensual reflex (constriction of the
contralateral pupil with illumination of the ipsilateral
pupil) is also noted. If CN III is affected, the ipsilateral
pupil will react sluggishly to both direct and consensual light. If the pupil involvement is “complete,” the
pupil will not react at all.
To examine the levator palpebrae muscle, note is
made of the portion of the iris that is covered by the
upper lid, and compared with the opposite side. Ptosis
can be exaggerated by having the patient look up. If
ptosis is present, the patient should be tested for lid
fatigue: the ptosis may worsen when the patient refrains
from blinking for a time or attempts to maintain upgaze.
Ptosis from myasthenia gravis is often asymmetric, fatigable, and improves with short periods of rest (4). Other
conditions causing ptosis include Horner’s syndrome,
botulism (or injection of botulinum toxin), palpebral
trauma, and cluster headache; ptosis also may be congenital (5). “Pseudoptosis” is caused by enopthalmos
(e.g., from an orbital blowout fracture), which makes the
lid seem to be relatively lower on the side with the
sunken globe.
Examination of the extraocular muscles should begin
with inspection of the resting position of the pupils when
the gaze is directed straight ahead. Subtle differences in
the orientation of the pupils can be detected by noting the
position of the reflection of the examiner’s light in the
pupil and comparing it to the opposite pupil. The patient
is then asked to perform ductions, or movement of the
eyes through all the cardinal directions. Any or all of the
motor divisions of CN III may be affected, and palsy
may be complete or partial; if there is complete palsy of
the oculomotor functions of CN III, the patient will be
unable to elevate or adduct the corresponding eye and the
eye will assume the classic “down and out” resting
position (Figure 1). This is due to the remaining input of
Table 1. Individual Functions of CN III
Muscle
Action
How to Test
Pupillary Constrictor
Ciliary muscles
Miosis (pupillary constriction)
Accommodation (thickening of the lens)
Levator palpebrae superioris
Superior rectus
Inferior rectus
Inferior oblique
Medial rectus
Opening of eyelid
Supero-lateral gaze
Infero-lateral gaze
Supero-medial gaze
Adduction
Shine light in each eye, compare response
Watch pupillary response as light is brought
close to patient’s nose
Examine resting position of lid relative to pupil
Test lateral/supero-lateral gaze
Test lateral/infero-lateral gaze
Test medial/supero-medial gaze
Test medial gaze
Third Nerve Palsy in the ED
Figure 1. Complete CN III palsy. The affected eye assumes a
“down and out” resting position due to unopposed input
from CN VI and CN IV. The pupil is dilatated and ptosis is
present.
the abducens nerve (CN VI—abduction of the eye) and
the trochlear nerve (CN IV—abduction and depression
of the eye).
In addition to examination of the cranial nerves, the
physical examination for diplopia or eye pain should
include inspection for chemosis or conjunctival injection,
proptosis, or evidence of trauma to the eye. If any physical examination findings are not consistent with CN III
palsy, other diagnoses should be considered.
Differentiating Third Nerve Palsy from Other Causes
of the Isolated Dilatated Pupil
Although there are very few data in the literature regarding CN III palsy presenting as an isolated dilatated pupil
with normal oculomotor function and without ptosis, it is
generally agreed to be extremely rare; an aneurysmal
cause is even rarer (6).
The more common causes of the isolated dilatated
pupil include exposure to pharmacologic agents, trauma
to the iris or ciliary ganglion, glaucoma, and Adie’s tonic
pupil. These can be determined using simple tests that
can be performed in the ED. A number of authors have
suggested a stepwise approach to determining the etiology of a dilatated pupil (7,8).
First, determine whether the pupil reacts normally. If
it constricts briskly to direct light, then the problem may
be a lack of sympathetic tone in the contralateral eye,
making the “normal” ipsilateral eye appear dilatated.
This can be caused by disruption of the sympathetic
pupillary fibers (such as in Horner’s syndrome) or by
pharmacologic agents such as pilocarpine. Additionally,
up to 20% of the population may have a slight physiologic anisocoria, usually 1 mm or less (9). In general, the
pupil that reacts slowly to light is the abnormal one.
Visual acuity and visual fields should be carefully
tested; ipsilateral optic nerve injury may result in a
relative afferent pupillary defect and vision loss. Relative
afferent pupillary defect is elicited with the swinging
flashlight test; the pupil will show decreased constriction
241
to direct illumination, but will constrict normally when
the contralateral eye is illuminated.
Next, test the extraocular movements. Normal extraocular movements make a third nerve palsy very unlikely. If extraocular movements are affected, the third
nerve palsy should be further investigated, as described
later in this article. With normal eye movements, the next
step is to exclude a pharmacologic cause. A careful
history directed at any inadvertent exposures to mydriatics is essential. Some authors recommend instilling
topical 1% pilocarpine into the affected eye; in the case
of pharmacologic blockade by parasympatholytics (scopolamine, atropine), the pupil will not constrict; in the
case of third nerve palsy, the pupil will constrict briskly.
In the case of mydriasis caused by sympathomimetics,
the pupil will also constrict, but these patients also
should have blanched conjunctivae and a retracted upper
eyelid (10).
Next, perform a careful slit-lamp examination. Structural abnormalities of the iris and anterior chamber can
cause acute sphincter dysfunction, and usually present
with a history of ocular trauma, visual loss, or eye pain.
Slit lamp examination may reveal sphincter tears. Intraocular pressure should be measured to exclude angleclosure glaucoma.
If the preceding diagnostic steps have been performed
and no definite etiology has been determined, the patient
may have a tonic pupil. Adie’s tonic pupil syndrome is
believed to be a defect affecting parasympathetic pupil
fibers after they leave the ciliary ganglion.
The condition occurs more frequently (70%) in
women, and the patient will often present with blurred
near vision, with relative sparing of distance vision.
Examination shows poor response to accommodation,
and a slit-lamp examination will reveal sector palsies of
the iris. Because the iris is functionally denervated, the
pupil will show super-sensitivity to low-dose (0.063–
0.125%) pilocarpine (11). A weaker concentration of
pilocarpine is preferred, as stronger concentrations may
cause a normal pupil to constrict and yield false-positive
results. Adie’s pupil requires non-emergent referral to an
ophthalmologist. Approximately 50% will recover within 2
years.
QUESTION 2: IS THIS AN ISOLATED
CN III PALSY?
CN III is most often affected in combination with other
cranial nerves, particularly II, IV, V, and VI. An understanding of the anatomy of the third nerve can help
identify neurological deficits that frequently accompany
CN III palsy. A careful cranial nerve examination, in
conjunction with a general neurological examination (in-
242
cluding observing the patient’s gait), will differentiate an
isolated CN III palsy from the more common situation
where multiple neurological deficits are present.
Midbrain/Brainstem
The nerve begins with a cluster of nuclei near the center
of the midbrain, at the level of the superior colliculus;
nerve fascicles exit ventrally through the brainstem into
the interpeduncular cistern (12,13). Isolated CN III palsy
has been reported from brainstem lesions, but lesions in
this region usually affect surrounding cerebellar or brainstem structures, and cause a number of syndromes: Weber’s syndrome (CN III palsy with contralateral limb
weakness), Benedikt’s syndrome (CN III palsy with contralateral cerebellar tremor), Nothnagel’s syndrome (CN
III palsy with cerebellar ataxia), or internuclear ophthalmoplegia (adduction weakness with contralateral nystagmus upon abduction) (14 –17). Infarction, arteriovenous
malformation, cavernous hemangioma, neoplasm, multiple sclerosis, and traumatic injury have been implicated
in this type of lesion (18,19).
Subarachnoid Space
In the subarachnoid space of the interpeduncular cistern,
the nerve passes the basilar artery, superior cerebellar
artery, and travels in close proximity to the posterior
communicating artery (Figure 2). Because there are few
other neural structures in this area, aneurysms of the
posterior communicating artery, basilar artery, and superior cerebellar artery tend to cause an isolated CN III
palsy.
Figure 2. Superior view of the Circle of Willis. An aneurysm
arising from the posterior communicating artery is shown
compressing papillary motor fibers in the supero-medial
aspect of CN III.
M. M. Woodruff and J. A. Edlow
Cavernous Sinus
The nerve then enters the cavernous sinus, where it is in
close proximity to nerves IV, V, VI, and the carotid
artery (20). Lesions in this region (cavernous sinus
thrombosis, carotid artery aneurysms) typically involve
some combination of III, IV, V, or VI palsy, along with
evidence of impaired venous drainage from the eye (chemosis or proptosis).
Orbital Apex
In the cavernous sinus, the nerve divides into superior
and inferior divisions, then enters the orbital apex
through the superior orbital fissure, where it travels with
the optic nerve, ophthalmic artery, nerve VI, and the
nasociliary branch of V1 (21). Lesions affecting CN III
in the orbital apex are usually accompanied by facial
numbness (superior division of CN V) and visual loss
(CN II) (22).
QUESTION 3: WHAT IS THE RISK OF
INTRACRANIAL ANEURYSM WITH
ISOLATED CN III PALSY?
The key issue to address for a patient presenting with CN
III palsy is whether or not the palsy is caused by an
intracranial aneurysm. Several recent studies have clarified the natural history of unruptured intracranial aneurysms: the 5-year risk of rupture is highly variable (between 0% and 50% per year), and depends on size and
location of the aneurysm. The aneurysms with the highest rates of rupture (posterior communicating and basilar
tip aneurysms) are also the aneurysms most likely to
cause an isolated CN III palsy; these posterior circulation
aneurysms have a rate of rupture between 2.5% and 50%,
depending upon the size of the aneurysm (23). In addition, cranial nerve palsy from an aneurysm likely reflects
an acute change (hemorrhage or expansion) in the aneurysm; these aneurysms may have a higher risk of rupture.
When intracranial aneurysms rupture, the subsequent
mortality and morbidity are extremely high. A large
percentage of patients die from the initial rupture, and the
rest (up to 70% in some series) experience significant
morbidity from rebleeding or subsequent vasospasm and
stroke (24 –27). Although some debate exists about the
best strategy for management of unruptured but symptomatic intracranial aneurysms, it is a diagnosis that
carries significant risk, and should be established or
excluded with urgency (28).
Isolated CN III palsy is a relatively rare phenomenon:
the exact incidence has not been established in the liter-
Third Nerve Palsy in the ED
ature, but roughly 1300 cases were reported at the Mayo
Clinic between 1958 and 1992 (29). A significant number (18 –29% in the larger series) of isolated CN III
palsies, however, are caused by cerebral aneurysms
(1,30). Over the years, a number of authors have attempted to define clinical and historical factors that identify patients at risk of having an aneurysmal cause of CN
III palsy. This approach is supported by anatomical data
and case series, but due to the low incidence of the
disease, not by large prospective studies.
CN III dysfunction can be classified according to
whether the pupil is involved (pupil-involving or pupilsparing) and the degree of extraocular muscle dysfunction (partial or complete). This distinction is important
because it has long been held that when an aneurysm (or
other compressive lesion) is the cause of third nerve
palsy, the pupil will almost always (95–97% of the time)
be involved; this has become known as “the rule of the
pupil” (1,31). The anatomic basis of the rule of the pupil
is the arrangement of the pupillary constrictor fibers
within the subarachnoid portion of the nerve. Fibers that
supply the pupillary constrictors are located superficially
in the dorsomedial aspect of the nerve (Figure 2), and are
readily compressed by an aneurysm arising from the
posterior communicating artery (32).
In early retrospective case series, there seems to be a
subset of third nerve palsies that do not involve the pupil
at all, and occur mainly in people with diabetes, hypertension, or with other vasculopathic risk factors (33,34).
These cases of CN III palsy tend to resolve over time,
and are attributed to pathologic changes in the vasa
nervorum and ischemic injury to the axons located
deeper within the nerve bundle.
Thus, the rule of the pupil came to mean that patients
with pupil-sparing CN III palsy, particularly those over
age 50 years with vasculopathic risk factors, could safely
be managed with outpatient observation, and without
cerebral angiography. This type of pupil-sparing CN III
palsy has become known as “diabetic third nerve palsy.”
The mechanism of this type of CN III palsy is not well
delineated, but pathological studies have revealed arteriolar thickening and demyelinating lesions consistent
with microvascular ischemia of the nerve (35,36).
Although there has been one case report of a pupilsparing complete oculomotor palsy caused by a basilar
apex aneurysm, it is generally accepted that patients over
the age of 50 years with vasculopathic risk factors and
complete pupil-sparing CN III palsy can be observed as
outpatients without neuroimaging (6,33,37). This should
be done in consultation with a neurologist or a neuroophthalmologist. Younger patients without strong risk
factors should undergo neuroimaging before the diagnosis of microinfarctive or “diabetic” palsy is made.
243
The “rule of the pupil” has an important caveat: there
have been numerous cases of incomplete CN III palsies
caused by aneurysms that do not involve the pupil (2,38 –
41). These partial extraocular palsies are likely due to the
fact that initially an aneurysm (in particular a basilar
apex aneurysm) may not compress the supero-medial
aspect of the nerve where the pupillary fibers travel.
Many partial oculomotor palsies that initially seem to
spare the pupil will eventually go on to involve the pupil
(33).
IMAGING DETECTION OF INTRACRANIAL
ANEURYSMS
Magnetic resonance imaging of the brain and cerebral
vessels is generally the preferred method of imaging
third nerve palsies, because it provides not only a means
of identifying intracranial aneurysms, but also a means of
identifying non-aneurysmal causes of CN III palsy such
as tumor and inflammatory conditions. The sensitivity of
MRA for aneurysms has increased in recent years as the
technology improves. Sensitivities between 88% and
97% have been reported for larger (⬎ 5 mm) aneurysms,
lower for smaller aneurysms (42,43). There is evidence,
though, that some types of aneurysms (e.g., thrombosed
and low-flow aneurysms) may be difficult to detect with
MRI, regardless of size. In addition, some patients cannot undergo MRI scan due to implanted materials, claustrophobia, or inability to lie still for a relatively lengthy
scan.
Computed tomography angiography (CTA) has the
advantages of being rapid, less invasive, and a lower
contrast load than contrast angiography. It also provides
a three-dimensional picture of the aneurysm and the
relevant skull-base anatomy. Sensitivity varies with aneurysm size, ranging from 86 –97% (44,45).
Catheter angiography, although traditionally the gold
standard for diagnosing aneurysms, carries a small risk
(approximately 1%) of neurologic morbidity and a small
risk of mortality. The emergency physician is unlikely to
be ordering this test without the involvement of a consultant, but should be aware that it is an option in the
evaluation of CN III palsy.
SUMMARY: DIAGNOSTIC APPROACH
(FIGURE 3)
Two subsets of CN III palsy seem to be at lower risk for
intracranial aneurysm. The first is the isolated dilatated
pupil. In the comatose patient, unilateral pupillary dilatation is often due to CN III compression by the medial
temporal lobe in the setting of elevated intracranial pres-
244
M. M. Woodruff and J. A. Edlow
Figure 3. Schema for evaluation of third nerve palsy.
sure: this is obviously an emergency. But in the awake,
neurologically normal patient with a dilatated pupil and
no other complaints, CN III palsy is exceedingly unlikely. Investigation in this situation should be aimed at
identifying the cause of pupil palsy (see previous text).
The second subset is the complete pupil-sparing CN III
palsy or “diabetic” CN III palsy. The existing evidence
suggests that if the patient fits the appropriate profile
(diabetic or other risk factors for microvascular disease,
age over 50 years), the patient may be safely discharged
with outpatient neurological follow-up. All other types of
isolated CN III palsy carry a higher risk of intracranial
aneurysm, and should prompt neuroimaging and consultation with a neurologist. In particular, complete pupilinvolving and partial pupil-involving CN III palsies represent the highest risk for aneurysm—in one study, 36%
of CN III palsies caused by aneurysm had complete pupil
involvement and complete extraocular palsy (2). Although obviously a decision that should be made in
consultation with a specialist, some authors recommend
proceeding to conventional catheter angiography in these
patients if MRA or CTA scan is negative. Some attempts
have been made in the literature to define the risk of
aneurysm by whether the oculomotor palsy is partial or
complete; however, there is very little standardization in
the neuro-ophthalmologic literature regarding the definition of a complete CN III palsy. Thus, this is probably
a determination best made by a neurologist or neuroophthalmologist and not by the emergency physician.
In general, it is our opinion that as neuroimaging
modalities become more accessible, the approach to imaging of third nerve palsy is becoming (appropriately)
Third Nerve Palsy in the ED
more liberal. The existing literature on CN III palsy is
largely from referral ophthalmology and neurology clinics, and probably does not represent the population seen
in the ED. In addition, the physicians evaluating the
patients in these case series are specialists with a great
deal of experience with the evaluation of cranial nerve
palsy. Much of the literature is also from the pre-MRA/
CTA era, and may reflect a different approach to imaging
than is currently recommended. Therefore, we advocate
a conservative approach to the workup of third nerve
palsies, with liberal use of consultation and imaging. The
decision of whether and how to image a CN III palsy is
best made in consultation with a specialist. Specifically,
the decision to follow an MRA or CTA scan with catheter angiography is based on the clinical likelihood of an
intracranial aneurysm as determined from the patient’s
symptoms, risk factors, and physical examination. The
clinician must be aware of the limitations of the various
imaging tests available, and recognize that if a high
pre-test probability of aneurysm exists, the post-test
probability may still be unacceptably high, even with a
negative test result (46).
Acknowledgment—The authors acknowledge the help of Jane
Hayward and Jennifer McGrath in preparing the illustrations.
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