The Journal of Emergency Medicine, Vol. 35, No. 3, pp.
239 246, 2008
doi:10.1016/j.jemermed.2007.04.020
Original
Contributions
EVALUATION OF THIRD NERVE PALSY IN THE EMERGENCY DEPARTMENT
Michael M. Woodruff, MD and Jonathan A. Edlow,
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 AbstractThird 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 exist-
ing literature on the pathophysiology, diagnosis, and man-
agement of third nerve palsy presenting to the Emergency
Department. 2008 Elsevier Inc.
e Keywordsthird nerve palsy; emergency medicine;
cra-nial 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 eval-uation due
to its frequent association with intracranial aneurysms
(1,2). Furthermore, the clinical presenta-tion 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 emer-gency
physician.
RECEIVED: 18 October 2005; FINAL SUBMISSION RECEIVED: 27 June 2006;
ACCEPTED: 12 November 2006
239
Copyright 2008 Elsevier Inc.
Printed in the USA. All rights reserved
0736-4679/08 $see front matter
MD
CASE PRESENTATION
A 59-year-old man with a history of migraines presented
to the Emergency Department (ED) complaining of ap-
proximately 5 weeks of progressive double vision and a
mild headache that began gradually 23 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 ar-
rival. 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
inabil-ity 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
con-tralateral eye was completely normal. Cranial
nerves II and IVXII 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 neurolo-gist agreed that
the patient had a high pre-test probability of an aneurysm
causing this type of CN III palsy; there-fore, the
neurosurgeon was consulted, and a traditional catheter
angiogram was performed. A 5-mm saccular aneurysm was
discovered originating from the posterior
240
communicating artery. After lengthy discussions, the pa-
tient 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
com-plaints relating to the eye. A CN III dysfunction can
present with diplopia, ptosis, eye pain, headache, pupil-
lary dilatation, monocular blurry vision, or any combi-
nation thereof (3). Unfortunately, the differential diag-
nosis 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 intra-
cranial infection, hemorrhage, ischemia, or mass. If any
historical or clinical features suggest spontaneous sub-
arachnoid hemorrhage (e.g., sudden onset of severe
headache, meningismus, photophobia) a non-contrast head
computed tomography (CT) scan should be per-formed; 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 physi-
cian must perform a detailed physical examination of the
eye. CN III has a number of motor functions (Table 1).
Table 1. Individual Functions of CN III
Muscle Action
Pupillary Constrictor Miosis (pupillary constriction)
Ciliary muscles Accommodation (thickening of the lens)
Levator palpebrae superioris Opening of eyelid
Superior rectus Supero-lateral gaze
Inferior rectus Infero-lateral gaze
Inferior oblique Supero-medial gaze
Medial rectus Adduction
M. M. Woodruff and J. A. Edlow
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 consen-sual
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, fat-
igable, and improves with short periods of rest (4).
Other conditions causing ptosis include Horners
syndrome, botulism (or injection of botulinum toxin),
palpebral trauma, and cluster headache; ptosis also may
be con-genital (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 examiners 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
How to Test
Shine light in each eye, compare response
Watch pupillary response as light is brought
close to patients 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 VIabduction of the eye) and
the trochlear nerve (CN IVabduction 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 phys-ical 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 regard-
ing 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 Adies 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 etiol-
ogy 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 Horners syndrome) or by
pharmacologic agents such as pilocarpine. Additionally,
up to 20% of the population may have a slight physio-
logic 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 ex-
traocular movements make a third nerve palsy very un-
likely. 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 mydri-
atics is essential. Some authors recommend instilling
topical 1% pilocarpine into the affected eye; in the case
of pharmacologic blockade by parasympatholytics (sco-
polamine, 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. Struc-
tural 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. In-
traocular pressure should be measured to exclude angle-
closure glaucoma.
If the preceding diagnostic steps have been performed
and no definite etiology has been determined, the patient
may have a tonic pupil. Adies 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. Adies 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 under-
standing 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 patients 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 brain-stem
structures, and cause a number of syndromes: We-bers
syndrome (CN III palsy with contralateral limb weakness),
Benedikts syndrome (CN III palsy with con-tralateral
cerebellar tremor), Nothnagels syndrome (CN
III palsy with cerebellar ataxia), or internuclear ophthal-
moplegia (adduction weakness with contralateral nystag-
mus upon abduction) (14 17). Infarction, arteriovenous
malformation, cavernous hemangioma, neoplasm, multi-
ple 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 supe-
rior 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
(che-mosis 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 clari-
fied the natural history of unruptured intracranial aneu-
rysms: the 5-year risk of rupture is highly variable (be-
tween 0% and 50% per year), and depends on size and
location of the aneurysm. The aneurysms with the high-est
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 addi-tion, cranial
nerve palsy from an aneurysm likely reflects an acute
change (hemorrhage or expansion) in the aneu-rysm; 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 symp-tomatic 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 num-ber
(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 at-tempted to define
clinical and historical factors that iden-tify 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 pupil-
sparing) and the degree of extraocular muscle dysfunc-
tion (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 (9597% 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, hyper-
tension, 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 arte-
riolar thickening and demyelinating lesions consistent with
microvascular ischemia of the nerve (35,36).
Although there has been one case report of a pupil-
sparing 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 neuro-
ophthalmologist. Younger patients without strong risk
factors should undergo neuroimaging before the diagno-sis
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 can-not undergo MRI scan due
to implanted materials, claus-trophobia, 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 an-
eurysm 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 con-
sultant, 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 dila-
tation is often due to CN III compression by the medial
temporal lobe in the setting of elevated intracranial pres-
244
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 un-likely.
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 consul-tation with a
neurologist. In particular, complete pupil-involving and
partial pupil-involving CN III palsies rep-resent the highest
risk for aneurysmin one study, 36%
M. M. Woodruff and J. A. Edlow
of CN III palsies caused by aneurysm had complete pupil
involvement and complete extraocular palsy (2). Al-though
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 defini-tion of a complete CN III
palsy. Thus, this is probably a determination best made by a
neurologist or neuro-ophthalmologist and not by the
emergency physician.
In general, it is our opinion that as neuroimaging
modalities become more accessible, the approach to
im-aging 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 clin-
ics, 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 cath-eter angiography is based on the
clinical likelihood of an intracranial aneurysm as
determined from the patients 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).
AcknowledgmentThe authors acknowledge the help of Jane
Hayward and Jennifer McGrath in preparing the illustrations.
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