Neuro-Ophthalmic Emergencies For The Neurologist: Abstract: A Variety of Acute Neurologic Disorders Present With

ORIGINAL ARTICLE
Neuro-Ophthalmic Emergencies for the Neurologist

Valerie Purvin, MD,* and Aki Kawasaki, MD
Abstract: A variety of acute neurologic disorders present with visual signs and symptoms. In this review the authors focus on those disorders in which the clinical outcome is dependent on timely and accurate diagnosis. The rst section deals with acute visual loss, specically optic neuritis, ischemic optic neuropathy (ION), retinal artery occlusion, and homonymous hemianopia. The authors include a discussion of those clinical features that are helpful in distinguishing between inammatory and ischemic optic nerve disease and between arteritic and nonarteritic ION. The second section concerns disc edema with an emphasis on the prevention of visual loss in patients with increased intracranial pressure. The third section deals with abnormal ocular motility, and includes orbital inammatory disease, carotid cavernous stulas, painful ophthalmoplegia, conjugate gaze palsies, and neuromuscular junction disorders. The nal section concerns pupillary abnormalities, with a particular emphasis on the dilated pupil and on carotid artery dissection. Throughout there are specic guidelines for the management of these disorders, and areas are highlighted in which there is ongoing controversy. Key Words: emergency, neuro-ophthalmology, acute visual loss (The Neurologist 2005;11: 195233)
Most patients with acute visual loss can be categorized into 3 groups: (1) those with optic nerve disease, most commonly optic neuritis (ON) or ischemic optic neuropathy; (2) those with retinal disease, usually arterial occlusion; and (3) patients with homonymous deficits.
ACUTE VISUAL LOSS

Acute visual loss can be caused by a variety of conditions affecting the retina, optic nerve, or brain. The approach to the patient with acute visual loss entails rst localizing the site of the disease process and then differentiating among specic disorders. Before embarking on an emergent evaluation, it is important to conrm that the visual loss in fact is acute; in other words, distinguishing between sudden onset and sudden discovery of a visual decit. Patients may be unaware of monocular visual loss until the fellow eye is occluded, as when rubbing one eye. It is therefore helpful to ask just what the patient was doing when the visual loss occurred. In addition to this temporal historical feature, patients are sometimes mistaken regarding the spatial nature of their visual lossspecically, they may not distinguish between monocular and hemield decits. The organization of the visual system that results in homonymous loss is not intuitively apparent to most individuals and many will perceive a homonymous hemianopic defect as involving just the eye with the temporal eld loss. While formal visual eld testing will usually clarify the true nature of the defect, we can generally get a helpful preview from the history. Inability to see half of someones face or half of a clock, for example, is inconsistent with monocular loss and points instead to homonymous hemianopia. A detailed description of the visual loss can often provide enough information to differentiate among disorders affecting the ocular media, the retina, and the optic nerve. For example, seeing halos around lights indicates aberration of the ocular media; acute onset of this symptom with eye pain
n this review of neuro-ophthalmic emergencies we start by limiting our discussion to those disorders that tend to present acutely and we further highlight those conditions in which the clinical outcome is dependent on a timely and accurate diagnosis. We emphasize conditions that typically present to the practicing neurologist, particularly those areas in which diagnostic errors are common. Our discussion is divided into sections on acute visual loss, disc edema, abnormal ocular motility, and anisocoria.
From the *Midwest Eye Institute and the Indiana University Medical Center, Departments of Ophthalmology and Neurology, Indianapolis, Indiana; and the Hopital Ophtalmique Jules Gonin, Lausanne, Switzerland. Reprints: Valerie Purvin, MD, Midwest Eye Institute, 201 Pennsylvania Parkway, Indianapolis, IN 46280. E-mail: vpurvin@iupui.edu. Copyright 2005 by Lippincott Williams & Wilkins ISSN: 1074-7931/05/1104-0195 DOI: 10.1097/01.nrl.0000159981.73413.2e
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is characteristic of the corneal edema produced by an attack of angle closure glaucoma. Visual distortions including alteration of size (micropsia) and shape (metamorphopsia) are highly characteristic of retinal disease and are not reported by patients with visual loss of optic nerve origin. Patients with optic neuropathy typically describe dimming or darkening of vision whereas problems with the ocular media cause blurring. The perception of a discrete, sharply demarcated scotoma is very characteristic of retinal disease. The perception of light ashes or photopsias occurs in both optic nerve and retinal disease, but when persistent and prolonged, indicates a retinal disorder. Photopsias induced by eye movement may also occur in ON. The presence or absence of pain is another helpful historical feature: Although certain optic neuropathies are typically associated with pain (eg, ON), retinal disease is characteristically painless. The exception to this observation is pain due to ischemia of other orbital structures that may accompany retinal visual loss secondary to giant cell arteritis or high-grade carotid stenosis. When the history suggests an optic nerve or retinal disorder, examination ndings can usually distinguish between the two. While detailed fundus examination may be helpful in this regard, such observation may not be available to the nonophthalmologist, especially in an emergency setting in which pharmacologic dilation may be contraindicated. In addition, in some retinal disorders ophthalmoscopic abnormalities may be subtle, invisible, or misleading. In most cases of monocular visual loss the most helpful feature of the examination is pupillary function. The presence of a relative afferent pupil defect (RAPD) indicates optic neuropathy. Marked visual loss due to retinal disease may cause a very small RAPD, but in such cases the retinal pathology is generally evident on fundus examination. Based on these clinical features, most patients with acute visual loss can be categorized into 3 groups: (1) those with optic nerve disease, most commonly ON or ischemic optic neuropathy; (2) those with retinal disease, usually arterial occlusion; and (3) patients with homonymous decits.
Optic Neuritis (ON)

While a number of inammatory diseases can cause inammation of the optic nerve, by far the most common form encountered in neurologic practice is acute demyelinating ON, which may occur in isolation or as a manifestation of multiple sclerosis (MS).1 ON usually affects young adults age 20 to 45 years. Most patients present with acute monocular visual loss that is usually associated with ipsilateral pain on eye movement. Central vision is usually affected, causing decreased visual acuity and loss of color vision. When unilateral, an RAPD is always present. The optic disc acutely may be swollen (papillitis) or normal (retrobulbar neuritis).2 ON is generally a clinical diagnosis. In cases with typical clinical ndings, laboratory testing is unlikely to be revealing3 (Table 1). Ancillary testing for possible systemic inammatory conditions such as systemic lupus erythematosus, syphilis, sarcoidosis, and Lyme disease should be considered optional. In cases with atypical ndings, it is appropriate to obtain additional laboratory testing. These atypical features include age outside the usual range, progression of visual loss for greater than 2 weeks, fever or other constitutional symptoms, and other neurologic or ocular decits. Although not generally required for diagnosing the condition, radiographic conrmation can be obtained in most cases. Computed tomography (CT) is relatively insensitive for the detection of optic nerve inammation, but magnetic resonance imaging (MRI) will show abnormalities in most cases4,5 (Fig. 1). One study of 32 patients with ON using a 1.5-T MRI scanner found increased STIR signal in 84% of cases and gadolinium enhancement in 97%.6 To achieve this level of sensitivity it is important to include dedicated orbit views with fat suppression and Gadolinium infusion. This technique is also helpful for distinguishing ON from optic perineuritis (OPN), considered a localized form of orbital inammatory disease (also termed orbital pseudotumor, discussed later) in which the optic nerve sheath is the target tissue.7 This distinction is best made on coronal views in which the enhancement appears within the nerve substance in
TABLE 1. Clinical Features That Distinguish Optic Neuritis From Optic Perineuritis Optic Neuritis Age at onset Visual loss Time course Natural history Response to corticosteroid treatment MRI Usually young adults (only 15% 50 years) Usually central Progression over days Spontaneous recovery Variable (uncommon relapse after stopping) Optic nerve enhancement white matter lesions Optic Perineuritis Broader range 36% 50 years Often paracentral/arcuate Progression over weeks Progressive visual loss Prompt, dramatic; common relapse after brief treatment Perineural enhancement; streaky fat EOM enhancement
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ON but around the nerve in OPN (Fig. 2). Although a denitive diagnosis of OPN is radiographic, several clinical features are helpful (Table 1). The distinction between ON and OPN has prognostic and therapeutic implications. In approximately 50% of patients with ON, MRI scanning also reveals white matter lesions in the brain, a nding with prognostic signicance.2 The likelihood of clinically denite MS developing in the next 2 years is 32% in patients with such MRI abnormalities versus only 3% in patients with a normal scan.8 By 10 years these numbers increase to 60% and 20% respectively.9 The natural history of ON includes a good prognosis for visual recovery, with 95% of patients achieving nal visual acuity of 20/40 or better.10 This visual outcome cannot be further improved with treatment.3 Corticosteroids have, however, been shown to affect the disease process temporarily by reducing the likelihood of suffering a second demyelinating event by one half for the next 2 years.8 This benecial effect has only been demonstrated with the intravenous (IV) route of administration and apparently wears off after 2 years. Treatment with oral corticosteroids, in contrast, has been associated with an increased likelihood of recurrent events over a similar time period and is therefore discouraged. Given that all patients in the study from which these data derive were treated within 7 days of onset, it is not known whether treatment beyond this interval confers similar benet. Ideally, corticosteroid treatment should not be given prior to MRI because the characteristic enhancement pattern of OPN may be dampened. While in the Optic Neuritis Treatment Trial study IV steroids were administered as 250 mg methylprednisolone every 6 hours for 3 days in an inpatient setting, the incidence of complications was so low that this treatment is now often given without hospital admission. For convenience, outpatient treatment is usually given as a single 1-g dose of methylprednisolone infused over 30 to 60 minutes each day for 3 days. IV treatment is then followed by an 11-day course of oral prednisone 60 mg/day (or 1 mg/kg/day) followed by a 4-day taper (20 mg on day 1, 10 mg on days 2 4). Corticosteroid treatment has also been shown to speed recovery, which is particularly valuable in cases with signicant pain and/or bilateral visual loss. Treatment considerations should be individualized and the question of when to treat with corticosteroids remains controversial.11 It should be clear to the physician and the patient that corticosteroids are not offered to improve the visual outcome, but rather to decrease the chances of developing MS for a nite time period. In patients with a normal MRI, this risk is already so low that no benecial effect can be demonstrated.
FIGURE 1. Idiopathic optic neuritis. (A) Axial fat-suppressed T1-weighted MRI with gadolinium shows enhancement of the 2005 Lippincott Williams & Wilkins
anterior half of the right intraorbital optic nerve. (B) Coronal view confirms enhancement within the substance of the nerve. (C) MRI of the head shows white matter lesions characteristic of multiple sclerosis.
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contrast to ON, oral prednisone in OPN is not contraindicated. Treatment is usually continued for several months.7
Vascular insufficiency in the territory of the posterior ciliary arteries causes infarction of the optic disc, termed anterior ischemic optic neuropathy.
Anterior Ischemic Optic Neuropathy (AION)

Vascular insufciency in the territory of the posterior ciliary arteries causes infarction of the optic disc, termed anterior ischemic optic neuropathy (AION). Ischemia of the retrobulbar optic nerve, termed posterior ION (PION), is much less common. Patients with AION typically experience sudden onset of monocular visual loss that is often present on awakening. Optic disc edema is often segmental, and splinter hemorrhages on the disc are common. AION is generally divided into cases due to giant cell arteritis (GCA), termed arteritic AION, and those due to other factors, referred to as nonarteritic AION (NAION). Prompt recognition and treatment of the arteritic form constitutes an important neuroophthalmic emergency and is emphasized in this discussion. Some clinical features are different in the arteritic and nonarteritic forms, and therefore the 2 disorders are discussed separately.
Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)

NAION is a relatively common disorder, typically affecting middle-age and older individuals.12,13 Pathogenesis is probably multifactorial, including some degree of atherosclerosis and an underlying predisposing optic disc structure (a crowded, cupless disk-at-risk).14 Recent interest has focused on the role of systemic hypotension in the pathogenesis of this disorder. Occasionally, episodes of profound hypotension (eg, cardiac arrest) precipitate ischemic optic neuropathy. In addition, a possible role of less cataclysmic nocturnal hypotension, particularly that induced by antihypertensive medication, has been posited in the pathogenesis of this disorder.15,16 Other mechanisms that may contribute to optic nerve infarction include vasospasm, loss of normal local autoregulation, hypercoagulable states, and the metabolic and circulatory changes that occur in sleep apnea syndrome (SAS).14 It is helpful to keep these various potential mechanisms in mind when making treatment decisions for patients with this condition.
FIGURE 2. Idiopathic optic perineuritis. (A) Axial T1-weighted MRI with gadolinium reveals intense enhancement along the left optic nerve sheath. (B) The coronal view confirms that the inflammation primarily involves the nerve sheath. In addition, there is streaky enhancement of the orbital fat and very mild swelling of extraocular muscles.
Treatment considerations for patients with OPN are different: The visual loss of OPN is highly corticosteroidresponsive and tends to be progressive if not treated. In
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Notably absent from this list of etiologic factors are carotid artery disease and emboli. In contrast to retinovascular occlusive events that involve the central retinal artery, emboli are rarely implicated in the pathogenesis of NAION. Due to laminar ow, emboli traveling within the ophthalmic artery are much more likely to arrive within the central or branch retinal arteries. The posterior ciliary arteries emerge more at a right angle from the ophthalmic artery and are therefore not susceptible to emboli. While rare cases of AION secondary to complete carotid occlusion,17 carotid dissection,18 or emboli19 have been reported, carotid artery disease has not been found in a higher percentage of patients with NAION compared with age-matched control subjects.20 When carotid artery stenosis is found in AION patients it is just as likely to involve the contralateral side as the side with the visual loss.21 Specic features that suggest that carotid artery disease may have played a role in an episode of AION include preceding transient monocular visual loss, dimming of vision with changes of posture or exertion, ipsilateral pain, and associated Horner syndrome. In these settings, carotid ultrasonography may be appropriate. In the large majority of patients with NAION, however, carotid artery imaging is not indicated. Visual loss due to NAION is usually painless and often present on awakening. Inferior altitudinal loss is the most common pattern, frequently with normal visual acuity. Optic disc edema may be diffuse or segmental, and peripapillary splinter hemorrhages are common (Fig. 3). Visual loss is most often maximal at onset but up to one third of patients experience further decline of vision over the next 10 days, termed progressive NAION.22 Once disc edema has resolved, usually within a few weeks, further visual loss is highly unlikely. Some modest improvement of visual acuity is common in the months following an episode of NAION, but visual eld defects are typically permanent.23 A repeat epi-
FIGURE 3. Nonarteritic anterior ischemic optic neuropathy. (A) The right optic disc is diffusely swollen with a few nerve fiber layer hemorrhages. (B) The left disc is crowded with no physiologic cup. 2005 Lippincott Williams & Wilkins
sode in the same eye is rare; however, 15 to 40% of patients will experience a similar attack in the fellow eye in the future.24 The diagnosis of NAION is a clinical one. In most cases few ancillary tests are needed. The main diagnostic challenge is usually identifying those patients with the arteritic variety of AION (discussed later). In the management of patients with NAION, it is important to look for possible contributory factors such as hypotension, anemia, and hypoxemia. Patients should be questioned regarding recent changes in antihypertensive medications (especially nighttime dosing) and the use of other medications that might have a hypotensive or vasoconstrictive effect, such as -blockers, diuretics, sildenal, and decongestants. Efforts should be made to reverse any possible systemic factors that may have played a role in disc infarction. In the case of hypotension, this might include discontinuing or decreasing the dose of antihypertensive medications, or changing the timing of the medication dose. In cases of an acute drop in perfusion pressure, the use of pressor agents, colloid, and blood replacement may be considered.25 This is especially true in postoperative ION. It has been suggested that obstructive SAS may play a role in NAION26 and it is therefore appropriate to inquire about prominent snoring with apneic spells, excessive daytime somnolence and recent weight gain, particularly in portly, middle-age men. Treatment options for NAION are limited. A variety of treatment modalities have been tried, but none with proven efcacy. Corticosteroids and hyperbaric oxygen have not been found to be benecial.27 Recent interest has focused on a possible role for topical brimonidine tartrate, which has been reported to exert a neuroprotective effect for retinal ganglion cells in an experimental animal model.28 There have been no controlled studies of the use of this agent in patients with NAION, but a retrospective series suggested that, rather than a benecial effect, treatment might actually worsen the visual outcome.29 Initial enthusiasm for optic nerve sheath fenestration30 was not supported by subsequent studies, including a prospective, randomized, multicenter trial in which patients treated surgically actually fared worse in terms of visual outcome compared with nonoperated control subjects.23 More recently, transvitreal radial optic neurotomy, which has been employed more extensively for patients with central retinal vein occlusion, has been considered as a possible treatment of NAION, but data at this point are quite preliminary.31 Although there are no established treatments for NAION, as clinicians we are often called on to make management decisions on the basis of incomplete information. To this end, some patients with acute NAION are treated empirically with brimonidine and/or pentoxifylline on the grounds that these agents are unlikely to be harmful and may confer some benet. The impulse to treat is particularly strong when caring for a patient who has suffered previous
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loss from NAION in the fellow eye. Many patients are started on aspirin in the hopes of preventing future vascular events. In occasional cases in which an inammatory component is suspected, oral corticosteroids are sometimes given.
TABLE 2. Visual Manifestations of Giant Cell Arteritis Ischemic optic neuropathy Anterior (most common) Posterior Retinal ischemia Central retinal artery occlusion Cilioretinal artery occlusion Cotton wool spots Anterior segment ischemia Poorly reactive pupil Corneal edema Conjunctival injection Low intraocular pressure Occipital ischemia Homonymous hemianopia Cortical blindness Abnormal ocular motility Extraocular muscle ischemia Cranial nerve palsy (III, IV, VI) Eye pain Transient visual loss or diplopia
Arteritic anterior ischemic optic neuropathy is sometimes preceded by episodes of transient monocular visual loss indistinguishable from embolic events.
Arteritic Anterior Ischemic Optic Neuropathy (Arteritic AION)

Giant cell arteritis (GCA) is an autoimmune disorder that affects older individuals.32,33 Average age at onset is about 70 years; the disease is rare in those younger than the age of 60 and is virtually unheard of in individuals younger than 50. An antigen-driven, T-cell-mediated attack on the internal elastic lamina leads to obstruction of the lumen of medium and large arteries, and thus causes signs and symptoms due to ischemia.34 The disease has a predilection for the extracranial circulation, frequently resulting in ischemic pain involving the head, face, and neck. Most patients also have constitutional symptoms including loss of appetite, fever, night sweats, malaise, and body aches. Such premonitory symptoms are usually present for 2 to 3 months prior to the onset of visual loss, but often elude diagnosis because of their varied expression. Involvement of the visual pathways is common in GCA, occurring in approximately 50% of patients.35 Visual loss most often takes the form of AION, but there are other clinical manifestations with which the clinician should be familiar as well36 (Table 2). Arteritic AION is sometimes preceded by episodes of transient monocular visual loss indistinguishable from embolic events. This is a rare occurrence in nonarteritic AION. Such episodic loss is typically associated with disc edema and is an ominous sign of impending visual loss. The degree of visual loss in GCA is often quite profound; many patients experience loss to the point of no light perception. Fundus examination usually reveals a chalky white swollen disc, in contrast to the more hyperemic swelling in cases of NAION (Fig. 4). Cotton wool spots, indicating retinal ischemia, may be present in the same or the fellow eye. Less commonly there is central retinal or cilioretinal artery occlusion; while less common, the latter is virtually a sine qua non of GCA. Bilateral ocular involvement is common, with the event in the second eye usually occurring within the rst 2 weeks after initial onset of visual loss. The
FIGURE 4. Giant cell arteritis. (A) The right disc shows marked pallid edema. Vision in this eye was no light perception. (B) The left disc is normal but there are cotton wool spots throughout the retina. The cup in this eye is larger than is usually seen in the fellow (unaffected) eye of nonarteritic anterior ischemic optic neuropathy. This observation should suggest a diagnosis of giant cell arteritis.
supercial temporal arteries are commonly but not always tender and may be rm and nonpulsatile (Fig. 5). Necrotic areas of the scalp, tongue, throat, or gums may occasionally be present as well. Laboratory abnormalities are common in GCA, including elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The ESR may, however, be normal in up to 20% of individuals with GCA, and therefore other clinical features must also be taken into account. CRP is more sensitive and is rarely normal in biopsy-proved cases of GCA.37 In addition, CRP is not affected by anemia or concentrations of plasma proteins. Anemia is common in
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Temporal Artery (TA) Biopsy Denitive diagnosis requires TA biopsy; however, biopsy results are falsely negative in 5 to 15% of cases.40,41 When TA biopsy is negative, contralateral biopsy may be performed, but the diagnostic yield in such cases is low.42 44 In cases with a relatively low clinical suspicion of the disease, one negative biopsy is generally sufcient.45 In cases when the clinical ndings are strongly suggestive of the disease, it may be appropriate to perform simultaneous bilateral biopsies, anticipating that the contralateral side will be needed if the rst specimen is negative. In select cases, continued treatment is given despite negative biopsies based on a strong clinical suspicion of disease.
Treatment should thus be initiated on suspicion of the diagnosis. Initial treatment of giant cell arteritis consists of high-dose corticosteroids.
FIGURE 5. Giant cell arteritis. This 80-year-old man had a 1-month history of scalp tenderness and jaw claudication. He sought medical attention because of episodes of diplopia. The superficial temporal arteries were prominent, tender, and nonpulsatile.
GCA and thrombocytosis is present in 44% of patients.38 Current laboratory investigation for suspected GCA should include both ESR and CRP, CBC with platelet count, and blood glucose determination. Cytokines, such as interleukin-6, which induce the acute-phase reactants, are currently being explored as possibly more accurate markers of disease activity.39
C-reactive protein is more sensitive and is rarely normal in biopsy-proved cases of giant cell arteritis.
Treatment Once visual loss has occurred, the chances of reversal with treatment are low. However, in most cases contralateral visual loss can be prevented with prompt intervention.46 Treatment should thus be initiated on suspicion of the diagnosis. Initial treatment of GCA consists of high-dose corticosteroids given either by an IV or oral route.47,48 Serologic markers for inammation are exquisitely responsive to corticosteroids and therefore blood for laboratory tests should be obtained prior to initiating treatment. The histopathologic changes of GCA, however, persist despite corticosteroid therapy48 and thus treatment should never be withheld for concern of obscuring biopsy results. As a general rule, if the clinical ndings are sufciently compelling to warrant biopsy, the patient should be protected with corticosteroids while results are pending.49 There are no randomized, prospective trials comparing different routes of steroid administration. Anecdotal reports have documented a surprising degree of visual recovery in occasional patients treated with either route. Retrospective studies by Liu et al50 and by Chan and ODay51 have suggested a better visual outcome with IV treatment; however, a larger series reported by Hayreh and Zimmerman52 found no such difference. Despite our lack of solid data on which to base a recommendation, many experts in this eld advocate immediate high-dose corticosteroids for patients with acute visual loss and for those in whom visual loss seems imminent (eg, those with disc edema and/or transient visual loss). Proposed regimens include dexamethasone 10
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mg IV push or methylprednisolone (SoluMedrol) 1 g infused IV over 1 hour. Methylprednisolone is usually continued at 1 to 4 g/day in 4 divided doses for 3 days followed by oral prednisone 80 mg/day. While high-dose IV corticosteroids were associated with a low incidence of complications in the treatment of ON,8 these results may not apply to an elderly patient population and thus we would recommend all such individuals be hospitalized for the duration of their IV treatment. Alternatively, for patients whose visual loss is less acute, oral corticosteroids may be appropriate, given as prednisone 60 to 100 mg once daily.53 Slow taper after either route can take a number of forms. One regimen uses prednisone 80 mg/day for the rst month, 60 mg/day for the second, and 40 mg/day for the third. The dose is subsequently tapered slowly, monitoring symptoms and laboratory parameters. A shorter course of high-dose prednisone in which patients are switched to alternate-day treatment after just 4 weeks has been proposed,54 but an apparent higher incidence of recurrent visual loss has led to questions about efcacy.55 Regardless of treatment regimen, in most cases of arteritic AION visual loss is severe and permanent.56,57 Further deterioration of vision after initiation of corticosteroids, however, is unusual and, when it does occur, is almost always within the rst 5 days.58 Later onset is rare,59,60 typically occurring in the setting of inappropriate lowering or discontinuation of corticosteroid treatment.61 63 In such cases there are usually symptoms and laboratory evidence suggesting reactivation,57 but rarely such individuals appear to be in remission,50,64 and in these cases repeat biopsy may be useful.47,64
TABLE 3. Clinical Features Distinguishing Optic Neuritis From Anterior Ischemic Optic Neuropathy (AION) Anterior Ischemic Optic Neuropathy (AION) Middle age to elderly Unusual Sudden, often present upon awakening Often 20/20 Commonly altitudinal Always swollen Often segmental Splinter hemorrhages common Minimal
Optic Neuritis Age Eye pain Onset Visual acuity Visual eld Optic disc Young adults Characteristic Progresses for a few days Decreased Central scotoma Normal or swollen When swollen: diffuse Without hemorrhage Excellent
Recovery
Differential Diagnosis Anterior Ischemic Optic Neuropathy (AION) versus Optic Neuritis (ON)
AION and ON can usually be distinguished on clinical grounds based on several key features (Table 3). Patients with ON are generally younger, usually experience eye pain, and have progression of their visual loss over several days.
Patients with AION are older, visual loss is usually painless, and is most often maximal at onset. The disc in AION is always swollen (by denition) whereas in ON the disc may be swollen or normal. Decreased acuity with a central scotoma is common in ON, whereas normal acuity with altitudinal loss is characteristic of AION. Good-quality MRI will demonstrate optic nerve enhancement in most cases of ON, whereas MRI in AION is usually normal. Occasional cases have features that overlap both disorders.62 In such cases the diagnosis can usually be made with more condence several months later, based on the more substantial visual recovery following ON.
Arteritic versus Nonarteritic Anterior Ischemic Optic Neuropathy (AION)

Once a diagnosis of AION is made, the main task is distinguishing arteritic from nonarteritic forms (Table 4). Although TA biopsy is the only denitive means for diagnosing GCA, biopsy is not necessary for all patients with
TABLE 4. Clinical Features That Distinguish Arteritic and Nonarteritic Ischemic Optic Neuropathy Nonarteritic Age Systemic symptoms Visual loss Disc edema Fundus Cup/disc in fellow eye Bilaterality ESR/CRP 5565 years None Moderate Segmental/hyperemic Otherwise normal Small or no cup Later occurrence (years) Normal Arteritic Elderly (average 70 years) Usually present Severe Pallid Cotton wool spots common May be generous Soon (within 2 weeks) Usually elevated
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AION. A number of factors should be taken into consideration in deciding which patients should undergo biopsy, including age, systemic symptoms, severity of visual loss, fundus ndings, and results of laboratory testing. While overall the nonarteritic form is more common, this is not the case at advanced ages. In fact, NAION is unusual in the very elderly. Thus, AION in a patient age 80 years or older is likely to be arteritic. Patients should be specically questioned about arteritic symptoms including polymyalgia rheumatica (especially neck pain), poor appetite, fever, and headache. Patients with scalp tenderness may not think of their pain as a headache. Jaw claudication, considered pathognomonic for GCA, must be distinguished from temporomandibular joint dysfunction and poorly tting dentures. Severe visual loss (hand motions or less), chalky disc edema, and cotton wool spots suggest GCA. Bilateral simultaneous AION that occurs spontaneously (ie, not following profound hypotension) should be assumed to be arteritic, even in the absence of GCA symptoms or laboratory abnormalities. Similarly, a generous cup-to-disc ratio is so unusual in nonarteritic AION that this nding alone should prompt a TA biopsy. All these clinical factors along with laboratory data should weigh into decisions regarding biopsy and interpretation of negative biopsy results.
hemorrhage produces abrupt loss of vision. Associated pain furthers the false impression of ON, although in the case of aneurysmal optic neuropathy the pain is not exacerbated by eye movement and globe tenderness is not present.68,69 Ophthalmic artery aneurysms are more common in women and are frequently bilateral. Patterns of visual eld loss in aneurysmal optic neuropathy vary, but defects that respect the vertical meridian are strongly suggestive of an intracranial localization and are distinctly uncommon in ON. Visual loss involving the nasal eld is characteristic and is sometimes mistaken for low-tension glaucoma.70,71 The presence of similar but subclinical eld loss respecting the vertical meridian in the fellow eye should also cast doubt on a diagnosis of ON. In addition to the pattern of eld loss, symptoms of subarachnoid hemorrhage (such as nuchal rigidity and somnolence) and older age at onset should suggest a diagnosis other than ON.
Pituitary Apoplexy
Hemorrhage or infarction of a pituitary tumor is termed pituitary apoplexy.72 This uncommon condition typically affects adults, with a range of clinical presentations.73 Most patients experience abrupt onset of severe headache, and associated symptoms and signs of meningeal irritation, altered mental status, and visual changes.74 76 The presence of nuchal rigidity, photophobia, and reduced level of consciousness may be mistaken for aneurysmal subarachnoid hemorrhage. MRI has now allowed the detection of hemorrhage into a pituitary tumor in occasional patients who have minimal or no symptoms, although some authors reserve the term apoplexy for those with a dramatic presentation as described here. Visual loss may be unilateral or bilateral and the severity is variable.77 Reduced level of consciousness may preclude detailed visual testing. When such testing is possible, a bitemporal pattern of loss is characteristic. Ophthalmoplegia, usually due to compression of the ocular motor nerves in the cavernous sinus, is also common and may also be unilateral or bilateral. The third nerve is most commonly affected, followed by the sixth and fourth cranial nerves (CNs).78 In the large majority of cases of pituitary apoplexy, the presence of a tumor was not suspected prior to hemorrhage.79 In about one third of patients some sort of precipitating factor can be identied.79 These factors are quite varied, including reduced blood ow to the pituitary gland (as from hypotension and Valsalva maneuvers), an acute increase in blood ow (as in malignant hypertension), stimulation of the pituitary gland (such as pregnancy or with exogenous estrogen administration), emboli from carotid artery surgery and coagulopathy (from administration of anticoagulant drugs, thrombolytic agents, and thrombocytopenia).79 The occurrence of headache and visual symptoms (afferent and/or efferent) in any of these settings should lead to a heightened
Retrobulbar Optic Neuropathies Posterior Ischemic Optic Neuropathy

Optic neuritis often affects the retrobulbar nerve and the clinical features in these cases are in other respects the same as in cases of papillitis. In contrast, the retrobulbar optic nerve is relatively immune to ischemia. When PION does occur, it is usually due either to GCA or to a severe drop in blood pressure. In the latter, prolonged hypotension is often coupled with anemia. Such cases usually occur following lengthy surgical procedures (particularly back surgery), cardiac arrest, or profound blood loss.65 The resulting visual loss is often severe and frequently affects both optic nerves. PION that is not due to GCA or hypotension is rare,66 and this diagnosis should always be made with great caution. Inltrative or compressive lesions at the orbital apex may be misdiagnosed as PION, even in this era of modern neuroimaging.67 Another condition that may be mistakenly attributed to PION is hyperacute central retinal artery occlusion if seen within the rst few hours, before the characteristic retinal whitening has developed. Acute disorders affecting the intracranial optic nerves are also in the differential diagnosis, including suprasellar aneurysms and tumors that may expand suddenly, such as pituitary adenomas.
Aneurysm
Ophthalmic artery aneurysms usually cause slowly progressive optic neuropathy that may be mistaken for normaltension glaucoma, but occasionally sudden expansion and/or
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awareness of the possibility of pituitary apoplexy. The diagnosis is usually apparent on MRI but may be missed with CT, which is often the most easily accessed radiologic study in an emergency room setting (Fig. 6). Acute management of most patients with pituitary apoplexy consists of immediate treatment with systemic corticosteroids in stress dosages (eg, hydrocortisone 100 mg IV every 6 8 hours) with careful monitoring of electrolyte balance.80 Surgical decompression is usually indicated, although occasional patients do well with conservative management.
Retinal Artery Occlusion

Obstruction of the retinal arterial tree may take the form of central retinal artery occlusion (CRAO) or branch retinal artery occlusion (BRAO). In either form, patients with retinal artery occlusion present with sudden, painless, unilateral
visual loss, occasionally heralded by a ash of light. Unlike patients with ischemic optic neuropathy who often notice their visual decit on awakening, patients with retinal artery occlusion can usually recount just what they were doing when their visual loss occurred. Many experience preceding episodes of transient visual loss, often with a curtainlike pattern. While carotid artery disease is the most commonly identied cause of CRAO, the prevalence of hemodynamically significant carotid atherosclerosis is only 11 to 45%.81 83 GCA is another important cause of CRAO in older patients. Ophthalmoscopic ndings in CRAO include retinal whitening, cotton wool spots, box car segmentation of the blood column in retinal arteries and a macular cherry-red spot (Fig. 7). BRAO and occlusion of smaller arteries produce patches of retinal edema and cotton wool spots (Fig. 8). Retinal emboli may be visible and can be a key to the source
FIGURE 6. Pituitary apoplexy. (A) This 38-year-old man presented with acute headache and ophthalmoparesis. (B) The right eye showed mild right upper lid ptosis, decreased adduction, elevation, and depression (partial third nerve palsy). Abduction was normal. (C) Goldmann perimetry revealed a mild bitemporal superior quadrantic defect. (D) Axial CT showed an ill-defined density in the suprasellar cistern. (E) MRI better revealed a pituitary tumor with extension into the right cavernous sinus and an area of recent hemorrhage. Subsequent endocrine evaluation confirmed the clinical impression of acromegaly.
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FIGURE 7. Central retinal vein occlusion. There is diffuse retinal edema with a characteristic cherry-red spot in the macula. The entire retinal artery is markedly thinned with a box car effect in some branches. The retinal veins are irregular in caliber and there are a few intraretinal hemorrhages.
FIGURE 8. Branch retinal artery occlusion. Blockage of the inferior retinal artery has produced retinal whitening with a sharp demarcation from the normal retina.
hours after occlusion, the visual outcome is usually poor, with spontaneous recovery occurring in less than 15% of cases.84 Treatment options are generally divided into 2 major categories: (1) conservative therapies, which include mechanical (ocular massage and paracentesis) and pharmacologic modalities; and (2) invasive measures, including IV and arterial infusion of thrombolytic agents. Although a number of studies have evaluated the relative benets of these various therapies there is, to date, insufcient evidence on which to judge among them.85 Nevertheless, the existing data suggest that treatment can improve on the natural history of this disorder. Incandela et al86 demonstrated an increase in retinal blood ow in 5 patients with CRAO treated with pentoxifylline compared with 5 patients who received placebo. Hyperbaric oxygen was found to improve the visual outcome in a group of 35 CRAO patients versus a control group of 37 who received conservative treatment.87 Improvement of visual acuity was reported in 10 of 12 patients treated with IV recombinant tissue plasminogen activator (rTPA), but all had residual eld defects.88 A systematic protocol that included multiple modalities with observations of retinal arterial ow following each step was shown to result in remarkable visual improvement compared with arbitrary treatment choices.89 Benecial effects on vision have been reported following selective ophthalmic artery catheterization infusion of tPA90,91 or urokinase.92,93 However the number of patients studied in each series was small, most were not randomized, many had no control group, and measured outcomes varied. A meta-analysis of 16 studies summarizing the visual outcome in 100 patients with retinal artery occlusion treated with selective intraarterial brinolysis found a nal visual outcome of 20/40 or better in 27%an outcome that is comparable with some of the conservative treatment studies.94 In this study, improvement of visual acuity was related to the level of vision at presentation and, surprisingly, unrelated to duration of symptoms. There was no difference among different thrombolytic agents. Treatment of hemispheric stroke with rTPA has been shown to be benecial only if infusion is started within 3 hours of symptom onset. Similar limitations presumably exist for the treatment of CRAO, but an exact duration beyond which thrombolytic infusion is futile has not been determined. If treatment of CRAO is contemplated it is important to have a specic plan formulated in advance.
of occlusion. Cholesterol emboli are yellow and squamouslike, and originate in the carotid artery or occasionally the aortic arch. Calcic emboli, in contrast, are whitish and globular, usually originating from the heart or occasionally the great vessels. Plateletbrin emboli, which are long and whitish, appear only eetingly as they pass through the retinal arterial tree. They can arise from either the heart or the vessels. Treatment considerations for CRAO remain problematic. Although recanalization occurs in most cases 48 to 72
Homonymous Visual Loss

The most common visual disturbance that presents acutely to neurologists is homonymous visual loss due to cerebrovascular disease. When due to stroke in the carotid artery territory other focal neurologic decits are usually present. An isolated homonymous visual eld defect of sudden onset is the hallmark of occipital stroke usually due to posterior cerebral artery occlusion.
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Occipital strokes are sometimes preceded by episodes of transient visual loss described as bilateral blurring or dimming, sometimes with ickering that may have a streaming effect like snowakes passing through a headlight beam.95 Embolism is a common cause of occipital infarction, often with a cardiac source. In many cases an embolus initially lodges at the bifurcation of the posterior cerebral arteries causing transient, complete loss of vision, before breaking up and moving to a smaller, more distal branch, resulting in a xed homonymous decit. Such a history is strongly suggestive of an embolic event. Occasionally an occipital stroke may be the rst sign of myocardial infarction or atrial brillation.96 Patients who present with occipital stroke should have an emergent electrocardiogram to look for such conditions. Other less common causes of homonymous visual loss include tumors, hemorrhage, radiation damage, demyelinating disease, and infections (particularly progressive multifocal leukoencephalopathy). MELAS syndrome (mitochondrial encephalopathy with lactic acidosis and strokelike episodes) may present with episodes of homonymous visual loss. A few disorders can cause homonymous visual loss with no detectable changes on MRI, most notably JacobCreutzfeldt disease, Alzheimer disease, and nonketotic hyperglycemia. The syndrome of reversible posterior leukoencephalopathy (RPLS) typically presents with acute visual distur-
TABLE 5. Causes of Reversible Posterior Leukoencephalopathy Hypertensive encephalopathy Eclampsia/preeclampsia Renal failure Seizures Porphyria Chemotherapeutic agents Cisplatin L-asparaginase Methotrexate Cytarabine Immunosuppressive agents Cyclosporine FK 506 Tacrolimus Interferon-alpha
ties of the cerebral vessels, which leads to hyperperfusion breakdown of the blood brain barrier and consequent vasogenic edema. Treatment is generally supportive and the prognosis for visual recovery is good.
OPTIC DISC EDEMA

Optic disc edema is not truly edema, but rather represents swelling of prelaminar retinal axons due to impairment of axoplasmic ow at the level of the lamina cribrosa. Normal axoplasmic ow can be disturbed by a variety of pathologic processes including mechanical obstruction, ischemia, inammation, and some toxins. Thus, optic disc edema is a nonspecic manifestation of injury to the optic nerve head or intraorbital optic nerve. Disease processes affecting the intracranial portion of the optic nerve (such as compressive lesions) do not cause swelling of the optic disc. By convention, the term papilledema refers to optic disc edema that is due to increased intracranial pressure (ICP). It is important to recall that in the face of increased ICP it takes more than 24 hours for disc edema to develop. Moreover, some individuals with increased pressure simply do not express it at the level of the optic disc, presumably for underlying anatomic reasons. Thus, the absence of papilledema never rules out increased ICP. Because disc edema is a nonspecic nding, other clinical features are used to distinguish the mechanism of injury and identify the specic disorder. The most important of these factors is optic nerve function. Conditions that cause optic disc edema with acute visual loss were discussed earlier. In contrast, optic disc edema with normal optic nerve function suggests a different set of disorders (Table 6). In this latter setting, the rst and often the most important task is determining whether disc edema is due to increased ICP.
Optic disc edema is not truly edema, but rather represents swelling of prelaminar retinal axons due to impairment of axoplasmic flow at the level of the lamina cribrosa.
bance usually associated with headache and altered mental status.97 RPLS can be triggered by a variety of conditions that are often, although not invariably, associated with marked systemic hypertension. These disorders include hypertensive encephalopathy, eclampsia and preeclampsia, renal failure, seizures, porphyria, and a variety of immunosuppressive and chemotherapeutic agents (Table 5).97105 MRI abnormalities are characterized by increased signal on T2-weighted and FLAIR sequences.106,107 Diffusion-weighted imaging can be normal or may demonstrate increased diffusion consistent with vasogenic edema.108,109 Contrast enhancement is variable.109 The parietal occipital regions are usually involved with relative sparing of the frontal regions. The syndrome is thought to represent a failure of the autoregulatory capabili-
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TABLE 6. Causes of Optic Disc Edema With Preserved Optic Nerve Function Papilledema (increased ICP) Compressive/inltrative orbital processes Tumors Graves disease Inammation (optic perineuritis) Central retinal vein insufciency Benign optic disc vasculitis Certain toxic optic neuropathies Amiodarone Cyclosporine Malignant hypertension Low grade ischemia Diabetic papillopathy Pre-AION Sleep apnea syndrome Posterior uveitis Sarcoidosis, other granulomatous disease Birdshot choroidopathy Acute zonal occult outer retinopathy Hypotony
9 and 10). Other accompanying fundus abnormalities may be useful in distinguishing the mechanism of disc swelling, and these can be divided into disc-related signs and retinal signs (Table 7). The presence of segmental optic disc swelling, disc pallor, and nerve ber layer hemorrhages (splinter or ameshaped hemorrhages seen on the disc surface or at the peripapillary margin) strongly point to an ischemic etiology. Optociliary shunt vessels on the disc usually indicate a previous central retinal vein occlusion or, when accompanied by disc pallor and decreased optic nerve function, an optic nerve sheath meningioma. Retinal signs accompanying disc edema can include intraretinal (dot/blot) hemorrhages, cotton wool spots, and macular edema or exudates. The clinical features discussed here assist in distinguishing between disc edema due to increased ICP and disc edema due to other mechanisms of optic nerve injury. However, even the best ophthalmoscopic examination is not a substitute for cerebrospinal uid (CSF) manometry. In the patient with suspected papilledema, ancillary testing is necessary to conrm or exclude increased ICP and should include urgent neuroimaging and lumbar puncture. Decisions regarding the relative merits of CT versus MRI should be individually based according to scan availability, patient cooperation, and the index of suspicion of specic intracra-
While occasional patients with increased ICP are completely asymptomatic, most do report symptoms and these are often helpful in pointing to the correct diagnosis. A history of headache in a patient with bilateral disc edema suggests increased ICP. When headaches are acute and severe, cerebral venous thrombosis (CVT), obstructive hydrocephalus, meningitis, or malignant hypertension are strong considerations. In contrast, headache in patients with idiopathic intracranial hypertension (IIH) is usually less severe and less abrupt in onset.110 Transient obscurations of vision (TOVs) are common in patients with increased ICP and usually described as brief episodes of visual loss, precipitated by postural changes such as standing up or bending over. TOVs usually last less than 30 seconds and may recur multiple times a day. Although TOVs are common in patients with papilledema, this symptom is nonspecic and may occur in other forms of acquired and congenital disc elevation.111 Noting the date of onset of TOVs may be helpful in estimating the onset of disc edema. Pulsatile tinnitus is another common symptom of increased ICP, presumably caused by turbulence in the transverse venous sinuses or jugular bulb. In addition, some patients experience horizontal diplopia at distance due to unilateral or bilateral sixth nerve palsy. On examination, determining whether the disc edema is unilateral or bilateral is the rst helpful clue. While disc edema due to increased ICP is not uncommonly asymmetric, truly unilateral papilledema occurs in only 5% of cases (Figs.
FIGURE 9. Asymmetric papilledema. This 28-year-old woman developed idiopathic intracranial hypertension following a 60-lb weight gain. (A) The right optic disc is markedly swollen with nerve fiber layer hemorrhages and hard exudates tracking toward the macula. (B) The left disc is also swollen, but the findings are less severe.
FIGURE 10. Unilateral papilledema in idiopathic intracranial hypertension. (A) The right disc is flat. (B) The left disc is moderately swollen. For anatomic reasons increased intracranial pressure in this individual is expressed in just one eye.
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TABLE 7. Fundus Findings Associated With Specific Causes of Disc Edema Fundus Abnormality Macular star Associated Disorders Neuroretinitis (dening feature) Malignant hypertension (common) Papilledema (unusual) Anterior ischemic optic neuropathy (AION) (occasional, partial) Central retinal vein occlusion Malignant hypertension Malignant hypertension Giant cell arteritis
Retinal hemorrhages Cotton wool spots
nial disorders. If neuroimaging fails to reveal a cause for intracranial hypertension, a lumbar puncture is essential. The opening pressure should be measured with the patient in the lateral decubitus position with legs extended and head neutral, and the CSF collected and analyzed for infection, inammation, hemorrhage, and neoplastic cells. Normal CSF opening pressure, measured in the lateral decubitus position, is generally less than 200 mm of water but may be as high as 250 mm in both obese and nonobese individuals.112 Causes of increased ICP are numerous and include intracranial mass lesions, obstructive hydrocephalus, subarachnoid hemorrhage, meningitis, CVT, hypertensive encephalopathy, toxins, and arteriovenous malformations (AVMs). Obesity alone does not cause elevated CSF pressure. The diagnosis of IIH applies only to patients with increased ICP in whom neuroimaging does not reveal a specic etiology, signs and symptoms are referable only to increased ICP, and the CSF composition is normal.113
Patients with venous sinus occlusion, for example, may present with signs and symptoms referable only to increased intracranial pressure, thus mimicking idiopathic intracranial hypertension.
Idiopathic Intracranial Hypertension (IIH)

Idiopathic intracranial hypertension (IIH) typically occurs in obese women of child-bearing age although the mechanism by which weight gain is related to increased ICP remains controversial.114 The diagnosis of IIH in a man, child, older, or nonobese female should arouse suspicion that an underlying cause for increased ICP has been missed.115,116
Patients with venous sinus occlusion, for example, may present with signs and symptoms referable only to increased ICP, thus mimicking IIH.117,118 Despite recent advances in neuroimaging, intracranial venous thrombosis not uncommonly escapes detection. CT scanning, often rst-line imaging in the emergency room setting, is relatively insensitive for the detection of venous clots. Sinus thrombosis is usually visible with MRI but may be missed when midline structures are involved or in the very early stages when the clot appears isointense with brain on T1-weighted images (Fig. 11). MR venography should be diagnostic in such cases. Although the clinical ndings in CVT may mimic IIH, the onset of CVT tends to be more abrupt and symptoms more severe.110 Permanent visual loss is the most serious potential complication of IIH (Fig. 12). The term benign intracranial hypertension fell out of favor because the incidence of serious visual loss in this condition became increasingly appreciated. The study by Corbett et al119 of 57 patients with IIH documented severe permanent visual loss in 24 eyes (21%), including 6 patients with bilateral blindness. In most cases this form of visual loss is preventable. Careful monitoring of visual function in patients with papilledema of any cause is crucial. Changes in the visual eld typically precede loss of central vision, and thus testing visual acuity alone is inadequate for these patients. Wall and George120 reported that only 22% of patients with IIH showed decreased visual acuity at the time of their initial evaluation. However, perimetric testing (either automated or Goldmann) demonstrated some form of visual eld loss in 92% and 96% of these patients respectively. Ideally, formal visual eld testing should be performed rather than relying on confrontation techniques, which are much less sensitive. Visual eld loss in IIH usually takes the form of disc-related defects (arcuate scotoma, nasal step) or a generalized decrease in visual sensitivity.119 Tests of foveal visual function such as contrast sensitivity and color vision are also more sensitive than acuity testing for detecting early dysfunction. Decompression of papilledema is the key to protecting visual function and preventing progressive visual loss. Only a subgroup of patients with papilledema experience signicant, persistent visual loss. Ideally this subgroup of patients should be treated more aggressively; however, predictive factors that identify this subgroup at the time of presentation are not yet available. In general, the amount of visual loss does correlate with the severity of papilledema. This was demonstrated by Wall and White,121 who meticulously tested and compared the interocular visual function in 12 patients with markedly asymmetric papilledema. But some patients with lesser degrees of papilledema also experience poor visual outcome while other discs tolerate marked swelling without developing irreversible visual loss. As a general rule, we would recommend more aggressive treatment of patients with high-grade papilledema, frequent TOVs, and signicant visual loss at the time of presentation. Patients with
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FIGURE 11. Superior sagittal sinus thrombosis. This 35-year-old man developed superior sagittal sinus thrombosis due to Behcet disease. (A, B) There was bilateral papilledema. (C) A sagittal T1-weighted MR image was initially interpreted as normal; however, the superior sagittal sinus (arrows) appears isointense with brain rather than appearing as a dark-flow void.
FIGURE 12. Visual loss in idiopathic intracranial hypertension. This obese 12-year-old girl presented with headaches and transient obscurations of vision. Acuity in the left eye was no light perception. (A) Goldmann perimetry in the right eye at presentation showed marked constriction with defects emerging from the blind spot. (B, C) Both discs were markedly elevated with cotton wool spots and splinter hemorrhages. A diagnosis of idiopathic intracranial hypertension was made and she underwent emergency placement of a lumboperitoneal shunt. Over the next few weeks her papilledema resolved and vision improved. (D) Goldmann perimetry 1 month later showed marked constriction bilaterally but with recovery to 20/50 in the left eye. (E, F) The discs are now pale and flat with a general paucity of nerve fiber layer and high-water marks in the peripapillary region.
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vascular disease may have optic discs that are more vulnerable to damage from papilledema and perhaps should also be considered a high-risk group. In contrast, children are less likely to suffer permanent visual loss from papilledema, although certainly they not immune to this complication, as suggested at one time.122 Management of the patient with papilledema includes (1) assessing the acute threat of herniation and instituting means of emergent ICP reduction (osmotic agents, corticosteroids, controlled hyperventilation, ventricular drainage), (2) identifying the cause of the increased ICP and initiating specic treatment modalities (antibiotics for meningitis, anticoagulants and/or endovascular recanalization for cerebral venous sinus thrombosis, ventriculoperitoneal shunting for obstructive hydrocephalus), and (3) recognizing symptoms and signs related to increased ICP, particularly visual loss, and tailoring therapy as needed. We address here the management of visual loss due to papilledema. Although most of the currently available modalities for treating IIH have been employed for years, there are to date no randomized, controlled studies demonstrating their effectiveness or comparing their efcacy and thus management decisions remain controversial. In the majority of patients with IIH, medical treatment is adequate for preventing permanent visual loss. Acetazolamide at sufciently high doses has been shown to lower ICP by decreasing CSF production. The sustained release form (500-mg Sequels) is better tolerated than the 250-mg tablets. The usual starting dose is 500mg twice daily. Patients should be specically warned to expect paresthesias around the mouth and hands. Furosemide 40 mg/day is an alternative or additive treatment modality. If both medications are used it is customary to add a potassium supplement. It is also important to treat any underlying systemic conditions that might contribute to optic nerve damage, such as anemia or hypoxia. Indications for surgical treatment include progressive deterioration of vision despite medical therapy and severe visual loss at the time of presentation. Surgery may also be considered for patients who are unable to perform visual eld testing reliably, are noncompliant with regular follow-up, and those with unstable blood pressure (eg, on dialysis).114 Repeated lumbar punctures or an externalized lumbar drain are acute temporizing measures that can be employed until a more denitive decompression procedure can be performed. The 2 most commonly used procedures are CSF diversion (ventriculoperitoneal shunting VPS or lumboperitoneal shunting LPS ) and optic nerve sheath fenestration (ONSF). LPS is a rapidly effective means for lowering ICP. Burgett et al123 reported the effects of LPS on visual status in 30 patients with IIH. LPS brought resolution of severe papilledema in 24 of 25 eyes (96%) and improved visual function in 19 of 28 eyes (68%) with no eyes demonstrating worsening of the visual eld. In addition, 82% of patients reported headache relief. The main drawback of LPS,
however, is a high rate of shunt malfunction in some patients necessitating multiple revisions.123125 Presenting the data on LPS as an average shunt revision rate (about 5 revisions per patient) is somewhat misleading insofar as 50% of patients are adequately managed with a single shunt procedure whereas a subgroup of patients seems to be particularly prone to shunt failure, requiring multiple revisions.123 More marked obesity may predispose to such shunt intolerance; however, this clinical impression has not been conrmed with data. Other complications of LPS include shunt infection, pleural effusion, acquired Chiari malformation, arachnoiditis, sciatica, peritonitis, catheter migration, and viscous perforation, but fortunately these complications are uncommon.114,123,124 VPS, although widely used for obstructive hydrocephalus, had not been technically feasible for other forms of intracranial hypertension in which the ventricles were not enlarged. However, the introduction of stereotactic or beroptic endoscopic VPS insertion has renewed interest in this procedure as an alternative to LPS, particularly in obese patients or in those patients who have undergone multiple LPS revisions.126,127 The advantages of VPS are less frequent malfunction, improved ability to regulate ICP, facilitation of noninvasive assessment of shunt function, and decreased risk of secondary Chiari malformation. ONSF requires an experienced orbital surgeon and, depending on the technique used, can be performed under local anesthesia. Placement of 1 or more incisions into the optic nerve sheath just behind the globe protects the optic disc either by acting as a localized shunt or by stimulating the formation of adhesions that prevent pressure from being transmitted anteriorly to the disc. ONSF does not accomplish decompression of the entire system and consequently headache and diplopia due to sixth nerve palsy may persist. The procedure is effective, however, for protecting optic nerve function. In some cases unilateral ONSF brings improvement of papilledema in the fellow eye. Visual outcomes with ONSF are comparable with those following LPS. Banta and Farris128 found that visual acuity stabilized or improved in 148 of 158 eyes (94%) treated with ONSF for IIH, and the visual eld stabilized or improved in 71 of 81 eyes (88%) compared with an overall rate of 97% and 88% respectively with LPS, as reviewed from the literature. The complication rate is approximately 40%, consisting primarily of diplopia and pupillary dysfunction, which are usually temporary.129 The most serious complication is severe visual loss from secondary vascular complications, which is fortunately rare.129,130 In contrast to LPS, most patients treated with ONSF do not require repeat surgery.131 While ONSF was popularized as a treatment of IIH (the most common indication for the procedure), it also has a role in the treatment of other causes of papilledema, including brain tumors, AVMs, meningitis, and CVT.132,133 Papilledema is a particularly common complication of cryptococcal meningitis. In this setting, LPS may be contraindicated whereas ONSF can be performed safely.134
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The relative merits of LPS versus ONSF remain controversial. In the face of severe and/or rapidly progressive visual loss, the procedure of choice is whichever can be performed most expediently. Either form of surgery will stabilize (and often improve) optic nerve function in most patients. In occasional severe cases in which vision continues to deteriorate despite surgery, the alternative procedure should then be performed.135,136 The most common reason for poor visual outcome in IIH is not the choice of surgical procedure, but failing to monitor optic nerve function adequately and being slow to respond to changes in the clinical picture. While most cases of IIH unfold over weeks to months, occasional cases pursue a rapidly downhill course, sometimes referred to as malignant pseudotumor cerebri,137 and in these cases the pace of treatment should be increased accordingly. In addition, assessing visual status in some patients with increased ICP may be quite challenging due to altered mental state and other medical complications. Patients may simply be too ill to report visual symptoms or perform visual tests. It is important for the clinician to maintain a heightened awareness of the potential for serious visual complications of papilledema and to have appropriate surgical treatment modalities available for these patients.
Blood pressure control is the only effective treatment of hypertensive optic neuropathy; however, overly aggressive attempts to lower the blood pressure rapidly can cause devastating infarction of the optic nerves.
FIGURE 13. Hypertensive disc edema. This 55-year-old woman underwent a neurologic workup for increased intracranial pressure because of headaches and papilledema. An MR image was normal, and cerebrospinal fluid opening pressure was elevated. Although a previous blood pressure determination was said to be 120/80 mmHg, repeat measurement showed marked hypertension at 240/160 mmHg. Renal artery stenosis was eventually diagnosed. (A, B) Both discs are swollen and there are numerous cotton wool spots throughout the fundi and hard exudates predominantly in the maculae. (C) Goldmann perimetry shows dense bilateral central scotomas due to macular edema and ischemia.
Hypertensive Optic Neuropathy

Blood pressure should be taken in both arms of any patient with unexplained disc edema. Occasionally disc edema is an isolated nding in a patient with severe hypertension. More typically, the additional ndings of retinal hemorrhages, exudates, and cotton wool spots in the posterior pole, as well as marked arteriolar narrowing, help to suggest the diagnosis of malignant hypertension. Disc edema with macular exudates in a star pattern may be mistakenly diagnosed as bilateral neuroretinitis (Fig. 13). When the retinal ndings of accelerated hypertension are mild in proportion to the disc edema, the funduscopic and clinical picture may be mistaken for papilledema. In these cases, nding an elevated CSF pressure on lumbar puncture furthers the false impression of a primary intracranial etiology such as IIH, when in fact the increased ICP is
secondary to systemic hypertension. A sudden or pronounced rise in blood pressure can disrupt autoregulation of the cerebral vasculature. The increased vascular permeability and extravasation of uid and proteins from the intravascular space into the interstitium leads to vasogenic brain edema that, if severe enough, can be detected radiographically (as discussed earlier).106 Patients may be mildly to severely symptomatic with headache, altered mental status, seizures, or focal neurologic decits. The combination of these clinical and radiographic ndings in a patient with an acute, severe increase in blood pressure is called hypertensive encephalopathy, and in pregnant women this is the syndrome of preeclampsia eclampsia. Hypertensive encephalopathy is usually reversible with normalization of the blood pressure. Malignant hypertension can also produce optic disc edema via local mechanisms in the absence of increased ICP. Data from experimentally induced renovascular hypertension in an animal model indicates ischemia is the mechanism for this form of disc swelling.138 Blood pressure control is the only effective treatment of hypertensive optic neuropathy (with or without encephalopathy); however, overly aggressive attempts to lower the blood
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pressure rapidly can cause devastating infarction of the optic nerves (and other organs) and must be avoided.25,139 The immediate goal of antihypertensive therapy is prevention of end-organ damage; the goal is not the restoration of blood pressure to a normal range as quickly as possible. If there is no evidence of encephalopathy, cardiac ischemia, pulmonary edema, or renal insufciency, gradual reduction of blood pressure over 24 to 48 hours in a monitored setting is recommended. Intravenous or oral medications may be used. Sublingual agents like nitroglycerin or nifedipine are contraindicated due to the precipitous fall in blood pressure that may result.139 In patients who are pregnant, and in those with encephalopathy or evidence of other end-organ damage, continuous intraarterial blood pressure monitoring in an intensive care unit is essential, and only IV medications are used. Currently favored agents include labetalol, nicardipine, and fenoldopam.140
Diabetic Disc Edema

Originally described in young adults with juvenileonset type I diabetes, diabetic papillopathy, also termed diabetic disc edema, refers to a relatively benign syndrome of unilateral or bilateral disc edema with minimal or no visual loss.150 153 The mechanism of disc edema in diabetic papillopathy is presumed to be local ischemia related to the microvascular changes of chronic diabetes or perhaps disc anoxia due to impaired glucose utilization. The description of this clinical entity was subsequently expanded to include patients with adult-onset type II diabetes as well.154 Some patients present with mild blurring of vision; in others, asymptomatic disc edema is discovered during routine eye examination.155 The most typical disc appearance is diffuse, hyperemic swelling of a mild-to-moderate degree with peripapillary splinter hemorrhages. A characteristic feature of diabetic papillopathy is the prominent telangiectasia on the disc surface, which must be distinguished from optic disc neovascularization. This distinction is important because patients with diabetic disc neovascularization should be treated with panretinal photocoagulation on an emergent basis. Referral to a retina specialist is appropriate for these patients. Diabetic papillopathy is a diagnosis of exclusion. Initial evaluation should include investigations for other causes of disc edema such as a compressive lesion and particularly increased ICP if disc edema is bilateral. All patients with bilateral disc edema and good optic nerve function should undergo some form of neuroimaging. If headaches and/or other symptoms of increased ICP are present, a lumbar puncture should also be performed. In the absence of such symptoms, with a normal scan and no underlying systemic cause for increased ICP, some patients can be followed expectantly without a spinal tap. Serial examinations are important to watch for evidence of progression.
Toxic Optic Neuropathies

Disc edema occasionally occurs as a side effect of medication. In some such cases the mechanism is well established from pathologic evidence and experimental animal models. For example, methanol-induced disc edema is a toxic optic neuropathy in which retrobulbar axonal death causes a block in axoplasmic ow,141,142 whereas hypervitaminosis A causes disc edema via increased ICP.143 Cyclosporine has also been associated with intracranial hypertension. In some patients who develop disc edema while on cyclosporine, the clinical picture is indistinguishable from IIH.144 In others, the clinical and radiologic ndings are indistinguishable from hypertensive encephalopathy, including papilledema, headache, confusion, seizures, and cortical visual loss. The MR appearance in such cases is consistent with vasogenic edema primarily in the white matter of the parietooccipital lobes.145 In occasional cases, ICP has been normal, suggesting an alternative mechanism for disc edema in patients on cyclosporine, presumably related to changes in permeability at the level of the optic disc. Similar questions regarding pathogenesis apply to the disc edema that occasionally develops in patients on amiodarone. The mechanism of amiodarone-related optic neuropathy has not been fully established, and the clinical spectrum appears to be fairly broad.146,147 Most commonly, these patients develop bilateral disc edema with preserved visual function.148 In occasional cases ICP has been elevated; more often it is normal. Disc edema resolves when amiodarone is discontinued. When a patient taking amiodarone develops acute unilateral optic disc edema, the relationship to amiodarone is less clear and other types of optic neuropathy, namely NAION, must be considered.149
Sleep apnea syndrome should be suspected in obese patients (especially men) whose clinical findings are suggestive of idiopathic intracranial hypertension but in whom lumbar puncture fails to document abnormally high cerebrospinal fluid pressure.
Sleep Apnea Syndrome (SAS)

Obstructive SAS is a sleep-related breathing disorder characterized by recurrent episodes of hypopnea or apnea
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during sleep due to partial or complete upper airway obstruction. Patients experience loud snoring, restless sleep, and excessive daytime somnolence. Apneic episodes may last seconds to minutes and occur multiples times throughout the night. A variety of cardiovascular, neurologic, and metabolic changes can result when signicant hypoxia and hypercarbia develop, including increased ICP.156 Possible mechanisms include hypercarbia-induced vasodilation with secondary increased cerebral blood volume and venous hypertension. Obstructive SAS was found to be an associated and perhaps contributory condition in 6 of 18 adult men (33%) with IIH157 and in 7 of 37 patients (18%) with IIH and symptoms of sleep disturbance.158 All the patients in these 2 studies met the modied Dandy criteria for IIHspecically, they had elevated CSF pressure by lumbar puncture. In some cases nocturnal elevations of ICP may be sufciently severe to cause persistent disc edema even though daytime ICP returns to normal. In such cases, routine lumbar puncture will show normal or borderline opening pressures, thus causing diagnostic confusion.159 SAS should be suspected in obese patients (especially men) whose clinical ndings are suggestive of IIH but in whom lumbar puncture fails to document abnormally high CSF pressure. In these patients it is important to inquire about snoring, excessive daytime sleepiness, and recent weight gain.
missed when subtle or obscured by changes in lid position. Other orbital signs include periorbital soft tissue and/or lid swelling, chemosis, and conjunctival injection. Limitation of eye movements with normal saccadic velocity is strongly suggestive of orbital restrictive disease, as is globe retraction on attempts to move the eye into the restricted eld of gaze. In the absence of orbital signs, it is helpful to consider next whether the pattern of ophthalmoplegia could be explained by a CN palsy or perhaps by a combination of CN palsies such as ipsilateral third and sixth nerve. It is important to be alert for partial third nerve palsies; however, it is worth emphasizing that weakness of a single third nerve-innervated extraocular muscle is extremely unusual. For example, isolated limitation of adduction is much more likely to represent internuclear ophthalmoplegia or myasthenia gravis (MG) rather than a partial third nerve palsy. Certain patterns of ocular motor abnormality are characteristic of brainstem disease. Conjugate horizontal gaze palsies are associated with profound saccadic slowing in the direction of the palsy. Internuclear ophthalmoplegia is likewise accompanied by marked slowing of medial rectus saccades as well as abduction nystagmus in the contralateral eye. A dissociation between voluntary and reex rexations is extremely helpful for determining a central location. Such supranuclear gaze palsies can be demonstrated by testing the vestibular ocular (dolls head) reex, Bell phenomenon, or caloric reexes.
Weakness of a single third nerve-innervated extraocular muscle is extremely unusual.
Orbital Disease
Orbital signs and symptoms may be due to primary orbit disease (eg, orbital cellulitis or pseudotumor) or may occur secondarily due to cavernous sinus disease that produces orbital venous congestion (eg, cavernous sinus thrombosis or stula). When orbital manifestations are severe, the location of the disease process is usually evident and ophthalmologic consultation is typically requested. The neurologist is more likely to become involved when orbital changes are more subtle.
ABNORMAL OCULAR MOTILITY

Most patients with a disorder of ocular motility present with diplopia. Occasionally abnormal eye movements remain conjugate and the patient describes (or the examiner notes) difculty looking in a particular direction. Unlike disorders ofthe afferent visual pathways, diplopia tends to present acutely regardless of its mechanism. Even in a patient with a slowly expanding mass, there is a moment when the vision suddenly goes from single to double. The usual rst step in diagnosis is to determine whether the abnormal eye movements are due to a disorder involving supranuclear pathways, cranial neuropathy, the neuromuscular junction, or the extraocular muscles (EOMs) themselves. A number of clinical features are helpful in distinguishing among these possibilities. The presence of orbital symptoms and signs can be very helpful in localization. Eye pain is common in acute orbit disease; a description of pain with eye movement is particularly characteristic. Proptosis is often present but may be
Orbital Pseudotumor
Idiopathic orbital pseudotumor is a nongranulomatous inammatory process that may affect orbital structures diffusely or may localize to just one particular orbital structure.160 The form of pseudotumor that is most likely to present to the neurologist is orbital myositis, in which the inammatory process is conned to one or more EOMs.161 Most orbital myositis is idiopathic, although occasional cases are due to a specic inammatory condition, including systemic lupus erythematosus,162 sarcoidosis,163 Crohn disease,164,165 Whipple disease,161 Lyme disease,166 and Wegener granulomatosis.167 Orbital myositis has rarely been identied as a paraneoplastic syndrome.161,168
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Orbital myositis usually affects otherwise healthy individuals, with a mean age at onset of 40 years but with a broad age range. There is a slight preponderance in women in most series.161 EOM involvement may be single or multiple and any muscle or muscles may be affected. The most common pattern is unilateral, single-muscle involvement. The inamed muscle may act in either a paretic or a restrictive fashion, or both. Thus, a swollen medial rectus muscle may cause limitation of abduction, (mimicking a sixth nerve palsy), may cause loss of adduction, or a combination of the two. Careful inspection will often reveal conjunctival injection over the muscle insertion (Fig. 14). Normal saccadic velocity in the direction of restriction and pain with eye movement should be helpful for distinguishing orbital myositis from sixth nerve palsy. MRI will typically demonstrate the EOM inammation but must include dedicated orbit views with fat suppression and gadolinium. In most cases a good-quality CT scan with contrast will reveal characteristic changes equally well. Involved muscles appear enlarged and enhance following contrast administration. Extension of the inammation anteriorly to involve the tendinous insertions helps to distinguish orbital myositis from Graves disease radiographically, which characteristically spares the tendons. (Clinically, the acute onset and pain of orbital myositis are usually sufciently different
from Graves disease, which is usually painless, that this distinction is not difcult.) Orbital myositis is dramatically responsive to steroids, with resolution of pain usually within 24 to 28 hours. Most patients respond to oral prednisone 60 to 100 mg/day for 2 weeks with a slow taper thereafter.169 Failure to show the expected response to corticosteroids should prompt biopsy.161 Despite a positive initial response, about half these patients experience recurrence,160,169 necessitating repeat treatment with corticosteroids, other immunosuppressive agents, and/or low-dose radiation.
Mucormycosis
Mucormycosis is an acute fungal infection occurring mostly in immunocompromised and debilitated patients. Infection is rapidly invasive with a high mortality rate. Common predisposing conditions are diabetes mellitus with or without ketoacidosis, neutropenia, chronic immunosuppression, organ transplantation, hematologic malignancies, hemodialysis, burns, and treatment with deferoxamine. Iron is an essential growth factor for the Mucorales fungi, and serum acidosis prevents iron binding in the blood, increasing serum levels of free iron and promoting rapid fungal growth.170 The fungi of the order Mucorales are ubiquitous saprophytes, present in the air, soil, and decaying organic matter. The 5 major clinical forms of mucormycosis are rhinal orbital
FIGURE 14. Orbital myositis. This patient presented with a 2-day history of intense right eye pain and diplopia. (A) The eyes are aligned in primary position and there is mild conjunctival injection medially. There is mild limitation of abduction and adduction in the right eye. (B) Axial MRI with contrast shows dramatic enhancement of the right medial rectus muscle, which is acting in both a paretic and a restrictive fashion. Coronal MRI shows right medial rectus inflammation and milder involvement of the right inferior rectus.
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cerebral (ROC), pulmonary, disseminated, gastrointestinal, and cutaneous. The most common of these is the ROC form, accounting for 44 to 49% of all cases of mucormycosis.171 The most common route of entry is via the respiratory tract. In immunocompetent hosts, inhaled fungal spores are rapidly destroyed and phagocytized by neutrophils and macrophages. Immune incompetence, particularly neutropenia, leads to a failure in clearing the spores, which germinate into hyphae within the nasal and palatal mucosa. The germinating hyphae have a predilection for invasion of blood vessels, causing thrombosis, infarction, and subsequent necrosis. ROC mucormycosis develops via direct orbital invasion through the lamina papyracea of the paranasal sinuses by germinating hyphae. Intracranial involvement occurs via the sphenoid sinus, superior orbital ssure, vascular structures, cribriform plate, or by perineural spread. Common signs and symptoms are fever, headache, periorbital pain, acute ophthalmoplegia, proptosis, periorbital edema, visual loss, conjunctival redness, and trigeminal anesthesia. Facial or periorbital pain, once believed to be a nearly universal symptom, was reported in only one third to two thirds of patients in recent series.172,173 Acute orbital cellulitis is often heralded or accompanied by blood-tinged nasal discharge or epistaxis. The characteristic necrotic eschar in the nose or on the hard palate is often overlooked or may develop too late in the clinical course to aid in diagnosis (Fig. 15). In the rst 72 hours of symptoms, one series found such nasal or palatal ulceration in only 52% of patients.173 Radiographic ndings may be relatively mild and nonspecic, such as sinus mucosal thickening or orbital inltration. More suggestive ndings include bony destruction, an airuid level, and ophthalmic vein thrombosis in the setting of sinusitis and/or orbital cellulitis. Diagnosis is based on the histologic nding of angioinvasive mycosis in sampled tissue. Classic hematoxylin eosin staining can be used for direct microscopic visualization of the hyphae as well as Gomori methenamine silver staining, periodic acidSchiff,
and treatment with 20% potassium hydroxide.171 Whenever ROC mucormycosis is suspected but no visible mucosal lesions are present, a blind nasal biopsy should still be considered. Lack of pain and bleeding during the biopsy is highly suspicious for Mucormycosis and should prompt an aggressive search for positive histopathology in the sampled tissue. Tissue cultures are unnecessary and unreliable because the Mucorales fungi are frequent laboratory contaminants. Treatment should be started immediately following diagnostic conrmation because the highest rates of mortality occur in the rst week of infection.174 Treatment is aimed at correction of underlying host risk factors and initiation of medical treatment with amphotericin B. Surgical debridement of necrotic tissue must be considered early because the drug does not distribute well within ischemic tissue. The role of hyperbaric oxygen in the treatment of ROC mucormycosis is not clearly established. Poor prognostic indicators include a treatment delay of more than 6 days, intracranial symptoms such as hemiplegia or seizures, bilateral sinus involvement, palatal involvement, facial necrosis, underlying leukemia, and deferoxamine therapy.171,172 The overall mortality rate in ROC mucormycosis ranges from 30 to 69%.171
Septic thrombosis of the cavernous sinus is another potentially life-threatening condition that may present with acute diplopia and orbital signs.
Cavernous Sinus Thrombosis

Septic thrombosis of the cavernous sinus is another potentially life-threatening condition that may present with
FIGURE 15. Diabetic ketoacidosis and rhinal orbital cerebral mucormycosis. (A) This 60-year-old man had acute diplopia, pain, and swelling around his left eye as well as spontaneous episodic epistaxis. (B) Oropharyngeal examination revealed necrotic areas in the upper palate. 2005 Lippincott Williams & Wilkins
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acute diplopia and orbital signs. A number of infectious processes may predispose a patient to developing septic thrombosis of the cavernous sinus, including facial infections, sinusitis, dental infections, otitis media, and, rarely, orbital cellulitis. Facial infections, particularly those involving the medial third of the face, are the most frequent source of infection. Bacteria entering the facial vein and pterygoid plexus are carried to the cavernous sinus through the ophthalmic veins. The usual pathogens in this setting are Grampositive bacteria, particularly Staphylococcus aureus.175,176 Acute or chronic sinusitis affecting the sphenoid and ethmoid air cells may cause septic thrombosis. When chronic sinusitis causes cavernous sinus thrombosis, Gram-negative rods, coagulase-negative staphylococci, and fungi such as Aspergillosis and Mucoraceae must be considered. Dental infections, usually affecting the maxillary teeth, cause about 10% of reported cases, and the most common organisms in these cases are streptococci, fusobacteria, and Bacteroides species. Orbital cellulitis is rarely complicated by septic thrombosis of the cavernous sinus, even though the superior and inferior ophthalmic veins drain into the sinus. Hematogenous seeding to the cavernous sinus from a remote infection is also rare. When this does occur it is usually in a patient who is immunocompromised. With the increased use of broad-spectrum antibiotics, septic sinus thrombosis is less common; occasional cases are due to a variety of prothrombotic conditions. Most patients present acutely with pain around the eye associated with proptosis, chemosis, ptosis, and ophthalmoparesis. Altered sensorium, headache, nausea, and vomiting are common, and are helpful in distinguishing cavernous sinus thrombosis from orbital cellulitis. Fever and leukocytosis point to an infectious etiology and should prompt urgent evaluation and treatment. Eyelid edema is especially prominent when the thrombosis is caused by facial, dental, or ethmoidal infection. Ophthalmoplegia often begins as an isolated ocular motor paresis, most commonly affecting the abducens nerve, in the setting of marked orbital congestion and proptosis. Distinguishing neurogenic from mechanical limitation of the EOMs may not be possible. As venous stasis within the orbit increases, the ocular fundus may show increasing dilation of retinal veins and low-grade optic disc swelling. Vision loss associated with cavernous sinus thrombosis may be due to neurotrophic keratopathy, optic neuropathy, or retinal ischemia. As the disease progresses, patients may show evidence of meningitis or brain abscess and seizures may occur.176 The CSF is abnormal in patients with associated meningitis, and the organism can often be isolated from blood and/or CSF cultures. CT or MRI typically shows enlargement of the superior ophthalmic vein and may show enlargement of the involved cavernous sinus. The clinical manifestations of orbital cellulitis are nearly identical to those of early cavernous sinus thrombosis,
and diagnostic differentiation, although difcult, is important because the mortality rate for patients with septic sinus thrombosis is about 30% regardless of therapy.177,178 Among survivors, full recovery occurs in less than 40% of patients and most have residual neurologic decits from damage to structures in the cavernous sinus.175 Treatment consists of appropriate antimicrobial coverage and debridement of necrotic/infected tissue in select cases. Underlying medical conditions that may predispose to thrombosis, such as malignancy or collagen vascular disease, should likewise be treated.
A direct carotid cavernous fistula is a potentially life-threatening condition due to intracranial hemorrhage from acute, increased intracranial venous hypertension or massive epistaxis.
CarotidCavernous Fistula (CCF)

A carotid cavernous sinus stula (CCF) represents an anomalous arteriovenous communication between the carotid artery and the cavernous sinus. A direct stula is a highpressure, high-ow shunting of blood from the internal carotid artery (ICA) into the cavernous sinus. It most commonly results from trauma to the wall of the carotid artery. Other causes include rupture of an intracavernous aneurysm, EhlersDanlos syndrome, bromuscular dysplasia, and pseudoxanthoma elasticum. Ocular symptoms and signs develop rapidly due to the ow of high-pressure arterial blood anteriorly into the orbital vein causing pulsating exophthalmos, marked periorbital congestion, ophthalmoplegia, visual loss, and increased intraocular pressure (Fig. 16). Two features are helpful for distinguishing between a CCF and cavernous sinus thrombosis: an audible supraorbital bruit (which may or may not be present) and the presence of arterialized corkscrew episcleral veins. Marked enlargement of the superior ophthalmic vein is easily visible on CT or MRI. A direct CCF is a potentially life-threatening condition due to intracranial hemorrhage from acute increased intracranial venous hypertension or massive epistaxis. Visual loss, seizures, and neurologic decits are signicant causes of morbidity. Rapid diagnosis and treatment are critical. Transarterial balloon embolization is the preferred initial treatment modality, with success rates over 90%.179 In contrast, most spontaneous (ie, nontraumatic) stulas are low-ow, dural-based AVMs. The anomalous com 2005 Lippincott Williams & Wilkins
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FIGURE 16. Traumatic direct carotid cavernous sinus fistula. (A) The patient acutely developed marked orbital congestion. (B) There was severe conjunctival edema, corneal haze, lid swelling, and a frozen globe. (C) Marked proptosis is evident. (D) A CT scan showed a dilated superior ophthalmic vein in the left orbit consistent with the diagnosis of traumatic carotid cavernous fistula.
munication occurs between small meningeal branches of the internal or external carotid artery and the cavernous sinus or its tributaries. In contrast to direct stulas, symptoms of a dural AVM or spontaneous stula are generally mild and subacute, including conjunctival injection, mild motility disturbance, and elevated intraocular pressure. MRI may show mild distention of the cavernous sinus but in many cases the sinus appears normal. Secondary signs, however, are usually present, including distention of the superior ophthalmic vein and enlargement of EOMs (Fig. 17). Angiography is the gold standard for the demonstration of these stulas but may not be indicated if signs and symptoms are not severe enough to warrant treatment.
and a dilated pupil. However, partial third nerve palsies are common and can present as mild weakness of the EOMs, or weakness of only 1 or 2 of the third nerve innervated muscles. The combination of ipsilateral ptosis and limited supraduction should be recognizable as a superior division third nerve palsy. Our discussion here focuses on third and sixth nerve palsies. Management of fourth nerve palsy only rarely represents an emergency situation. Most are due to trauma or ischemic infarction. Neoplasms and aneurysms are rare causes of acute fourth nerve palsy. Important, although unusual, causes include GCA and increased ICP, and in the appropriate clinical setting these possibilities should be addressed.
Cranial Nerve Palsies

When features of orbitopathy are absent, the ocular motility examination should focus on identifying which EOMs are paretic and on determining whether the pattern of the ophthalmoplegia could be explained by a palsy of one of the ocular motor nerves. For example, weakness of abduction in one eye might be explained by a sixth nerve palsy on that side. A complete third nerve palsy is easy to recognize: complete ophthalmoplegia except abduction and incyclotorsion with ptosis
Third Nerve Palsy

Patients with a third nerve palsy that is accompanied by neurologic decits such as hemiplegia, tremor, or ataxia likely harbor a lesion in the brainstem, and high-resolution MRI without and with contrast enhancement will usually reveal the lesion. Most cases of fascicular (brainstem) third nerve palsies are vascular in origin. Patients with a third nerve palsy and symptoms of meningeal irritation such as headache,
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FIGURE 17. Indirect (dural) cavernous fistula. (A) There is conjunctival injection in the left eye with a mild abduction deficit and a little ptosis. (B) A close-up shows characteristic corkscrew vessels. (C) Coronal MRI with contrast shows no abnormality of the cavernous sinus. (D) However, orbital views reveal mild enlargement of extraocular muscles secondary to venous engorgement. (E) MR angiography shows hypervascularity of the left cavernous sinus (arrow).
stiff neck, or photophobia should undergo spinal uid examination for hemorrhage, infection, and neoplastic cells. Patients with a third nerve palsy and evidence of ipsilateral fourth nerve palsy, sixth nerve palsy, rst-division trigeminal dysfunction, or Horner syndrome should be investigated for lesions in the superior orbital ssure and cavernous sinus. The evaluation of a patient with an acute neurologically isolated third nerve palsy remains a more challenging task. Isolated acute third nerve palsy is most often due to small vessel disease (termed a vasculopathic cranial monon-
europathy; Fig. 18) or to compression by a posterior communicating artery aneurysm (Fig. 19). Presentations are similar but the evaluation and management of these 2 disorders are quite different. Patients with a vasculopathic third nerve palsy are usually older than 50 years of age and have one or more vascular risk factors, including hypertension, diabetes, and hyperlipidemia.180 Third nerve palsy often develops abruptly but may show progression from 1 to 2 weeks after onset in at least half of cases.181 Pain is usually present, localized behind the eye or to the same side of the head. Spontaneous recovery
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Most vasculopathic third nerve palsies spare the pupil.
Distinguishing Aneurysmal Third Nerve Palsy

Aneurysmal third nerve palsy is almost always associated with pain; however, the severity and quality of the pain is not helpful for distinguishing aneurysmal from vasculopathic palsy, which is also commonly painful.182 The most helpful clinical feature for making this distinction is the state of the pupil. Because of the dorsal, peripheral location of the pupillomotor bers in the third nerve, pupillary involvement is an early and frequent feature of aneurysmal palsy, noted in 86 to 95% of cases.183,184 In contrast, most vasculopathic third nerve palsies spare the pupil. Although a small degree of anisocoria is not uncommon in vasculopathic third nerve palsy (found in 10 of 26 patients in Jacobsons series185), greater than 2.5 mm of anisocoria is distinctly unusual. In cases of aneurysmal third nerve palsy in which pupillary function is normal, other third nerve muscles are spared as well. These observations were formulated by Trobe184 as The Rule of the Pupil, which states that a patient with an otherwise complete but pupil-sparing third nerve palsy does not harbor an aneurysm. The addendum or footnote to this rule points out that if the third nerve palsy is partial, the state of the pupil is not helpful.186 Of this subgroup with partial third nerve palsies, 30 to 40% are aneurysmal.187 The pattern of EOM involvement in partial third nerve palsy may be helpful. Patients with partial vasculopathic third nerve palsy typically demonstrate incomplete paresis of all third nerve-innervated muscles, whereas partial aneurysmal palsies are more likely to show weakness of just one or more but not all muscles.188
FIGURE 18. Vasculopathic third nerve palsy. This 65-year-old hypertensive, diabetic woman experienced sudden onset of left-side headache and left third nerve palsy. (A) There was complete left upper lid ptosis and loss of adduction, elevation, and depression with normal pupillary function and no anisocoria. (B) Three months later, oculomotor function recovered.
Neither MR nor CT angiography replaces conventional arteriography as the gold standard procedure for detecting aneurysms.
within 6 months after onset (usually after 23 months) is characteristic. The age range for aneurysmal third nerve palsy is broader, most commonly from 20 50 years and includes young adults without vascular risk factors.
These observations regarding the clinical features of acute third nerve palsy have been translated into a set of recommendations regarding the appropriate management for these patients, but this area remains controversial, or perhaps more appropriately, in transition.187,189 As the sensitivity of noninvasive imaging improves, the need for conventional arteriography decreases. At this point, MR angiography (MRA) and CT angiography (CTA) are extremely sensitive for the detection of
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FIGURE 19. Aneurysmal third nerve palsy. (A) A complete right third nerve palsy developed acutely accompanied by ipsilateral headache. The right pupil was larger than the left and reacted sluggishly to light. (B) A carotid arteriogram revealed an aneurysm at the junction of the posterior communicating and internal carotid arteries.
cerebral aneurysms but have not yet achieved 100% accuracy.190 The sensitivity of these techniques depends on the size of the aneurysm. The ability of MRA or CTA to detect an aneurysm approaches 100% for aneurysms larger then 5 mm; however, the risk of aneurysmal rupture for aneurysms smaller than 5 mm can approach 10%.187 Thus neither MRA nor CTA replaces conventional arteriography as the gold standard procedure for detecting aneurysms. In addition, clinicians should be cautious about applying data from published series to their own practice. The level of noninvasive technology available at a particular community hospital may not be equivalent to that of a tertiary care center.
Patients without vascular risk factors are considered to be at such high risk for harboring an aneurysm that conventional arteriography is appropriate regardless of the specific features of the third nerve palsy.
One approach to the evaluation of the patient with an acute isolated third nerve palsy is summarized in Figure 20. Patients without vascular risk factors (adults from age 20 50 years without diabetes or hypertension) are considered to be at such high risk for harboring an aneurysm that conventional arteriography is appropriate regardless of the specic features of the third nerve palsy (ie, complete, pupil sparing, or involving). Within this group of younger patients, the subgroup with third nerve palsy that is otherwise complete but pupil sparing represents an area of continued controversy. In this clinical setting, the likelihood of an aneurysm is admittedly extremely low; on the other hand, patients in this group have a very low risk for complications of arteriography. For patients older than 50 years with an acute third nerve palsy that is pupil involving, arteriography is also appropriate. Patients older than 50 with vascular risk factors and an otherwise complete but pupil-sparing third nerve palsy can be managed expectantly; no form of neuroimaging is required, but patients should be observed for the development of other neurologic decits. For patients with vascular risk factors who have a partial palsy that is pupil sparing, a high-quality MRA or CTA is usually sufcient. The risk of a complication from angiography outweighs the likelihood of nding an aneurysm in this group.
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Figure 20. Evaluation of third nerve palsy.
Patients older than 50 with vascular risk factors and an otherwise complete but pupil-sparing third nerve palsy can be managed expectantly.
Sixth Nerve Palsy

A complete sixth nerve palsy produces esotropia and an abduction decit; lesser degrees of sixth nerve paresis may produce esotropia without a ductional decit. Restrictive orbitopathy affecting the medial rectus muscle can mimic a sixth nerve palsy. The characteristic slowing of abducting saccades seen in sixth nerve palsy but not in restrictive eye disease is a helpful clinical sign for distinguishing these mechanisms. The differential diagnosis of sixth nerve palsy is lengthy. A useful approach is to consider its anatomic course and to look for other clinical signs that may localize the site of sixth nerve injury. Are there long-tract signs or facial palsy indicating pontine injury? Bilateral sixth nerve palsies suggest a lesion at the clivus, where both nerves are in close proximity. Are there other cranial neuropathiesnamely third, fourth, or ophthalmic division of fth decits or an ipsilateral Horner syndrome that would point to a cavernous sinus lesion? Are there orbital symptoms or signs? Headache and papilledema suggest sixth nerve palsy as a false localizing sign of increased ICP.
The age of the patient is also important to consider in determining the most likely etiology of an acquired sixth nerve palsy. In children, the most common causes are trauma and tumor (usually a pontine glioma). The spectrum of etiologies in adults is different. Peters et al191 reviewed causes of nontraumatic sixth nerve palsy in 45 young adults age 20 to 50 years and found tumor in 33%, multiple sclerosis in 24%, postviral infection in 9%, IIH in 7%, and meningitis in 7%. Despite a thorough evaluation, 13% were classied as idiopathic. This series was not restricted to those in whom sixth nerve palsy was isolated. Among the 15 patients with tumor, only 3 had a neurologically isolated sixth nerve palsy; the other 12 patients had other signs and symptoms. However, among 11 patients with multiple sclerosis, an isolated sixth nerve palsy was the only presenting sign in 8 (Fig. 21). Based on these considerations, MRI of the brain and orbit is indicated in patients with an acquired sixth nerve palsy if the patient is younger than 50 years old. If the MRI is nondiagnostic, a lumbar puncture is appropriate. In patients older than 50 years of age, especially with vascular risk factors, the most common cause of an acute, isolated sixth nerve palsy is microvascular disease causing a vasculopathic or ischemic cranial mononeuropathy. While there are no ancillary tests that demonstrate the lesion, such cases prove themselves by resolving spontaneously over several months. No neuroimaging is indicated for these patients, and close (every 12 weeks) observational management is sufcient. The one exception to this conservative approach is the patient with a history of malignancy; in these patients neuroimaging should
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FIGURE 21. Sixth nerve palsy in multiple sclerosis. A 27-yearold woman developed an acute right sixth nerve palsy. (A) Sagittal T2-weighted MRI showed a hyperintense lesion in the central pons. (B) Axial head MRI showed a single white matter lesion. Two years later she had an episode of optic neuritis, at which time a diagnosis of multiple sclerosis was made.
be obtained at presentation. In older individuals a directed history for systemic symptoms of GCA and a sedimentation rate and CRP should be obtained. Neuroimaging becomes necessary if the palsy continues to progress after 2 weeks, fails to show some recovery by 2 months, or if other neurologic symptoms and signs appear. MRI of the brain and orbits with contrast is the imaging modality of choice because of its greater sensitivity for lesions at the skull base, within the cavernous sinus and in the brainstem. Note that bilateral sixth nerve palsy is never vasculopathic and demands a full evaluation at presentation regardless of the age of the patient. Increased ICP and lesions in the clivus (primary or metastatic tumors) are the prime considerations in this setting. Such bony lesions are often overlooked even with highquality neuroimaging (Fig. 22). A lumbar puncture is important both for the identication of possible increased ICP and meningitis.
FIGURE 22. Clival metastasis. Sagittal MRI with contrast demonstrates a hypointense lesion in the clivus and distortion of the clival margins. The patient had bilateral sixth nerve palsies.
a parasellar lesion. Etiologies include neoplasm, infection, inammation, and vascular lesions (Table 8). Most cavernous sinus tumors present with slowly progressive decits. In contrast, inammatory disease such as TolosaHunt syndrome (THS) and pituitary apoplexy usually present acutely. TolosaHunt Syndrome (THS) TolosaHunt syndrome is a syndrome of acute, painful ophthalmoplegia due to idiopathic granulomatous inammation in the cavernous sinus. Patients experience acute onset of periorbital or hemicranial pain with ipsilateral paralysis of one or more ocular motor CNs, ophthalmic division trigeminal neuropathy (numbness, paresthesias), and Horner syn-
TABLE 8. Causes of Painful Ophthalmoplegia
In patients older than 50 years of age, especially with vascular risk factors, the most common cause of an acute, isolated sixth nerve palsy is microvascular disease.
Combined Cranial Neuropathies

Any combination of third, fourth and sixth nerve palsy on one side, especially when there is ipsilateral trigeminal nerve or oculosympathetic dysfunction, should suggest the possibility of
Aneurysmal 3rd NP (posterior communicating artery) Vasculopathic cranial nerve palsy Cavernous sinus disease Thrombosis Intracavernous carotid aneurysm Inammatory (Tolosa Hunt, sarcoid, Wegener granulomatosis) Carotid dissection Pituitary apoplexy Giant cell arteritis Nasopharyngeal carcinoma Basilar meningitis (infectious or neoplastic)
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drome in varying combinations.192 It is important to recognize that this constellation of ndings simply localizes a lesion to the cavernous sinus and is not specic for THS. A diagnosis of THS is one of exclusion after other causes have been ruled out (Table 9). MRI may be normal or abnormal; distinct MRI criteria for THS do not exist. MRI in THS may show enlargement of the cavernous sinus, enhancement of the adjacent dural wall, and abnormal soft tissue surrounding and narrowing the cavernous ICA (Fig. 23). There may even be extension of the soft tissue abnormality into the orbital apex, sphenoid sinus, or oor of the middle cranial fossa. These radiographic abnormalities are nonspecic and can be seen also with meningioma, lymphoma, sarcoidosis, and other conditions. In some patients with THS, MRI may be completely normal; in these cases the diagnosis is a clinical one. The etiology of the inammatory process of THS remains unknown and is likely to represent one part of the spectrum of the idiopathic orbital inammation syndrome (discussed earlier). Like the orbital pseudotumor syndrome, corticosteroids are the mainstay of treatment. Pain resolution within 24 to 48 hours is sometimes used as a diagnostic criterion for this disorder, but it is important to remember that other granulomatous, infectious, or neoplastic processes involving the cavernous sinus may also be dramatically steroid responsive. Pituitary Apoplexy Acute hemorrhage into a pituitary adenoma or enlarged pituitary gland leads to acute compression of the optic nerves and chiasm (visual loss), invasion laterally into the cavernous sinuses (facial pain, diplopia), hemorrhage into the CSF (headache, stiff neck), and acute endocrinologic insufciency (dizziness, hypotension, potential cardiovascular collapse). Some patients with pituitary apoplexy present with painful ophthalmoplegia, most often affecting the third nerve. Prompt diagnosis (MRI) and immediate treatment (medical and/or surgical) may be life-saving, as described earlier.
FIGURE 23. TolosaHunt syndrome. (A) This 40-year-old African-American woman developed painful right ophthalmoplegia. (B) Axial T1-weighted MRI with gadolinium showed enhancement of the right cavernous sinus with extension posteriorly along with the dura. An extensive evaluation for specific inflammatory diseases was negative and she showed a dramatic response to oral steroids.
Conjugate Gaze Abnormalities

Conjugate gaze palsies are disorders that cause symmetrically restricted movements of both eyes in the vertical
and/or horizontal direction. Because there is no ocular misalignment, patients with conjugate gaze palsies do not complain of diplopia. Slowing of saccadic velocity is characteristic and is sometimes quite profound. The designation of a gaze palsy as conjugate implies a central lesion. While an acute hemispheric event can produce a conjugate gaze palsy, such lesions cause other neurologic decits that predominate the clinical picture. In contrast, patients with brainstem disorders may present with solely or predominantly ocular motor ndings. This section focuses on a few acute brainstem syndromes for which urgent evaluation and treatment may prevent serious morbidity and mortality.
TABLE 9. Suggested Evaluation for Painful Ophthalmoplegia Blood tests for specic inammatory disorders CBC, ESR, metabolic prole Angiotensin converting enzyme, lysozyme VDRL, FTA-ABS Antineurtrophilic cytoplasmic antibodies (ANCA) Chest x-ray MRI with gadolinium and thin coronal sections Lumbar puncture Nasopharyngeal examination with blind biopsy
Dorsal Midbrain Syndrome

The constellation of ndings due to lesions of the dorsal midbrain is also referred to as the pretectal syndrome, Parinaud syndrome, and the syndrome of the superior colliculus. Classic ndings are vertical gaze palsy, pupillary light/near dissociation, convergenceretraction nystagmus, lid retraction, and abnormalities of convergence and accommodation. When all signs of the syndrome are present, the diagnosis is straightforward. However, early compression of the dorsal midbrain may produce only a conjugate upgaze paresis. Upward pursuit may initially be intact, but upward saccades will be slowed and hypometric.
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Gaze-evoked, upbeat nystagmus is another early sign. In most cases, reex upgaze remains intact. In advanced cases there may be tonic downward deviation of both eyes. Accommodative and convergence insufciency are occasionally early signs. Children who suddenly complain of difculty seeing near objects or reading should be carefully examined for upgaze paresis, including assessment of the velocity and accuracy of upward saccades. In infants and young children, the most common cause of an acute dorsal midbrain syndrome is tectal compression due to obstructive hydrocephalus or a pineal tumor. In patients with a VPS due to obstructive hydrocephalus, signs of a dorsal midbrain syndrome can indicate developing shunt malfunction, even in the absence of radiologic changes.193 Ventricles may be normal or slitlike in the presence of symptomatic shunt obstruction.194 In addition to the features of dorsal midbrain syndrome, these patients often exhibit nystagmus and esotropia.195 The latter may be multifactorial, due to sixth nerve palsy, convergence spasm, and sometimes to amblyopia consequent to visual loss from papilledema.194 Optic atrophy is also a common nding in these patients.196 Recognition of the neuro-ophthalmic signs that herald this syndrome is crucial. It may take particular fortitude to insist on the diagnosis in the face of assurances by the radiologist (and sometimes the neurosurgeon) that the shunt is working properly.
Wernicke Encephalopathy
Wernicke encephalopathy is an acute neurologic disorder caused by thiamine (B1) deciency and characterized by the clinical triad of ophthalmoplegia, ataxia, and mental confusion. Predisposing states for thiamine depletion include chronic alcoholism, gastric resection, prolonged IV hyperalimentation, hyperemesis gravidarum, anorexia nervosa, and chronic renal dialysis. Wernicke encephalopathy is probably more common than clinically recognized, owing to variations in the clinical presentation. Ophthalmoplegia commonly takes the form of horizontal and/or vertical gaze palsy often accompanied by bilateral abduction decits. Upbeat nystagmus is characteristic. Mental status changes may be mild and therefore unappreciated. Recent studies have shown that the pathologic changes of Wernicke encephalopathy can often be detected with MRI, particularly on T2-, FLAIR, or contrast T1-weighted images.200 The most characteristic pattern consists of symmetric lesions in the periaqueductal area, midbrain tegmentum, mamillary bodies, and dorsomedial thalamus. These MRI abnormalities have been found in 50 to 60% of patients who are imaged within 2 weeks of symptom onset.201 Diffusion-weighted MRI may be more sensitive for detecting these changes and may also provide prognostic information.202 The diagnosis of Wernicke encephalopathy can be conrmed by measuring erythrocyte transketolase activity, a blood test result that is not immediately available in the emergency setting. The characteristic MRI ndings, when present, are quite specic and can be used to conrm quickly the diagnosis in patients with an atypical clinical presentation. However, the absence of MRI abnormalities does not rule out the diagnosis. It is important to be able to recognize variation in the clinical presentations of Wernicke encephalopathy so that treatment can be started promptly while waiting for diagnostic conrmation. The condition is lifethreatening at worst and is associated with high neurologic morbidity, namely Korsakoff amnesia. Acute treatment is 100 mg thiamine given intravenously or intramuscularly. Clinical symptoms and signs often resolve within hours of thiamine repletion, and radiographic abnormalities may also resolve within a few days. In chronic cases, mamillary body atrophy and dilation of the third ventricle and aqueduct may persist, as do cognitive decits and ataxia.
Top of the Basilar Syndrome

Injury to the vascular areas supplied by the rostral basilar artery is referred to as the top of the basilar syndrome.197 The majority of such cases are due to embolism. Clinical ndings vary, including a wide array of visual, ocular motor, behavioral, sensory, and motor signs that may cause diagnostic confusion. In one series, 47 of 61 patients with this syndrome presented with an acute confusional state, and the majority of these were initially thought to suffer from drug intoxication, psychiatric illness, or infection.198 Neuroophthalmic abnormalities were noted in 56 of the patients (92%) in this study, most commonly affecting vertical eye movements. These decits include selective upgaze or downgaze palsy or both, vertical one-and-a-half syndrome, Parinaud (dorsal midbrain) syndrome, skew deviation, and third and fourth nerve palsies. Disorders of horizontal gaze are less common and include convergence paresis or excess (the latter sometimes termed pseudo sixth nerve palsy) and internuclear ophthalmoplegia. Nystagmus (particularly upbeat and seesaw forms) and poorly reactive pupils (with or without light/near dissociation) are associated ndings in some patients, as is homonymous visual eld defects or actual cortical blindness, visual hallucinations or illusions, and other disturbances of higher cortical visual integration due to posterior hemispheric damage. Confusion, memory decits, and hypersomnolence are also common, related to thalamic infarction.199
Myasthenia gravis should be considered in any patient with a painless and pupil-sparing disorder of ocular motility.
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Neuromuscular Junction Disorders

Disorders of the neuromuscular junction frequently affect, but are not limited to, the EOMs. Specic conditions that may present acutely include MG and botulism.
Myasthenia
Myasthenia gravis (MG) should be considered in any patient with a painless and pupil-sparing disorder of ocular motility. Diplopia or ptosis is the initial symptom in 75% of patients with MG and can eventually develop in the remainder.203 Ocular myasthenia does not, in itself, constitute a medical emergency. The main reason to consider it in the context of a discussion of neuro-ophthalmic emergencies is its tendency to mimic a variety of other ocular motor disorders, some of which do require emergency intervention. Prompt identication of MG can save a patient from a battery of unnecessary neurologic investigations. Myasthenic weakness can mimic virtually any ocular motor syndrome, including CN palsies, horizontal or vertical gaze paresis, and nystagmus. Myasthenia occasionally creates the appearance of a pupil-sparing third nerve palsy. The absence of pain in this setting should suggest the possibility of a myasthenic pseudo third nerve palsy (Fig. 24). The disease often has a predilection for the medial rectus, creating a pseudo internuclear palsy. Myasthenic ptosis may be unilateral or bilateral, may alternate, may be quite variable during and between examinations, and may be accompanied by weakness of the orbicularis oculi muscles. This combination of facial muscle weakness and ocular motility disturbance effectively rules out CN palsy as the cause. Examination usually reveals some degree of fatigue and variability, especially when ptosis is present. Preservation of saccadic velocity even in the face of marked limitation of eye movements is characteristic and also helps to exclude cranial neuropathy. This is best demonstrated with small-amplitude eye movements; large-amplitude saccades may show intrasaccadic fatigue, so the beginning of the excursion is rapid but the end shows deceleration.204 The best method for conrming a clinical impression of MG is still the Tensilon (edrophonium chloride) test, although
some have advocated the use of the sleep test205 or ice test206,207 as a safer alternative. This remains an area of controversy.208 The general safety of the Tensilon test has been well documented,209 but the risk of serious complications may be higher in patients with cardiovascular disease, specically the chance of triggering an arrhythmia. In these patients it is reasonable to pursue other methods for making the diagnosis, such as blood tests for antibodies210 and electrophysiologic tests for evidence of generalized disease.211
The presence of gastrointestinal symptoms as well as impairment of pupillary responses and accommodation helps to distinguish botulism from myasthenia gravis.
Botulism
Botulism is a toxin-mediated disorder causing descending, symmetric paralysis from impaired cholinergic neurotransmission at the neuromuscular junction and cholinergic autonomic synapses. Clostridium botulinum is a spore-forming, anaerobic Gram-positive bacillus that is widespread throughout the soil. C. botulinum produces several types of neurotoxin, of which types A, B, and C account for 99.5% of human botulism. Common routes of infection are ingestion of toxin in contaminated canned goods or meats, spore-contaminated wound infection (particularly in heroin addicts who use subcutaneous injections known as skin popping), and gastrointestinal colonization by C. botulinum in infants. In cases due to ingestion of contaminated food (food-borne botulism), onset is usually 8 to 36 hours after eating; in cases of wound contamination, onset is 4 to 17 days after injury. Regardless of the
FIGURE 24. Myasthenic pseudo third nerve palsy. There is complete left upper lid ptosis and levator palsy. Horizontal eye movements are full. A superior division third nerve palsy was suspected however, following 0.4 mL Tensilon there was a dramatic reversal of the deficits. 2005 Lippincott Williams & Wilkins
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portal of entry, clinical manifestations begin when the toxin is distributed through the bloodstream and binds to nerve ending receptors and irreversibly blocks neurotransmission at all ganglionic synapses, all postganglionic parasympathetic synapses, and all neuromuscular junctions. External ophthalmoplegia and ptosis are often the initial neurologic manifestations of the disease, preceding or coinciding with the presence of dilated, poorly reactive pupils and paralysis of accommodation. Dysphagia, dysarthria, dysphonia, and symmetric descending muscular paralysis quickly follow. Patients maintain an alert sensorium. The presence of gastrointestinal symptoms (nausea and vomiting) as well as impairment of pupillary responses and accommodation helps to distinguish botulism from MG. Any patient suspected of botulism should be closely observed for signs of impending cardiorespiratory collapse. The fatality rate is estimated between 5 to 20% for food-borne botulism, with lesser rates in infant and wound botulism. Diagnosis is usually made from the clinical history and presentation. Demonstration of toxin in serum or gastrointestinal contents as well as in the suspected food source using mouse bioassay is conrmatory for foodborne disease, but treatment should not be delayed while awaiting assay results.212 Equine trivalent botulinum antitoxin is recommended for adults with food-borne and wound botulism, especially if administered within 24 hours of symptom onset, and infants may receive botulism human immunoglobulin. Supportive care in an intensive care setting is mandatory.
decreased vision prompts the patient to look closely in the mirror, at which point the pupillary abnormality is noticed. In these cases, the anisocoria may well be an unrelated, preexisting asymmetry. The rst challenge when approaching a patient with anisocoria is to determine which is the abnormal pupil. In some cases there are associated physical ndings that help to make this distinction. For example, ptosis and ipsilateral ophthalmoplegia on the side with the larger pupil indicates a third nerve palsy; mild ptosis on the side with the smaller pupil suggests a Horner syndrome. When the anisocoria is an isolated nding, decreased reactivity to light stimulation of the larger pupil suggests the abnormal side. Cases in which the anisocoria is an isolated nding and pupillary reactivity to light stimulation appears normal in both eyes are more challenging. In this setting it is helpful to compare the degree of pupillary asymmetry in different lighting conditions. Anisocoria that is more marked in dim illumination suggests a sympathetic defect (Horner syndrome) on the side with the smaller pupil. Anisocoria that is greater in light indicates a parasympathetic defect on the side with the larger pupil. Physiologic anisocoria, present in approximately 20% of the normal population, is often of equal magnitude in bright and dim lighting, but in some patients may appear more prominent in dim light, thus causing confusion with a Horner syndrome.213
The Large, Poorly Reactive Pupil

The association of a xed, dilated pupil with transtentorial herniation is well established, and consequently this nding often generates great concern among medical personnel. When pupillary dilation occurs in this setting, due to compression of the third nerve by the herniating uncus, there is almost invariably altered consciousness if not frank coma. In an awake, alert, and conversant individual, the presence of a large and/or poorly reactive pupil does not indicate impending herniation. The most likely cause for this nding is either an Adie tonic pupil or a local pharmacologic effect. Other considerations may include trauma to the iris sphincter, intraocular inammation, and iris ischemia. Damage to the ciliary ganglion results in paresis of the iris sphincter and ciliary muscle. While many pathologic processes such as trauma (accidental or iatrogenic), tumor, infection, or ischemia can cause this damage, most cases occur spontaneously and it is this idiopathic form that has been termed an Adie tonic pupil.214 Affected individuals are typically women age 30 to 40 years who present with acute onset of unilateral blurring of near vision, mild eye or brow ache, and an enlarged, poorly reactive pupil. Under slit-lamp magnication, the segments of iris sphincter that do not contract to light (segmental palsy) are readily visible against normally contracting segments of iris sphincter.215 More important, the nding of segmental palsy rules out the pos 2005 Lippincott Williams & Wilkins
The first challenge when approaching a patient with anisocoria is to determine which is the abnormal pupil.
One case of food-borne, adult-onset botulism should alert the physician to the possibility of many cases, and public health ofcials should be notied accordingly.
ANISOCORIA
Bilateral poorly reactive pupils are sometimes a sign of serious intracranial disease but are rarely noticed by the patient. Pupillary inequality, in contrast, is more likely to come to attention because either the patient or a family member notices the asymmetry. Anisocoria is sometimes discovered when a visual symptom such as eye pain or
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sibility of pharmacologic instillation and makes an acute third nerve palsy highly unlikely. A large, poorly reactive pupil and blurred vision can also be due to pharmacologic instillation (accidental or factitious) of any atropinelike substance, including mydriatic eye drops, scopolamine patches, certain insecticides, belladonna alkaloids such as Jimson weed, anticholinergic inhalants, gentamicin, and lidocaine. Substances that stimulate the dilator muscle can also produce anisocoria. Examples include epinephrine, phenylephrine, ephedrine, hydroxyamphetamine, cocaine, ocular decongestants, and adrenergic inhalers. The mydriatic effects of a dilator stimulator can be suspected based on blanching of the conjunctival vessels and mild lid retraction in the eye with the larger pupil. Pupillary dilation and decreased reactivity also occur in the setting of third nerve palsy, particularly when due to aneurysmal compression. In such cases there are virtually always other signs of third nerve dysfunction, although occasionally these signs may be subtle. These patients should be examined carefully for ipsilateral ptosis, and crossover testing in adduction and in upgaze is important for revealing mild medial rectus or superior rectus paresis. Pharmacologic testing with direct-acting cholinomimetic agents can help in differentiating an Adie tonic pupil from a pharmacologically dilated pupil and from third nerve palsy. Pilocarpine in varying concentrations is most commonly used, instilling 1 drop in each eye and then comparing the magnitude of pupil constriction in the 2 eyes. About 80% of Adie pupils demonstrate cholinergic denervation supersensitivity (manifest as more pupillary constriction in the eye with the dilated pupil compared with the fellow eye) in response to dilute or one eighth of a percent of pilocarpine. However, this nding takes 5 to 8 days to become apparent.214,216 In occasional cases a pupil that is dilated due to a preganglionic lesion (ie, a third nerve palsy) may show similar cholinergic supersensitivity to dilute pilocarpine.217 In cases of atropinization, the dilated pupil will fail to constrict to dilute and even to full-strength (0.5 4%) pilocarpine.218 It is important to remember that direct damage to the iris sphincter muscle can cause a reduced response to cholinomimetics, similar to what is seen with a pharmacologic pupil. If there is a history of iris trauma, the presence of sphincter tears or iris atrophy can be conrmed with slit-lamp examination. Iris ischemia can be a manifestation of highgrade carotid stenosis or GCA. In addition, angle-closure glaucoma can produce a xed, dilated pupil due to iris ischemia. In each of these clinical settings there is often associated ipsilateral pain. In some cases ischemia may also cause corneal decompensation, in which case blurring of vision and halos around lights may be prominent. Transient, isolated pupillary dilation sometimes occurs in healthy individuals, particularly young women, and has
been designated as benign unilateral mydriasis and springing pupil, among other terms.219 These episodes are sometimes associated with vascular headaches, and affected individuals often have a personal and/or family history of migraine, leading many to conclude that this form of anisocoria represents a form of vasomotor instability.220,221 It is not clear whether the underlying mechanism in these cases is parasympathetic paresis or sympathetic overactivity. The occurrence of a permanent AdieHolmes syndrome after one such episode supports the former theory.221 Cases in which one segment of the pupil appears peaked during an episode is more suggestive of the sympathetic spasm.222 Regardless of mechanism, these attacks are benign and do not require extensive neurologic investigation.
Horner Syndrome
Anisocoria that is greater in dim illumination is characteristic of oculosympathetic paresis. Weakness of Muellers muscle causes mild upper lid ptosis and sometimes reverse lower lid ptosis, giving the impression of enophthalmos on the side of the smaller pupil. Acutely there is often conjunctival hyperemia as well. While the responsible lesion may be in a variety of locations, those that present acutely and in isolation are usually postganglionic (ie, involving bers from the superior cervical ganglion distally).223 Most cases of acute postganglionic Horner syndrome are associated with ipsilateral pain, and the 2 main diagnostic considerations are carotid dissection and cluster headache.224 The nonremitting nature of the pain in dissection should help to distinguish these patients from those with cluster. Patients with cluster headache typically experience abrupt episodes of pain, often occurring during the night, lasting 45 to 60 minutes and often associated with a Horner syndrome that is usually transient but may become a xed decit after repeated episodes. In some affected individuals, cluster attacks are precipitated by ingestion of alcohol and, for reasons that remain obscure, they often prefer to pace about during their attacks rather than rest in bed.
Carotid Dissection
The most common clinical manifestation of ICA dissection is pain, which may be localized to the head, eye, jaw, face, or neck.225228 Scalp tenderness may occur, suggesting the diagnosis of GCA. Pain may occasionally be the only manifestation of dissection.226,229 Postganglionic Horner syndrome occurs in up to 58% of patients230 and is often the presenting manifestation.231233 About 30% of patients report transient monocular blindness,230 which is probably due to decreased perfusion from reduction of the carotid lumen, rather than representing an embolic event. Retinal emboli can occur secondary to ICA dissection,234 237 but such an occurrence is rare, probably because of reversal of ow through the ophthalmic artery. Episodes of transient monocular visual
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loss due to dissection are often precipitated by postural change and may be associated with positive visual phenomena including sparkles and scintillations.230,238 In rare cases visual loss may occur secondary to disc infarction18,239 or ocular ischemic syndrome.240 While permanent visual loss is distinctly uncommon, stroke is not. In a series of 80 patients with ICA dissection, Biousse et al241 found that 40% of patients with inaugural symptoms that were local (ie, isolated Horner syndrome or head/neck pain) had a subsequent infarction (retinal or cerebral) that occurred up to 1 month after onset of symptoms. These ndings suggest that treatment should be initiated promptly but is still worthwhile even 1 month later. If stroke has not occurred during the rst few weeks, it is unlikely to do so later. Between 10% and 15% of patients with ICA dissection develop CN palsies, most commonly involving lower CNs.242 Symptoms include tongue weakness, dysarthria, dysphagia, and an unpleasant metallic taste. Ocular motor palsies are uncommon, occurring in only 1 to 3% of patients.230,242244 Ophthalmoparesis may also occur secondary to orbital ischemia.245 Most dissections heal within 3 months with recovery of CN palsies, although complete recovery was seen in only 29% of the patients in one prospective series.246 In another follow-up study, 80% of initially stenotic vessels were subsequently found to be normal, and one third of initially occluded arteries were found to have recanalized.247 Even in patients with persistent high-grade stenosis or occlusion, the annual stroke rate is quite low 0.7% on the side of the dissection and 1.4% overall.248 Dissection can be diagnosed with noninvasive methods, including MRI, MRA, CTA, and carotid Doppler.249 251 The study of choice is axial T1-weighted MRI of the head without contrast that includes images down to the carotid bifurcation. On such images the dissection appears as a bright crescent around the ICA (Fig. 25). Signicant narrowing of the lumen, when present, is better documented with MRA or by conventional angiography. Treatment usually consists of bed rest plus anticoagulation to prevent the risk of embolization and thrombus formation. In patients in whom the diagnosis is made weeks after onset of symptoms, the risk of stroke is admittedly low and in these individuals antiplatelet therapy may be adequate. In either case, long-term monitoring with some form of noninvasive imaging is important to help identify patients who are at higher risk of stroke.249
FIGURE 25. Carotid dissection. This woman developed rightside head and face pain with drooping of the right upper lid the day after watching an air show for several hours. (A) There is mild right upper and reverse lower lid ptosis and a smaller pupil on that side. (B) Axial T1-weighted MRI shows a bright crescent around the internal carotid, indicating intimal dissection.
conclude by once more emphasizing some specic areas in which mistakes or a delay in diagnosis are likely to be costly: 1. Failure to recognize some of the less common clinical manifestations of GCA, such as transient visual loss and diplopia, delays diagnosis. 2. Delay in initiating treatment of GCA, while pursuing additional investigations, can result in devastating visual loss. 3. Steroid treatment of GCA at inadequate levels fails to prevent visual loss. 4. Failure to recognize a partial third nerve palsy delays the detection of an expanding aneurysm. Arteriography is the gold standard. 5. Overestimating the sensitivity of noninvasive neuroimaging fails to detect an aneurysm. 6. CT, although more readily available in an emergency room setting, is relatively insensitive for visualizing certain disorders, most notably pituitary apoplexy and CVT. 7. Failure to appreciate risk factors for Wernicke encephalopathy delays diagnosis. Signs and symptoms are nonspecic; the diagnosis should be suggested by the clinical context. 8. Monitoring the appearance of papilledema without adequately measuring optic nerve function (especially visual elds) leads to a false impression of improvement in the face of progressive optic neuropathy.
CONCLUSION
We have provided a practical review of common neuroophthalmic emergencies. We also tried to provide specic guidelines for the management of these disorders and to highlight areas in which there is ongoing controversy. We
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9. Postponing surgical intervention for papilledema in patients with progressive visual loss leads to permanent blindness. 10. Failing to recognize Parinaud syndrome as a sign of incipient shunt failure in the face of normal-size ventricles delays diagnosis and appropriate treatment. REFERENCES
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ORIGINAL ARTICLE

Neuro-Ophthalmic Emergencies for the Neurologist

ACUTE VISUAL LOSS

The Neurologist Volume 11, Number 4, July 2005

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Optic Neuritis (ON)

2005 Lippincott Williams & Wilkins

The Neurologist Volume 11, Number 4, July 2005

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Anterior Ischemic Optic Neuropathy (AION)

Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)

The Neurologist Volume 11, Number 4, July 2005

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Arteritic Anterior Ischemic Optic Neuropathy (Arteritic AION)

The Neurologist Volume 11, Number 4, July 2005

2005 Lippincott Williams & Wilkins

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Arteritic versus Nonarteritic Anterior Ischemic Optic Neuropathy (AION)

2005 Lippincott Williams & Wilkins

The Neurologist Volume 11, Number 4, July 2005

Retrobulbar Optic Neuropathies Posterior Ischemic Optic Neuropathy

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Retinal Artery Occlusion

2005 Lippincott Williams & Wilkins

The Neurologist Volume 11, Number 4, July 2005

Homonymous Visual Loss

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

OPTIC DISC EDEMA

The Neurologist Volume 11, Number 4, July 2005

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Retinal hemorrhages Cotton wool spots

Idiopathic Intracranial Hypertension (IIH)

The Neurologist Volume 11, Number 4, July 2005

2005 Lippincott Williams & Wilkins

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

The Neurologist Volume 11, Number 4, July 2005

Hypertensive Optic Neuropathy

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

Diabetic Disc Edema

Toxic Optic Neuropathies

Sleep Apnea Syndrome (SAS)

The Neurologist Volume 11, Number 4, July 2005

Weakness of a single third nerve-innervated extraocular muscle is extremely unusual.

ABNORMAL OCULAR MOTILITY

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

2005 Lippincott Williams & Wilkins

The Neurologist Volume 11, Number 4, July 2005

Cavernous Sinus Thrombosis

Purvin and Kawasaki

The Neurologist Volume 11, Number 4, July 2005

CarotidCavernous Fistula (CCF)

The Neurologist Volume 11, Number 4, July 2005