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The Journal of Emergency , Vol. 35, No. 3, pp. 239–246, 2008 Copyright © 2008 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/08 $–see front matter doi:10.1016/j.jemermed.2007.04.020

Original Contributions

EVALUATION OF THIRD 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 CASE PRESENTATION that carries significant risk of serious due to both the variability of its presentation and its association with A 59-year-old man with a history of migraines presented intracranial . In this article, we review the exist- to the Emergency Department (ED) complaining of ap- ing literature on the pathophysiology, diagnosis, and man- proximately 5 weeks of progressive double vision and a agement of third nerve palsy presenting to the Emergency Department. © 2008 Elsevier Inc. mild headache that began gradually 2–3 days prior. On the day of presentation, the patient had noted left facial e Keywords—third nerve palsy; emergency medicine; cra- and eye pain that was described as “sharper” in nature, nial neuropathy; dilatated and unusual. The patient had vomited once before ar- rival. In the ED, the patient appeared comfortable and had normal vital signs. There was of the left INTRODUCTION , with a sluggishly reactive pupil and partial inabil- ity to adduct the left eye. In its resting position, the left Of all the cranial nerve palsies, isolated dysfunction of eye was deviated laterally and inferiorly. On further the third nerve (CN III) is a particularly thorny issue examination, there was no chemosis or proptosis of the for the emergency physician. Although rare, it is a affected eye, and visual acuity was normal. The con- condition that demands thorough and appropriate eval- tralateral eye was completely normal. Cranial II uation due to its frequent association with intracranial and IV–XII were normal. Strength, sensation, reflexes, aneurysms (1,2). Furthermore, the clinical presenta- and cerebellar function were normal. tion of third nerve dysfunction is remarkably varied— The team was consulted, and they agreed the nerve supplies seven different muscles, and almost that this was a case of isolated partial CN III palsy. A any combination of these can be affected to varying magnetic resonance imaging (MRI) scan of the was degrees. Over the past 50 years, a good deal of work normal, and magnetic resonance angiography (MRA) has been done to define the anatomic and pathologic showed no evidence of an causing the CN III features of third nerve palsies to enable clinicians to dysfunction. The emergency physician and the neurolo- determine when an aneurysm might be the cause of the gist agreed that the patient had a high pre-test probability palsy. In this article we review the existing literature of an aneurysm causing this type of CN III palsy; there- on CN III palsy and offer a straightforward approach fore, the neurosurgeon was consulted, and a traditional to the problem that is useful to the practicing emer- catheter angiogram was performed. A 5-mm saccular gency physician. aneurysm was discovered originating from the posterior

RECEIVED: 18 October 2005; FINAL SUBMISSION RECEIVED: 27 June 2006; ACCEPTED: 12 November 2006 239 240 M. M. Woodruff and J. A. Edlow communicating artery. After lengthy discussions, the pa- To examine the pupil, a is shined directly into tient opted for endovascular coiling of the aneurysm, the eye, and note is made of the degree of constriction of because the risk of rupture of symptomatic aneurysms is the muscle. Bright ambient light may interfere with likely to be higher than that of asymptomatic aneurysms. this examination by constricting the pupil too much, so ideally the room should be dimmed. The process is repeated in the opposite eye, and the two responses are compared. The consensual reflex (constriction of the QUESTION 1: IS THIS A THIRD NERVE contralateral pupil with illumination of the ipsilateral PALSY? pupil) is also noted. If CN III is affected, the ipsilateral pupil will react sluggishly to both direct and consen- The presentation of third nerve palsy is extremely varied, sual light. If the pupil involvement is “complete,” the so the clinician must think of this possibility with com- pupil will not react at all. plaints relating to the eye. A CN III dysfunction can To examine the levator palpebrae muscle, note is present with , ptosis, eye pain, headache, pupil- made of the portion of the iris that is covered by the lary dilatation, monocular blurry vision, or any combi- upper lid, and compared with the opposite side. Ptosis nation thereof (3). Unfortunately, the differential diag- can be exaggerated by having the patient look up. If nosis for these complaints is broad and includes ptosis is present, the patient should be tested for lid myasthenia gravis, botulism, orbital infections, orbital fatigue: the ptosis may worsen when the patient refrains trauma, pathology, retinal pathology, migraine, and from blinking for a time or attempts to maintain upgaze. dysfunction of III, IV, and VI. Ptosis from myasthenia gravis is often asymmetric, fat- A careful history will quickly narrow the differential. igable, and improves with short periods of rest (4). Other For example, it must be established whether the diplopia conditions causing ptosis include Horner’s syndrome, is monocular (does not resolve with closing one eye) or botulism (or of botulinum toxin), palpebral binocular (resolves on closing one eye), because the trauma, and cluster headache; ptosis also may be con- differential diagnosis for monocular diplopia is generally genital (5). “Pseudoptosis” is caused by enopthalmos limited to refractive or ocular problems. The physician (e.g., from an orbital blowout fracture), which makes the must search for any associated symptoms, such as facial lid seem to be relatively lower on the side with the or extremity weakness, fevers, or changes in speech, gait, sunken . or coordination that might suggest the presence of intra- Examination of the should begin cranial infection, hemorrhage, ischemia, or mass. If any with inspection of the resting position of the when historical or clinical features suggest spontaneous sub- the gaze is directed straight ahead. Subtle differences in arachnoid hemorrhage (e.g., sudden onset of severe the orientation of the pupils can be detected by noting the headache, meningismus, ) a non-contrast position of the reflection of the examiner’s light in the head computed tomography (CT) scan should be per- pupil and comparing it to the opposite pupil. The patient formed; if CT is non-diagnostic, lumbar puncture should is then asked to perform ductions, or movement of the be performed. Although opthalmoplegic migraine can eyes through all the cardinal directions. Any or all of the cause CN III palsy, the diagnosis of migraine headache motor divisions of CN III may be affected, and palsy in a patient without a history of such should not be made may be complete or partial; if there is complete palsy of without neurologic workup. the oculomotor functions of CN III, the patient will be To confirm the diagnosis of CN III palsy, the physi- unable to elevate or adduct the corresponding eye and the cian must perform a detailed physical examination of the eye will assume the classic “down and out” resting eye. CN III has a number of motor functions (Table 1). 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 (pupillary constriction) Shine light in each eye, compare response Ciliary muscles (thickening of the lens) Watch as light is brought close to patient’s nose Levator palpebrae superioris Opening of eyelid Examine resting position of lid relative to pupil Superior rectus Supero-lateral gaze Test lateral/supero-lateral gaze Inferior rectus Infero-lateral gaze Test lateral/infero-lateral gaze Inferior oblique Supero-medial gaze Test medial/supero-medial gaze Medial rectus Adduction Test medial gaze Third Nerve Palsy in the ED 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 Figure 1. Complete CN III palsy. The affected eye assumes a “down and out” resting position due to unopposed input history directed at any inadvertent exposures to mydri- from CN VI and CN IV. The pupil is dilatated and ptosis is atics is essential. Some authors recommend instilling present. topical 1% pilocarpine into the affected eye; in the case of pharmacologic blockade by (sco- polamine, ), the pupil will not constrict; in the the (CN VI—abduction of the eye) and case of third nerve palsy, the pupil will constrict briskly. the (CN IV—abduction and depression In the case of caused by sympathomimetics, of the eye). the pupil will also constrict, but these patients also In addition to examination of the cranial nerves, the should have blanched conjunctivae and a retracted upper physical examination for diplopia or eye pain should eyelid (10). include inspection for chemosis or conjunctival injection, Next, perform a careful slit-lamp examination. Struc- proptosis, or evidence of trauma to the eye. If any phys- tural abnormalities of the iris and anterior chamber can ical examination findings are not consistent with CN III cause acute sphincter dysfunction, and usually present palsy, other diagnoses should be considered. with a history of ocular trauma, visual loss, or eye pain. examination may reveal sphincter tears. In- traocular pressure should be measured to exclude angle- Differentiating Third Nerve Palsy from Other Causes closure . of the Isolated Dilatated Pupil If the preceding diagnostic steps have been performed and no definite etiology has been determined, the patient Although there are very few data in the literature regard- may have a tonic pupil. Adie’s tonic pupil syndrome is ing CN III palsy presenting as an isolated dilatated pupil believed to be a defect affecting parasympathetic pupil with normal oculomotor function and without ptosis, it is fibers after they leave the . generally agreed to be extremely rare; an aneurysmal The condition occurs more frequently (70%) in cause is even rarer (6). women, and the patient will often present with blurred The more common causes of the isolated dilatated near vision, with relative sparing of distance vision. pupil include exposure to pharmacologic agents, trauma Examination shows poor response to accommodation, to the iris or ciliary ganglion, glaucoma, and Adie’s tonic and a slit-lamp examination will reveal sector palsies of pupil. These can be determined using simple tests that the iris. Because the iris is functionally denervated, the can be performed in the ED. A number of authors have pupil will show super-sensitivity to low-dose (0.063– suggested a stepwise approach to determining the etiol- 0.125%) pilocarpine (11). A weaker concentration of ogy of a dilatated pupil (7,8). pilocarpine is preferred, as stronger concentrations may First, determine whether the pupil reacts normally. If cause a normal pupil to constrict and yield false-positive it constricts briskly to direct light, then the problem may results. Adie’s pupil requires non-emergent referral to an be a lack of sympathetic tone in the contralateral eye, ophthalmologist. Approximately 50% will recover within 2 making the “normal” ipsilateral eye appear dilatated. years. 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, QUESTION 2: IS THIS AN ISOLATED up to 20% of the population may have a slight physio- CN III PALSY? logic , usually 1 mm or less (9). In general, the pupil that reacts slowly to light is the abnormal one. CN III is most often affected in combination with other Visual acuity and visual fields should be carefully cranial nerves, particularly II, IV, V, and VI. An under- tested; ipsilateral may result in a standing of the anatomy of the third nerve can help relative afferent pupillary defect and vision loss. Relative identify neurological deficits that frequently accompany afferent pupillary defect is elicited with the swinging CN III palsy. A careful cranial nerve examination, in flashlight test; the pupil will show decreased constriction conjunction with a general neurological examination (in- 242 M. M. Woodruff and J. A. Edlow cluding observing the patient’s gait), will differentiate an isolated CN III palsy from the more common situation where multiple neurological deficits are present. 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- The nerve begins with a cluster of nuclei near the center mosis or proptosis). of the midbrain, at the level of the ; nerve fascicles exit ventrally through the brainstem into the (12,13). Isolated CN III palsy Orbital Apex has been reported from brainstem lesions, but lesions in this region usually affect surrounding cerebellar or brain- In the cavernous sinus, the nerve divides into superior stem structures, and cause a number of syndromes: We- and inferior divisions, then enters the orbital apex ber’s syndrome (CN III palsy with contralateral limb through the superior orbital fissure, where it travels with weakness), Benedikt’s syndrome (CN III palsy with con- the optic nerve, ophthalmic artery, nerve VI, and the tralateral cerebellar tremor), Nothnagel’s syndrome (CN nasociliary branch of V1 (21). Lesions affecting CN III III palsy with cerebellar ), or internuclear ophthal- in the orbital apex are usually accompanied by facial moplegia (adduction weakness with contralateral nystag- numbness (superior division of CN V) and visual loss mus upon abduction) (14–17). , arteriovenous (CN II) (22). malformation, cavernous hemangioma, neoplasm, multi- ple sclerosis, and traumatic injury have been implicated in this type of lesion (18,19). QUESTION 3: WHAT IS THE RISK OF WITH ISOLATED CN III PALSY?

Subarachnoid Space The key issue to address for a patient presenting with CN III palsy is whether or not the palsy is caused by an In the subarachnoid space of the interpeduncular cistern, intracranial aneurysm. Several recent studies have clari- the nerve passes the basilar artery, superior cerebellar fied the natural history of unruptured intracranial aneu- artery, and travels in close proximity to the posterior rysms: the 5-year risk of rupture is highly variable (be- communicating artery (Figure 2). Because there are few tween 0% and 50% per year), and depends on size and other neural structures in this area, aneurysms of the location of the aneurysm. The aneurysms with the high- posterior communicating artery, basilar artery, and supe- est rates of rupture (posterior communicating and basilar rior cerebellar artery tend to cause an isolated CN III tip aneurysms) are also the aneurysms most likely to palsy. 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 (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 Figure 2. Superior view of the Circle of Willis. An aneurysm excluded with urgency (28). arising from the posterior communicating artery is shown compressing papillary motor fibers in the supero-medial Isolated CN III palsy is a relatively rare phenomenon: aspect of CN III. the exact incidence has not been established in the liter- Third Nerve Palsy in the ED 243 ature, but roughly 1300 cases were reported at the Mayo The “rule of the pupil” has an important caveat: there Clinic between 1958 and 1992 (29). A significant num- have been numerous cases of incomplete CN III palsies ber (18–29% in the larger series) of isolated CN III caused by aneurysms that do not involve the pupil (2,38– palsies, however, are caused by cerebral aneurysms 41). These partial extraocular palsies are likely due to the (1,30). Over the years, a number of authors have at- fact that initially an aneurysm (in particular a basilar tempted to define clinical and historical factors that iden- apex aneurysm) may not compress the supero-medial tify patients at risk of having an aneurysmal cause of CN aspect of the nerve where the pupillary fibers travel. III palsy. This approach is supported by anatomical data Many partial oculomotor palsies that initially seem to and case series, but due to the low incidence of the spare the pupil will eventually go on to involve the pupil disease, not by large prospective studies. (33). 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- IMAGING DETECTION OF INTRACRANIAL tion (partial or complete). This distinction is important ANEURYSMS because it has long been held that when an aneurysm (or other compressive lesion) is the cause of third nerve Magnetic resonance imaging of the brain and cerebral palsy, the pupil will almost always (95–97% of the time) vessels is generally the preferred method of imaging be involved; this has become known as “the rule of the third nerve palsies, because it provides not only a means pupil” (1,31). The anatomic basis of the rule of the pupil of identifying intracranial aneurysms, but also a means of is the arrangement of the pupillary constrictor fibers identifying non-aneurysmal causes of CN III palsy such within the subarachnoid portion of the nerve. Fibers that as tumor and inflammatory conditions. The sensitivity of supply the pupillary constrictors are located superficially MRA for aneurysms has increased in recent years as the technology improves. Sensitivities between 88% and in the dorsomedial aspect of the nerve (Figure 2), and are 97% have been reported for larger (Ͼ 5 mm) aneurysms, readily compressed by an aneurysm arising from the lower for smaller aneurysms (42,43). There is evidence, posterior communicating artery (32). though, that some types of aneurysms (e.g., thrombosed In early retrospective case series, there seems to be a and low-flow aneurysms) may be difficult to detect with subset of third nerve palsies that do not involve the pupil MRI, regardless of size. In addition, some patients can- at all, and occur mainly in people with diabetes, hyper- not undergo MRI scan due to implanted materials, claus- tension, or with other vasculopathic risk factors (33,34). trophobia, or inability to lie still for a relatively lengthy These cases of CN III palsy tend to resolve over time, scan. and are attributed to pathologic changes in the vasa Computed tomography angiography (CTA) has the nervorum and ischemic injury to the located advantages of being rapid, less invasive, and a lower deeper within the nerve bundle. contrast load than contrast angiography. It also provides Thus, the rule of the pupil came to mean that patients a three-dimensional picture of the aneurysm and the with pupil-sparing CN III palsy, particularly those over relevant skull-base anatomy. Sensitivity varies with an- age 50 years with vasculopathic risk factors, could safely eurysm size, ranging from 86–97% (44,45). be managed with outpatient observation, and without Catheter angiography, although traditionally the gold cerebral angiography. This type of pupil-sparing CN III standard for diagnosing aneurysms, carries a small risk palsy has become known as “diabetic third nerve palsy.” (approximately 1%) of neurologic morbidity and a small The mechanism of this type of CN III palsy is not well risk of mortality. The emergency physician is unlikely to delineated, but pathological studies have revealed arte- be ordering this test without the involvement of a con- riolar thickening and demyelinating lesions consistent sultant, but should be aware that it is an option in the with microvascular ischemia of the nerve (35,36). evaluation of CN III palsy. 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 SUMMARY: DIAGNOSTIC APPROACH the age of 50 years with vasculopathic risk factors and (FIGURE 3) complete pupil-sparing CN III palsy can be observed as outpatients without neuroimaging (6,33,37). This should Two subsets of CN III palsy seem to be at lower risk for be done in consultation with a neurologist or a neuro- intracranial aneurysm. The first is the isolated dilatated ophthalmologist. Younger patients without strong risk pupil. In the comatose patient, unilateral pupillary dila- factors should undergo neuroimaging before the diagno- tation is often due to CN III compression by the medial sis of microinfarctive or “diabetic” palsy is made. 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, of CN III palsies caused by aneurysm had complete pupil neurologically normal patient with a dilatated pupil and involvement and complete extraocular palsy (2). Al- no other complaints, CN III palsy is exceedingly un- though obviously a decision that should be made in likely. Investigation in this situation should be aimed at consultation with a specialist, some authors recommend identifying the cause of pupil palsy (see previous text). proceeding to conventional catheter angiography in these The second subset is the complete pupil-sparing CN III patients if MRA or CTA scan is negative. Some attempts palsy or “diabetic” CN III palsy. The existing evidence have been made in the literature to define the risk of suggests that if the patient fits the appropriate profile aneurysm by whether the oculomotor palsy is partial or (diabetic or other risk factors for microvascular disease, complete; however, there is very little standardization in age over 50 years), the patient may be safely discharged the neuro-ophthalmologic literature regarding the defini- with outpatient neurological follow-up. All other types of tion of a complete CN III palsy. Thus, this is probably isolated CN III palsy carry a higher risk of intracranial a determination best made by a neurologist or neuro- aneurysm, and should prompt neuroimaging and consul- ophthalmologist and not by the emergency physician. tation with a neurologist. In particular, complete pupil- In general, it is our opinion that as neuroimaging involving and partial pupil-involving CN III palsies rep- modalities become more accessible, the approach to im- resent the highest risk for aneurysm—in one study, 36% aging of third nerve palsy is becoming (appropriately) Third Nerve Palsy in the ED 245 more liberal. The existing literature on CN III palsy is 13. Porter JD, Guthrie BL, Sparks DL. Innervation of monkey extraoc- largely from referral and neurology clin- ular muscles: localization of sensory and motor neurons by retro- grade transport of horseradish peroxidase. J Comp Neurol 1983; ics, and probably does not represent the population seen 218:208–19. in the ED. In addition, the physicians evaluating the 14. Keane JR. Isolated brain-stem third nerve palsy. Arch Neurol patients in these case series are specialists with a great 1988;45:813–4. 15. Mark AS. 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