Neuro-Ophthalmologic Emergencies

INTRODUCTION:

Emergencies are patient presentations that, if not identified and treated promptly, may lead to significant morbidity or mortality. Accordingly, neuro-ophthalmic emergencies are those presenting with neuro-ophthalmic signs and symptoms. In determining what topics to review in this article, consideration was given to differentiation of conditions needing emergent versus urgent management. For the purposes of this article, we define emergency as any condition requiring evaluation within 24 hours, often through emergency room referral. For example, the differential diagnosis for a patient presenting with retrobulbar optic neuropathy is broad including, in increasing order of urgency optic nerve sheath meningioma, optic neuritis, and giant cell arteritis, with the latter constituting an emergency.

Additionally, most patients do not present with an emergent diagnosis, rather with symptoms and signs suggesting this. Thus, organization by diagnosis may not be as useful to the clinician. Therefore, we frame our discussion around acute vision loss, diplopia, and pupillary abnormalities. Within these categories we discuss important considerations when assessing these symptoms, highlight emergent conditions that cause them, their evaluation, and their management. Due to the myriad ways that many neuro-ophthalmic diseases present, it is impossible to be all encompassing, but we hope that our presentation helps students, practicing physicians, and other healthcare providers build and begin to fill in their own framework for approaching patients with neuro-ophthalmic emergencies.

ACUTE VISION LOSS

Approach to the history and examination

As in most neurologic conditions, localization is an important first step in diagnosing a patient. For visual complaints, both ophthalmic and neurologic structures need to be considered (Table 1). History questions that can provide insight include severity of vision loss (what can the patient see/not see?), nature of vision loss (positive [bright] , negative [ dark or dim] , distortion), binocularity (right eye, left eye, both eyes together or separately), and location (central or peripheral visual field). Comparison of vision loss between eyes is particularly helpful to localize vision loss anterior to, within or posterior to the chiasm. It should be noted that many people with bilateral homonymous visual field deficits can misinterpret these as monocular in origin.¹ If the symptom persists, active comparison of vision between the eyes is instructive. If the symptom has resolved, questioning the patient regarding symptom change if they closed one eye or the other when symptomatic can provide clues.

Table 1:

Approach to history and examination in a patient with vision loss due to afferent visual pathway dysfunction

History:
1. What can the patient see/not see?
2. What is the nature of vision loss? (positive [bright], negative [dark or dim], distortion)
3. Is the vision loss monocular or binocularity? (right eye, left eye, both eyes together or separately)
• Did the patient compare one eye to the other eye?
4. Where in the visual field is there vision loss? (central or peripheral visual field)
Exam:
1. Visual acuity in each eye separately
• Snellen eye chart, ability to count fingers, identify hand motion or light perception
2. Color vision compare between eyes
• red desaturation
3. Confrontation visual fields in each eye separately
• typically count fingers in 4 quadrants
4. Pupillary exam
• direct response, relative afferent pupillary defect (anisocoria is not caused by afferent visual pathway dysfunction)
5. Fundoscopic exam
• disc margin and color, cup:disc ratio, caliber of arteries/veins, spontaneous venous pulsations

The physical exam should include visual acuity, color vision (red desaturation), confrontation visual fields, pupillary exam, and fundoscopic exam in addition to a targeted neurologic exam. Visual acuity should be checked using a patient’s habitual refractive correction for testing distance and/or pinhole. If large text can’t be discerned, ability to count fingers, identify hand motion or see light should be determined. Visual acuity that improves 2 or more lines on Snellen when using a pinhole is likely optical in origin, related to refractive error or cataract. Red desaturation can be tested by having the patient cover each aye alternately, while asking them to compare the brightness/hue of a red object or stimulus. If the color is perceived differently between eyes, usually described as a lighter red or pink in the affected eye this is positive finding. Bedside testing of confrontation visual fields has poor sensitivity; however, specificity of finger counting is reasonable.² Central (visual acuity) and/or peripheral (confrontation visual fields) testing demonstrating vision loss in one eye localizes anterior to the optic chiasm; in the temporal aspect of both eyes, localizes to the chiasm; or on the same side of both eyes (i.e. homonymous defects) localizes to the visual pathways behind the chiasm or to the same problem on both sides anterior to the chiasm. In a patient with symmetric pupils, comparison of the direct and indirect responses to light is helpful to detect asymmetric optic nerve disease. This can be visualized using the swinging flashlight test, looking for dilation when moving to the worse eye and constriction when moving to the better eye (a relative afferent pupillary defect(rAPD)). The anterior ophthalmic and funduscopic exams will identify most ophthalmic causes of vision loss and are also important for identification of optic nerve head abnormalities such as swelling or pallor and retinal vascular changes.

Particular attention should be paid to symptoms and signs localizing to near the afferent visual pathway or suggesting neurological syndromes that can involve vision loss. Associated signs and symptoms that can help to localize an optic neuropathy include

• Orbit: proptosis, orbital pain, extra-ocular movement limitations

• Orbital apex: ipsilateral CN III, IV, VI, V1 dysfunction

• Skull base/pituitary: CN III, IV, VI, V1, V2, sympathetic pathway dysfunction

• Cerebral hemispheres: sensorimotor deficit, aphasia, cognitive dysfunction

Some emergent neuro-ophthalmic causes of vision loss are giant cell arteritis, pituitary apoplexy, retinal arterial occlusion and cerebral ischemic or hemorrhagic stroke. With the exception of pituitary apoplexy these diseases can present in transient form (e.g. transient ischemic attacks) and are thus important differential considerations in the patient with transient or fixed vision loss .

Giant Cell Arteritis (GCA)

Background/Presentation:

GCA is a medium and large vessel vasculitis that almost exclusively affects those greater than the age of 50.³ Its prevalence in the general population is < 1%, estimated to be 0.36 per 100,000.^4,5 Due to its vision threatening, as well as life threatening complications, its early recognition is crucial. Sudden monocular vision loss due to optic neuropathy (anterior or posterior) caused by arteritis of branches of the ciliary or ophthalmic arteries is the most common presenting visual symptom of GCA. Often this is preceded by transient episodes of vision loss. Without treatment about one half of patients will have arteritic anterior optic neuropathy (AAION) in the fellow eye and such double eye involvement is commonly blinding. Stroke, aortic dissection, aortitis, and myocardial infarction are notable, yet less common, life threatening complications of GCA.

Although sudden monocular vision loss due to ischemic optic neuropathy is the most common ocular presenting symptom, GCA can present with other causes of acute vision loss including ophthalmic artery occlusion or posterior circulation ischemic stroke.⁶ Cranial nerve or orbital involvement can cause diplopia.⁷ Although visual manifestations may be intermittent initially, persistent visual deficits are usually irreversible once they occur. An estimated 4-20% will present with primary visual symptoms; however, 50% will experience visual symptoms over the course of the disease. GCA is associated with many systemic symptoms caused by systemic inflammation and focal ischemia (Table 2).⁸ Careful questioning regarding pain anywhere in the distribution of the external carotid artery (lateral face/temple, neck, ear, jaw, occipital, or scalp) should be performed. However, a minority of patients do not have any systemic symptoms.

Table 2:

Systemic Symptoms in GCA⁴

symptom	prevalence
Headache	57%
Polymyalgia rheumatica	50%
Jaw claudication	48%
Weight loss	40%
Malaise	37%
Anorexia	31%
Myalgias	28%
Scalp tenderness	20%
Neck pain	17%
No systemic symptoms	20%

Examination:

When the symptoms are transient, it is common for the neuro-ophthalmic exam to be normal between episodes, so a high clinical suspicion and careful history are necessary to make this diagnosis. If there is persistent vision loss the clinician should be able to measure this in the ways described above. RAPD and fundoscopic exam showing pallid disc edema suggest AAION, while rAPD and a normal anterior optic nerve suggests posterior ischemic optic neuropathy.

Laboratory Evaluation:

ESR and CRP should be drawn given the high sensitivity (~86.9% and 84.1% respectively) in patients with temporal artery biopsy-proven GCA.⁹ Implicit in this imperfect sensitivity is that GCA can occur without elevation of systemic inflammatory blood tests. A complete blood count can be helpful in evaluating for thrombocytosis, anemia, and leukocytosis, but this has a significantly lower sensitivity.

Imaging:

Retinal fluorescein angiography, available in many ophthalmology clinics, can demonstrate choroidal perfusion deficits and delayed choroidal filling that are suggestive of GCA. MRI or ultrasound of the temporal artery can demonstrate arteritis. Ultrasound is in widespread use in Europe, where it is used as a substitute for temporal artery biopsy if the case presents typically. However, in the US, this is not widely available. In about one third of patients, the temporal arteries are not involved, and CT MRI and PET of the chest can be helpful to diagnose aortitis or involvement of other large arteries by GCA.¹⁰ The aorta should be routinely assessed in all GCA patients at diagnosis and at follow up.

Diagnosis:

Temporal artery biopsy (TAB) demonstrating multinucleated giant cell and inflammatory infiltrate (giant cells do not need to be present) is diagnostic of GCA and in the US this is pursued for diagnostic confirmation in patients in whom there is high clinical suspicion due to combination of ischemic presentation, systemic symptoms, and/or elevated systemic inflammatory markers. One may need to look for healed arteritis (this may be described as focal disruption of the internal elastic lamina) if there is a delay in biopsy by more than 2 weeks after initiation of steroids. If the first biopsy is negative (seen in 4–10% of cases) a second site should be considered in high risk patients. In some geographic regions, temporal artery ultrasound showing findings consistent with arteritis is diagnostic in lieu of TAB.

Treatment:

In patients with acute vision loss suspected due to GCA, emergent initiation of steroids before TAB is appropriate to prevent further ischemic episodes. 3 days of high dose IV methylprednisolone (1000mg per day) followed by a slow prednisone taper over a year is a common regimen, though oral only regimens are also used. IV therapy may diminish the likelihood of fellow eye involvement and was associated with a slightly better prognosis for visual improvement.¹¹ In regards to the frequent ischemic events seen in GCA at sites other than the eye, such as MI and stroke, some evidence supports the use of low dose daily aspirin.¹² Chronic therapy of GCA is beyond the scope of this review, but is often done in coordination with rheumatology.⁹

Clinics Care Points

• Up to 20% of patients who present with visual symptoms from GCA may not have systemic manifestations

• Patients with visual symptoms from suspected GCA should be urgently evaluated by an eye care provider, yet this should not delay empiric treatment

• ESR/CRP are most sensitive for GCA, but can be nonspecific and negative in up to 10% of patients

• Temporal artery biopsy remains the gold standard for diagnosis in the United States, but arranging this should not delay treatment as the pathologic findings can still be seen within 2 weeks of initiation of steroids

• Initiation of GCA treatment is emergent, because untreated GCA is associated with recurrent ischemic events particularly in those with visual presentations

Pituitary Apoplexy

Background/Presentation:

Pituitary a poplexy is a life-threatening condition that results from sudden enlargement of the pituitary gland as a result of hemorrhage or infarction. It is a rare complication of pituitary adenomas, occurring in 0.6% to 9% of pituitary adenomas, though up to 81% of affected patients are unaware that they have a pituitary tumor prior to experiencing apoplexy.¹³ It is a neurosurgical emergency. Associated disruptions in endocrine function can be fatal if not treated promptly. Corticotropic deficiency, occurring in 50%-80% of cases, can be life-threatening, potentially causing severe hemodynamic problems and hyponatremia due to acute secondary adrenal insufficiency.

Common symptoms are sudden onset severe headache; neck stiffness; vision loss due to chiasm, optic nerve or optic tract compression; and diplopia due to cavernous sinus invasion (Table 3). There may also be symptoms of pituitary hormone imbalance. Most cases present spontaneously, while a minority are precipitated by malignant hypertension, anticoagulation, or dopamine agonists.¹⁴

Table 3:

Presenting findings in pituitary apoplexy¹³

Symptom/Sign/Condition	Prevalence
Headache	87%
Panhypopituitarism	73%
Decreased visual acuity	56%
Bitemporal hemianopsia	34%
Diabetes Insipidus	8%

Examination:

Observation of the patient’s mental status is imperative as brainstem or hypothalamic compression can lead to depressed consciousness and cardio-pulmonary dysfunction. In regard to neuro-ophthalmologic examination in the emergent setting, one should check for cranial nerve palsies as well as central and peripheral vision loss. Variable patterns of visual-field impairment may be observed, bitemporal hemianopsia due to compression of the optic chiasm being most common.

Laboratory Evaluation:

Endocrine evaluation at presentation should include random cortisol, free T4, thyroid stimulating hormone, growth hormone (insulin like growth factor-1; IGF-1), prolactin, complete blood count and metabolic panel. Anterior pituitary hormonal dysfunction is present in 80% of patients upon presentation.¹⁵ Evaluation of the hypothalamic pituitary axis function should not delay treatment with glucocorticoids.

Imaging/Diagnosis:

Standard non-contrast head CT has a low sensitivity for pituitary apoplexy as it can be difficult to observe on axial images at standard spacing. CT protocolled for visualization of the pituitary or MRI are preferred. MRI in particular is superior for evaluation of hemorrhage, tumor burden, and compression of surrounding structures (figure 1).

Figure 1:

Neuro-imaging features of pituitary apoplexy. Non-contrast axial CT scan (top left) with normal appearing sella. Axial T2 weighted MRI (top center) and Axial T1 weighted MRI without contrast (top right) from the same patient demonstrating layer layering hemorrhage in the sella. Coronal (bottom left) and sagittal (bottom right) T1 MRI without contrast (bottom left) showing a well-circumscribed sellar mass with suprasellar extension and mass effect on the optic chiasm, containing central and peripheral rim T1 hyperintense signal suggestive of areas of hemorrhage. Images Courtesy Bryan Lanzman, MD, Department of Radiology, Stanford University.

Management:

The risk of acute secondary adrenal insufficiency warrants empiric corticosteroid supplementation (preferably preceded by blood draw for serum cortisol determination) prior to confirmatory imaging.¹⁶ Therapy should consist of hydrocortisone 50 mg every 6 hours or a bolus of 100–200 mg followed by 50–100 mg every 6 hours.¹⁶ These patients should be admitted for close monitoring to a neurologic ICU. Endocrinology input for management of pituitary dysfunction as well as neurosurgery input for tumor management are important. Although some patients can be successfully managed with close observation and medical treatment, surgical decompression improves visual acuity and visual fields in the majority of cases (76% and 79% respectively).¹³

Clinical Care Points

• MRI is the imaging modality of choice for pituitary apoplexy; Pituitary protocol CT is preferred over non-contrast CT head

• Pituitary apoplexy is a neurosurgical emergency, warranting emergent consultation of neurosurgery, neurocritical care, and endocrinology

• Initiation of empiric steroids is critical for treatment of secondary adrenal insufficiency

• Surgical decompression is most useful in patients with clinical signs of compression of structures underlying visual or other vital functions

Ocular vascular events: Central retinal artery occlusion/BRAO/Amaurosis Fugax

Background/Presentation:

Central retinal artery occlusion (CRAO), branch retinal artery occlusion (BRAO) and amaurosis fugax (transient vision loss from retinal or optic nerve ischemia) etiologies include large artery occlusive disease (atherothrombosis, embolus, dissection), arterial emboli, hypercoagulable disorders, and calcific emboli. The final common pathway for these disorders is ischemia to the retina, the optic nerve, or both. In one study, 24% of patients with monocular ischemic vision loss had concurrent cerebra farcts on MRI, reinforcing that these are strokes of the eye. This includes 9% of patients with transient monocular vision loss due to ocular TIA.^17,18 Emergent evaluation is essential due to the high short term risk of second event due to presence of undiagnosed or insufficiently managed risk factors such as carotid artery stenosis or atrial fibrillation

Patients with a CRAO experience acute, painless, monocular vision loss, with 80% of affected patients having visual acuity of count fingers vision or worse. Those with BRAO will experience visual field loss in the territory of the occluded artery, often an altitudinal monocular visual field defect.¹⁹ A monocular TIA (Amaurosis Fugax) typically causes severe vision loss lasting one to 15 minutes.²⁰

Examination:

Ischemic retina can appear normal in the hyperacute stage, before becoming pale due to edema. In CRAO there is a cherry red spot in the macula which is not perfused by the central retinal artery (figure 2). In CRAO, BRAO and amaurosis fugax the examiner may be able to identify a cholesterol or calcium plaque in one of the retinal arteries.

Figure 2:

Ophthalmic imaging features of acute central artery occlusion. Widefield retinal images (top) show a retinal whitening due to edema in the affected (left) compared to unaffected (right eye). The edema spares the macula leaving a “cherry red spot.” Optical coherence tomography cross sectional images through the macula and optic nerve (bottom) show the edema in the affected eye (left) as retinal thickening not seen in the unaffected eye (right).

Testing:

In patient s presenting less than 72 hours after symptom onset, emergent evaluation is recommended, preferably at a stroke center. Workup should include standard of care for stroke, including lipid panel, hemoglobin A1c, ECG and cardiac telemetry, transthoracic echocardiogram, and MRI of the brain with the addition of vessel imaging (CTA or MRA). Updated guidelines are regularly published by the American Heart Association.²¹

Management:

There is heterogeneity in acute treatment among academic institutions for treatment of CRAO.²² Some interventions aim to increase perfusion by lowering intra-ocular pressure (e.g. via intraocular paracentesis, IV acetazolamide, or topical glaucoma drops). Studies examining the utility of systemic thrombolysis using alteplase suggest that the timewindow for successful intervention is likely to be <~6 hours. ^23,24 There has been mixed data in regard to efficacy of intra-arterial thrombolysis with some case series and at least one meta-analysis showing benefit; however, a more recent randomized control study failing to show improvement in visual acuity with intra-arterial thrombolysis.^19,25

Monitoring during the early period when risk for second eye or brain events is highest is essential. This offers the opportunity to identify and intervene on secondary risk factors. For non-cardioembolic events the use of antiplatelet agents is recommended to reduce the risk of recurrent stroke or cardiovascular events. Prevention should include initiation of an antiplatelet or anticoagulant depending on the clinical situation.²¹

Clinics Care Points:

• Patients with acute BRAO, CRAO or monocular transient vision loss thought to be due to ischemia should be emergently referred to a stroke center for evaluation

• Emergent evaluation should include lipid panel, hemoglobin A1c, ECG and cardiac telemetry, transthoracic echocardiogram, and MRI of the brain with the addition of vessel imaging (CTA or MRA)

• Acute treatment aimed at improving retinal perfusion may include lowering intraocular pressure and systemic and/or directed endovascular thrombolysis.

Ischemic and Hemorrhagic Stroke

Background/Presentation:

Cerebral infarction and hemorrhage impacting the optic radiations or visual cortex cause acute vision loss with homonymous visual field loss. Lateral geniculate nucleus lesions are associated with wedge shaped homonymous contralateral visual field loss in both eyes. Isolated visual symptoms are rare but can occur from either anterior circulation (anterior choroidal artery) or posterior circulation (posterior choroidal artery) strokes. Dysfunction of the optic radiations is associated with incongruous visual field loss in the opposite field in both eyes. Due to the distributed nature of the radiations, it is rare for injury to them to cause isolated visual symptoms and it is typical to have other symptoms/signs that localize to the relevant parietal/temporal lobe. Occipital lobe dysfunction is associated with congruous visual field loss in the opposite field in both eyes. Unlike visual field defects localizing to the optic radiations, those from occipital lobe dysfunction commonly occur in the absence of other neurological dysfunction. Central vision may be spared due to dual arterial supply from both anterior and posterior circulations to the occipital poles.

Diagnosis/Management:

CT and MRI are helpful for diagnosis of acute cerebral ischemic stroke or hemorrhage. The reader is referred to excellent reviews on diagnosis and management of acute stroke for further detail.²¹

Papilledema due to Increased Intracranial Pressure (ICP)

Background/Presentation:

High intracranial pressure causes optic nerve head swelling due to compression of the optic nerve by the high-pressure cerebrospinal fluid in the optic nerve sheath. Papilledema is an emergency to prevent both vision loss and neurological deterioration from the underlying cause. The former occurs in about half of affected people and is severe in 10%. If not treated promptly this vision loss can be permanent.

Common symptoms of high ICP include headache and pulsatile tinnitus. When papilledema causes vision loss it typically impacts the periphery and central vision is spared. Transient visual obscurations, described as blacking or graying out of vision in one or both eyes for seconds provoked by head movements, might be a marker of borderline optic nerve head perfusion. Diplopia due to sixth nerve palsy is a false localizing sign of high ICP.

Examination:

Optic nerve swelling is typically bilateral but can be asymmetric. Retinal hemorrhages or cotton wool spots suggest acute and severe injury. In late stages the swelling can reduce and become pale due to atrophy.

Imaging:

Neuro-imaging to exclude a mass lesion or venous sinus thrombosis as a cause of high ICP should be pursued emergently. Additionally, ultrasonography demonstrating enlarged optic nerve sheath diameter and change in diameter with eye movement may allow for early diagnosis of intracranial hypertension when direct ICP measurement is not feasible or delayed. In one meta-analysis, consisting of primarily TBI and ICH patients with ICP monitoring, a positive ultrasound was found to be associated with a 51 fold higher risk of elevated ICP and was shown to have a sensitivity of 90% and specificity of 85%.²⁶

Diagnosis:

If a secondary cause is not found on imaging, lumbar puncture with measurement of opening pressure in the lateral decubitus position is important to identify CSF inflammation or infection, confirm high ICP, and provide temporary treatment.

Management:

Primary management is directed at any underlying cause. In patients with vision loss, regardless of whether ICP elevation is primary or secondary, ICP directed therapy is important. Medications (acetazolamide, furosemide, topiramate) are first line with surgical interventions (optic nerve sheath fenestration, CSF diversion shunt, venous sinus stenting) reserved for progression or severe vision loss cases.²⁷ Surgical procedure selection varies across institutions. Many times, the decision is often based on local expertise and surgeon availability with predominant symptom and patient preference being taken into consideration.²⁸

DIPLOPIA

Approach to the history and examination

The first thing a clinician should establish when evaluating a patient with diplopia is whether they are experiencing monocular or binocular diplopia. Binocular diplopia due to ocular misalignment will resolve with covering either eye. If diplopia persists with either eye covered, this is unlikely to be a neurological problem and likely due to a problem with the optics of the anterior visual pathway. It is important to note that in a minority of people (e.g. those with poor vision in one eye or poor integration of the eyes) ocular misalignment does not cause diplopia.

The goal of a comprehensive eye movement examination is to facilitate pattern identification to localize the lesion. Examination of the extent of eye movements may be sufficient to characterize the eye movement disorder causing diplopia. If there are any limitations, evaluation of eye movements induced by reflex maneuvers (e.g. vestibulo-ocular reflex using dolls eyes or caloric tests) can be helpful to localize any eye limitation to a supranuclear or cranial nerve/nuclear origin. However, it is important to recognize that full extraocular movements DO NOT exclude a neurological disorder causing diplopia, as very small degrees of ocular misalignment not apparent on examination can cause diplopia. The patient can help to characterize this by describing if the images are horizontally, vertically or obliquely oriented with respect to each other and if the images change in orientation/separation distance in different directions of gaze. Methods of eye alignment testing include examining the reflection of light in the pupils for relative displacement off of the center of the pupil (e.g. if the light reflects off the inner iris of one eye this suggests the eyes are relatively turned out). Alternately covering each eye while the patient fixates on an object is an easy bedside test. If there is ocular misalignment the newly uncovered eye will saccade to regain fixation. The eye movement exam is a small part of the cranial nerve exam and must be interpreted in the context of a full neurological examination and history.

Patterns of ocular motility disorders and their emergent causes are discussed below. Following this is a discussion of two diseases causing complex ocular misalignment patterns necessitating emergent intervention.

Ocular motility disorder patterns & emergent causes:

Cranial nerve 3 Palsy:

A non-nuclear third nerve palsy in isolation affects the superior rectus, inferior rectus, medical rectus, and inferior oblique (i.e. all EOM except the superior rectus and lateral rectus). Additional localizing signs are a larger and less reactive ipsilateral pupil, and ptosis. A nuclear third nerve palsy additionally causes bilateral ptosis and bilateral upgaze deficits .

Emergent causes of third nerve palsy include:

• Aneurysm compressing the ipsilateral nerve (see section below)

• Uncal herniation (typically associated with altered mental status)

• Brainstem parenchymal event (stroke, demyelination, tumor) including:

  • Benedikt syndrome (with contralateral movement disorder due to involvement of the Red Nucleus)
  • Claude syndrome (with contralateral ataxia due to involvement of the superior cerebellar peduncle)
  • Weber syndrome (with contralateral hemiparesis due to involvement of the cerebral peduncle)

Cranial Nerve 4 Palsy:

A non-nuclear fourth nerve palsy in isolation affects the superior oblique muscle, causing vertical diplopia that is worse in down gaze, contralateral gaze, and ipsilateral head tilt. Due to the torsional action of the superior oblique the image in the affected eye can appear tilted. Patients may adopt a compensatory head tilt away from the affected eye. A nuclear fourth nerve palsy causes contralateral superior oblique dysfunction due to the fact that the 4^th cranial nerve crosses before innervating the superior oblique. The eye movements often appear full. An isolated fourth nerve palsy is rarely from an emergent cause. However, it is easy to confuse a fourth nerve palsy with a skew deviation (see below).

Cranial Nerve 6 Palsy:

A non-nuclear sixth nerve palsy in isolation affects the lateral rectus muscle to cause horizontal diplopia in ipsilateral gaze that resolves in contralateral gaze. Usually, but not always, there is an obvious abduction deficit on the affected side. A nuclear sixth nerve palsy causes an ipsilateral gaze palsy (i.e. affecting both eyes and therefore without diplopia).

Emergent causes of sixth nerve palsy include:

• Elevated ICP (e.g. tumor, venous sinus thrombosis, meningitis) causing 6^th nerve palsy as a “false” localizing sign

• Cavernous sinus syndrome: The 6^th nerve floats freely within the cavernous sinus and can be affected in isolation by pathologies in this region (see below)

• Gradenigo syndrome (with retro-orbital pain due to V1 involvement and otitis media) due to petrous apicitis

• Brainstem parenchymal event (stroke, demyelination, tumor)

Horizontal Gaze Palsy:

A devastating impairment of horizontal gaze results from pontine lesions that affect the horizontal gaze center and 6^th cranial nerve nucleus - strokes being a common cause. In palsies due to stroke the eyes will not move as either a voluntary or vestibular reflexive response. Another common cause of horizontal gaze palsy is a contralateral cerebral hemisphere insult to the frontal eye fields (also typically caused by a stroke). The conjugate gaze palsy resulting from a supratentorial lesion will inhibit voluntary eye movement but vestibular eye movement is intact (e.g. response to cold caloric testing and VOR).

Internuclear ophthalmoplegia (INO):

This is caused by a lesion of the medial longitudinal fasciculus and is characterized by horizontal diplopia that is present in contralateral gaze only. Often there is nystagmus of the abducting (normal) eye and slowed adducting saccade of the affected eye. Adduction of the affected eye is often better during convergence, since this does not use the MLF. An emergent cause is focal brainstem infarct.

Skew Deviation:

This is a supranuclear disorder is characterized by vertical diplopia with tilting of images in both eyes. Typically, it is associated with other vestibular or cerebellar symptoms and signs. Emergent causes include stroke involving the brainstem and/or cerebellum.

Background/Presentation:

Rhino-orbital-cerebral mucormycosis is typically fatal without urgent therapy. This opportunistic fungal infection arising in the paranasal sinuses is seen in patients with diabetes mellitus, diabetic ketoacidosis, hematologic malignancies, those who are chronically immunosuppressed, and those with elevated serum iron.²⁹ Extension into the orbit can cause blindness and subsequent extension into the cavernous sinus can be fatal due to invasion of the cavernous segment of the carotid artery, promoting intracranial thrombosis or mycotic aneurysm formation, infarction, or subarachnoid hemorrhage.^30,31 Rapid diagnosis and treatment is important at the time of recognition of orbital symptoms due to the risk of mortality.³¹ Late diagnosis, bilateral sinusitis, immunosuppression, presence of hemiplegia or hemiparesis, and the extent of invasion are correlated with a worse prognosis, despite treatment.³² Mortality is still extremely high even with treatment and has been reported up to 50 %.³³

Typical symptoms of mucormycosis invading the orbital apex include pain, vision loss from optic neuropathy, diplopia, ptosis, and decreased corneal sensation (Table 4).

Table 4 –

Early Findings in Mucormycosis³⁰

Symptom/sign	Prevalence
Fever	44%
Nasal mucosal ulceration/necrosis	38%
Periorbital and facial swelling	34%
Decreased vision	30%
Ophthalmoplegia	29%
Sinusitis	26%
Headache	25%
Black eschar of skin, nasal mucosa, or palate	20%

Imaging:

Orbit protocol imaging can be helpful to identify bone erosion (CT), cavernous sinus involvement (MRI) and soft tissue changes in the nasal sinuses and orbit. Fungi can appear dark on T2 sequences of MRI which adds a diagnostic challenge. Imaging is insensitive; thus negative imaging does not exclude this entity.³¹

Diagnosis:

Endoscopic evaluation of the paranasal sinuses for eschar and biopsy should be considered for definite diagnosis. If sinus biopsy histopathology is unrevealing then orbital apex biopsy can be considered.^30,31

Treatment:

Rhino-orbital mucor treatment consists of immediate antifungal therapy with amphotericin B. (5-10 mg/kg/d, the latter if central nervous system involvement). Surgical debridement of the infected areas should be performed if possible.

Clinical Care Points:

• Negative imaging does not exclude rhino-orbital-cerebral mucormycosis and nasal endoscopy with biopsy or orbital biopsy may be necessary

• Treatment with immediate antifungal therapy and surgical debridement improves outcomes, but mortality remains high

• Emergent ophthalmology, otorhinolaryngology, and infectious disease consultations are indicated

Cavernous Sinus Thrombosis:

Background/Presentation:

Cavernous sinus thrombosis is a life-threatening condition that should be considered when evaluating patients with combinations of cranial nerve 3,4, and 6 palsies, Horner syndrome, and sensory changes in the distribution of the ophthalmic and/or maxillary divisions of the trigeminal nerve. When the underlying etiology may be due to a septic sinus thrombosis morbidity and mortality remains high even in the modern era of antibiotic treatment (30%).³⁴ The most common pathogen causing septic cavernous sinus thrombosis is staphylococcus aureus (66%), with streptococcus pneumoniae, gram negative bacilli, and anaerobic bacteria being less frequently identified.³⁵ Infection typically spreads to the cavernous sinus through the venous system from a primary site in the sphenoid/ethmoid sinuses, mouth, ear, or orbitalregions. Aseptic cavernous sinus thrombosis occurs in the setting of prothrombotic disorders (polycythemia, pregnancy OCPs) as well as extrinsic damage to the cavernous sinus (surgery, compression from tumor, trauma).

Presenting features of these patients are directly related to the anatomical structures involved, mass effect, infection, and impaired venous outflow. Therefore, patients will present with some combination of fever, proptosis, and cranial nerve palsies. Any process that elevates venous pressure in the cavernous sinus can transmit this pressure to the orbit to cause significant orbital signs including proptosis and red eyes. Vision can be affected if the process extends superiorly to the optic chiasm or if blood flow to the eye is impaired. 50% to 80% of patients will present with periorbital edema, headache, lethargy, altered sensorium, optic disc edema, and retinal venous engorgement. Eye findings are nearly universal (90%). Less than 50% have decreased visual acuity, sluggish or dilated pupils, periorbital and corneal sensory loss, and meningismus. Rarely, seizures and hemiparesis may occur, typically due to cerebral venous infarction. Due to the inter-cavernous sinus, spread to the opposite site is common in the first days.^34,35

Laboratory evaluation:

Blood cultures should be obtained routinely and are frequently positive. Lumbar puncture is important to exclude meningitis and may show elevated opening pressure and pleocytosis even in culture-negative samples. Blood cultures are more sensitive than CSF cultures (70% vs. 20%).³⁴ Screening for thrombophilia may give false results if anticoagulation therapy has been started and should be delayed until after treatment is completed.³⁶

Imaging:

High-resolution contrast-enhanced head CT typically shows cavernous sinus expansion and irregular filling defects, in addition to dilated superior ophthalmic veins, soft-tissue edema, proptosis, and concurrent thrombosis of the tributary veins.³⁷ High-resolution head MRI, is helpful to access the extension of infection.³² CT venogram (CTV) and contrast-enhanced MR venogram (MRV) are highly sensitive, whereas non-contrast CT and time-of-flight MRV may miss the diagnosis.³⁶

Treatment/Management:

Empiric antibiotic therapy with vancomycin, a third- or fourth-generation cephalosporin, and metronidazole should be started as soon as the diagnosis is suspected and prior to return of culture results.³⁸ This regimen can later be tailored to culture and sensitivity results. Prolonged duration of intravenous antibiotic therapy is recommended - typically three to four weeks, or at least two weeks beyond clinical resolution. Anticoagulation is controversial and has not been convincingly shown to reduce mortality; however, there is a trend towards decreased morbidity. Current evidence favors the use of anticoagulation along with antibiotics early in the course.^38–41 Corticosteroids are often given but without demonstrated efficacy.³⁶

Clinical Care Points:

• CT venogram (CTV) and contrast-enhanced MR venogram (MRV) are highly sensitive, whereas non-contrast CT and time-of-flight MRV may miss the diagnosis

• Because the distinction between aseptic and septic CST may not be initially known management with broad antibiotics is recommended, until a septic etiology is ruled out

• Anticoagulation with UFH or LWMH is definitely indicated in aseptic cases and probably beneficial in septic etiologies.

SUMMARY:

This article was intended to give the clinician both a framework for approaching patients with potentially vision-and life-threatening neuro-ophthalmologic conditions as well as review the presentation, evaluation, and emergency treatment of select conditions. There is a much broader differential diagnosis for each presentation than presented herein. We hope that guidance on clinical approach to patients who present with acute vision loss or diplopia will help the reader to localize the presentation in order to direct further investigations and institute vision and life-saving therapies in a timely fashion.

Synopsis:

Neuro-ophthalmologic emergencies include optic nerve, central visual pathway, and ocular motility disorders that, if not identified and treated promptly, may lead to permanent vision loss, other significant morbidity, or mortality. This article provides a framework for approaching patients with these symptoms and reviews the presentation, evaluation, and treatment of select emergent conditions that can cause them. Emergent causes of optic neuropathy, retinal vascular events, papilledema and diplopia, including giant cell arteritis, cardio-embolic disease, and aggressive infection are discussed.

Key Points:

• Sudden monocular vision loss is the most common ocular presenting symptom of giant cell arteritis, and in patients with acute vision loss for whom this is a consideration, emergent initiation of steroids before temporal artery biopsy is appropriate to prevent further ischemic episodes.

• Pituitary apoplexy results from the sudden enlargement of the pituitary gland, and the risk of acute secondary adrenal insufficiency warrants empiric corticosteroid supplementation.

• Patients with acute branch retinal artery occlusion, central artery occlusion, or monocular transient vision loss thought to be due to ischemia should be emergently referred to a stroke center for evaluation.

• Rhino-orbital-cerebral mucormycosis is typically fatal without urgent therapy, and treatment includes emergent antifungal therapy with amphotericin B.

• Cavernous sinus thrombosis is a life-threatening condition, and for suspected infectious causes, antibiotic therapy directed at the primary infection is recommended. Empiric treatment with third-generation cephalosporin, vancomycin, and metronidazole prior to return of culture results is recommended.