The Wills Eye Manual

Chapter 10. Neuro-ophthalmology

10.1 Anisocoria

Eyelid position, globe position (e.g., to rule out proptosis), and extraocular motility MUST be evaluated when anisocoria is present (see Figure 10.1.1).

FIGURE 10.1.1 Flow diagram for the workup of anisocoria. *Hydroxyamphetamine should not be used within 24 to 48 hours of cocaine or apraclonidine to avoid possible interference with each other.

(Modified from Thompson HS, Pilley SF. Unequal pupils. A flow chart for sorting out the anisocorias. Surv Ophthalmol. 1976;21:45-48, with permission.)

Classification

1. The abnormal pupil is constricted.

• Unilateral exposure to a miotic agent (e.g., pilocarpine).

 Iritis: Eye pain, redness, and anterior chamber cell and flare.

NOTE: In cases of inflammation resulting in posterior synechiae formation, the abnormal pupil may appear irregular, nonreactive, and/or larger.

 Horner syndrome: Mild ptosis on the side of the small pupil. See 10.2, Horner Syndrome.

 Argyll Robertson (i.e., syphilitic) pupil: Always bilateral, irregularly round miotic pupils, but a mild degree of anisocoria is often present. See 10.3, Argyll Robertson Pupils.

 Long-standing Adie pupil: The pupil is initially dilated, but over time may constrict. Hypersensitive to pilocarpine 0.125%. See 10.4, Adie (Tonic) Pupil.

2. The abnormal pupil is dilated.

 Iris sphincter muscle damage from trauma or surgery: Torn pupillary margin or iris transillumination defects seen on slit lamp examination.

 Adie (tonic) pupil: The pupil may be irregular, reacts minimally to light, and slowly and tonically to accommodation. Hypersensitive to pilocarpine 0.125%. See 10.4, Adie (Tonic) Pupil.

 Third cranial nerve palsy: Always has associated ptosis and/or extraocular muscle palsies. See 10.5, Isolated Third Cranial Nerve Palsy.

 Unilateral exposure to a mydriatic agent: Cycloplegic drops (e.g., atropine), scopolamine patch for motion sickness, ill- fitting mask in patients on nebulizers (using ipratropium bromide), and possible use of sympathetic medications (e.g., pseudoephedrine). If the mydriatic exposure is recent, pupil will not react to pilocarpine 1%.

3. Physiologic anisocoria: Pupil size disparity is the same in light as in dark, and the pupils react normally to light. The size difference is usually, but not always, <2 mm in diameter.

Workup

1. History: When was the anisocoria first noted? Associated symptoms or signs? Ocular trauma? Eye drops or ointments? Syphilis history (or risk factors)? Old photographs?

2. Ocular examination: Try to determine which pupil is abnormal by comparing pupil sizes in light and in dark. Anisocoria greater in light suggests the larger pupil is abnormal; anisocoria greater in dark suggests the smaller pupil is abnormal. Test the pupillary reaction to both light and near. Evaluate for the presence of an afferent pupillary defect. Look for ptosis, evaluate ocular motility, and examine the pupillary margin with a slit lamp.

 If the abnormal pupil is small, a diagnosis of Horner syndrome may be confirmed by a cocaine or apraclonidine test (see 10.2, Horner Syndrome).

 If the abnormal pupil is large and there is no sphincter muscle damage or signs of third cranial nerve palsy (e.g., extraocular motility deficit, ptosis), the pupils are tested with one drop of pilocarpine 0.125%. Within 10 to 15 minutes, an Adie pupil will constrict significantly more than the fellow pupil (see 10.4, Adie [Tonic] Pupil).

NOTE: For an acute Adie pupil, the pupil may not react to a weak cholinergic agent.

 If the pupil does not constrict with pilocarpine 0.125%, or pharmacologic dilation is suspected, pilocarpine 1% is instilled in both eyes. A normal pupil constricts sooner and to a greater extent than the pharmacologically dilated pupil. An eye that recently received a strong mydriatic agent such as atropine usually will not constrict at all.

See 10.2, Horner Syndrome, 10.3, Argyll Robertson Pupils, 10.4, Adie (Tonic) Pupil, and 10.5, Isolated Third Cranial Nerve Palsy.

10.2 Horner Syndrome

Symptoms

Ptosis and anisocoria. May have anhydrosis. Often asymptomatic.

Signs

(See Figure 10.2.1.)

FIGURE 10.2.1 Right Horner syndrome with ptosis and miosis.

Critical. Anisocoria that is greater in dim illumination (especially during the first few seconds after the room light is dimmed). The abnormal small pupil dilates less than the normal, larger pupil. Mild ptosis (2 mm) and lower eyelid elevation (“reverse ptosis”) occur on the side of the small pupil.

Other. Lower intraocular pressure, lighter iris color in congenital cases (iris heterochromia), loss of sweating (anhydrosis, distribution depends on the site of lesion), and transient increase in accommodation (older patients hold their reading card closer in the Horner eye). Involved eye may have conjunctival hyperemia due to decreased episcleral vascular tone. Light and near reactions are intact.

Differential Diagnosis

See 10.1, Anisocoria.

Etiology

 First-order neuron disorder: Stroke (e.g., vertebrobasilar artery insufficiency or infarct), tumor, multiple sclerosis (MS). Rarely, severe osteoarthritis of the neck with bony spurs.

 Second-order neuron disorder: Tumor (e.g., lung carcinoma, metastasis, thyroid adenoma, neurofibroma), aortic aneurysm (e.g., tertiary syphilis). Patients with pain in the arm or scapular region should be suspected of having a Pancoast tumor. In children, consider neuroblastoma, lymphoma, or metastasis.

 Third-order neuron disorder: Headache syndrome (e.g., cluster, migraine, Raeder paratrigeminal syndrome), internal carotid dissection, varicella zoster virus, otitis media, Tolosa-Hunt syndrome, neck trauma/tumor/inflammation, cavernous sinus pathology.

 Congenital Horner syndrome: May also be caused by birth trauma.

 Other rare causes: Cervical paraganglioma, ectopic cervical thymus.

Workup

1. Diagnosis confirmed by a relative reversal in anisocoria with apraclonidine (0.5% or 1%). The miotic pupil with Horner syndrome will appear larger than the normal pupil after apraclonidine instillation. Alternatively, 10% cocaine may be used. Place one drop of either medication in both eyes. Check in 15 minutes. If no change in pupillary size is noted, repeat drops and recheck the pupils in 15 minutes (repeat until normal pupil dilates). A Horner pupil dilates less than the normal pupil.

NOTE: There may be a high false-negative rate to pharmacologic testing in an acute Horner syndrome.

2. A third-order neuron disorder may be distinguished from a first- order and second-order neuron disorder with hydroxyamphetamine. Place one drop of 1% hydroxyamphetamine in both eyes. Check in 15 minutes and repeat if no change in pupillary size is noted. Failure of the Horner pupil to dilate to an equivalent degree as the fellow eye indicates a third-order neuron lesion, which may help guide the workup. However, most experts feel the entire sympathetic pathway should be imaged in Horner syndrome regardless of the results of pharmacologic testing. Additionally, hydroxyamphetamine is often unavailable even from compounding pharmacies.

NOTE: The hydroxyamphetamine test has a sensitivity of up to 93% and a specificity of 83% for identifying a third-order neuron lesion. Hydroxyamphetamine should not be used within 24 to 48 hours of cocaine or apraclonidine to avoid possible interference with each other. Both drops require an intact corneal epithelium and preferably no prior eye drops (including anesthetic drops) for accurate results.

3. Determine the duration of the Horner syndrome from the patient’s history and an examination of old photographs. New-onset Horner syndrome requires a more urgent diagnostic workup to exclude life-threatening etiologies (e.g., internal carotid artery dissection, which can present with transient visual loss, head/neck/face pain, pulsatile tinnitus, or dysgeusia [foul taste in the mouth]). An old Horner syndrome is more likely to be benign.

4. History: Headaches? Arm pain? Previous stroke? Previous surgery that may have damaged the sympathetic chain, including cardiac, thoracic, thyroid, or neck surgery? History of head or neck trauma? Ipsilateral neck pain?

5. Physical examination (especially check for supraclavicular nodes, thyroid enlargement, or a neck mass).

6. Complete blood count (CBC) with differential.

7. Computed tomography (CT) or magnetic resonance imaging (MRI) of the chest to evaluate lung apex for possible mass (e.g., Pancoast tumor).

8. MRI of the brain and neck.

9. .Magnetic resonance angiography (MRA) or CT angiography (CTA) of the head/neck to evaluate for carotid artery dissection (especially with neck pain). Obtain carotid angiogram if MRA or CTA yield equivocal results.

10. Lymph node biopsy when lymphadenopathy is present.

Treatment

1. Treat the underlying disorder if possible.

NOTE: Carotid dissection usually requires antiplatelet therapy to prevent carotid occlusion and hemispheric stroke in consultation with neurology and neurosurgery. Anticoagulation is occasionally used. Rarely, ischemic symptoms in the distribution of the dissection persist despite antiplatelet therapy. In these cases, surgical intervention may be considered.

2. Ptosis surgery may be performed electively.

Follow Up

1. Workup acute Horner syndromes as soon as possible to rule out life-threatening causes. Neuroimaging (as above) should be performed immediately for dissection. Remaining workup may be performed within 1 to 2 days.

2. Chronic Horner syndrome can be evaluated with less urgency. There are no ocular complications that necessitate close follow up.

10.3 Argyll Robertson Pupils

Symptoms

Usually asymptomatic.

Signs

Critical. Small, irregular pupils that exhibit “light-near” dissociation (react poorly or not at all to light but constrict normally during accommodation/convergence). By definition, vision must be intact.

Other. The pupils dilate poorly in darkness. Always bilateral, although may be asymmetric.

Differential Diagnosis of “Light-Near” Dissociation

• Bilateral optic neuropathy or severe retinopathy: Reduced visual acuity with normal pupil size.

 Adie (tonic) pupil: Unilateral or bilateral irregularly dilated pupil that constricts slowly and unevenly to light. Normal vision. See 10.4, Adie (Tonic) Pupil.

 Dorsal midbrain (Parinaud) syndrome: Associated with eyelid retraction (Collier sign), supranuclear upgaze palsy, and convergence retraction nystagmus. See 10.4, Adie (Tonic) Pupil and “Convergence-Retraction" in 10.21, Nystagmus.

 Rarely caused by third cranial nerve palsy with aberrant regeneration. See 10.6, Aberrant Regeneration of the Third Cranial Nerve.

 Others: Diabetes, alcoholism, etc.

Etiology

 Tertiary syphilis.

Workup

1. Test the pupillary reaction to light and convergence: To test the reaction to convergence, patients are asked to look first at a distant target and then at their own finger, which the examiner holds in front of them and slowly brings in toward their face.

2. Slit lamp examination: Look for interstitial keratitis (see 4.17, Interstitial Keratitis).

3. Dilated fundus examination: Search for chorioretinitis, papillitis, and uveitis.

4. Fluorescent treponemal antibody absorption (FTA-ABS) or treponemal-specific assay (e.g., microhemagglutination assay-Treponema pallidum [MHA-TP]) and rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test.

5. If the diagnosis of syphilis is established, lumbar puncture (LP) may be indicated. See 12.12, Syphilis, for specific indications.

Treatment

1. Treatment is based on the presence of active disease and previous appropriate treatment.

2. See 12.12, Syphilis, for treatment indications and specific antibiotic therapy.

Follow Up

Pupillary findings alone are not an emergency. Diagnostic workup and determination of syphilitic activity should be undertaken within a few days.

10.4 Adie (Tonic) Pupil

Symptoms

Difference in size of pupils, blurred near vision, and photophobia. May be asymptomatic.

Signs

Critical. An irregularly dilated pupil that has minimal or no reactivity to light. Slow, tonic constriction with convergence, and slow redilation. May have vermiform iris movement and/or sectoral iris sphincter paresis.

NOTE: Typically presents unilaterally and more commonly in young women.

Other. May have an acute onset and become bilateral. The involved pupil may become smaller than the normal pupil over time.

Differential Diagnosis

See 10.1, Anisocoria.

 Parinaud syndrome/dorsal midbrain lesion: Bilateral mid-dilated pupils that react poorly to light but constrict normally with convergence (not tonic). Associated with eyelid retraction (Collier sign), supranuclear upgaze paralysis, and convergence retraction nystagmus. An MRI should be performed to rule out pinealoma and other midbrain pathology.

 Holmes-Adie syndrome: Tonic pupil and tendon areflexia. May be associated with autonomic and peripheral neuropathy.

 Argyll Robertson pupils: See 10.3, Argyll Robertson Pupils.

Etiology

Idiopathic most commonly. Orbital trauma, surgery, and varicella zoster virus infection are seen frequently. Early syphilis, parvovirus B19, herpes simplex virus, botulism, paraneoplastic syndrome, giant cell arteritis (GCA), panretinal photocoagulation, and neurologic Lyme disease less commonly. Rare associations reported with endometriosis, seminomas, and Sjögren syndrome.

Workup

See 10.1, Anisocoria, for a general workup when the diagnosis is uncertain.

1. Evaluate pupils and iris at slit lamp or with a muscle light for irregular slow constriction or abnormal movement.

2. Test for cholinergic hypersensitivity. Instill 0.125% pilocarpine in both eyes and recheck pupils in 10 to 15 minutes. An Adie pupil constricts while the normal pupil does not.

3. If bilateral simultaneous Adie pupils, consider further laboratory investigations including testing for the aforementioned etiologies. For unilateral involvement, no further laboratory investigations are necessary.

NOTE: The dilute pilocarpine test may occasionally be positive in familial dysautonomia. Hypersensitivity may not be present with an acute Adie pupil and may need to be retested a few weeks later.

4. If Adie pupil is present in a patient younger than 1 year, consult a pediatric neurologist to rule out familial dysautonomia (Riley- Day syndrome).

Treatment

Pilocarpine 0.125% b.i.d. to q.i.d. may be considered for cosmesis and to aid in accommodation.

Follow Up

If the diagnosis is certain, follow up is routine.

10.5 Isolated Third Cranial Nerve Palsy

Symptoms

Binocular diplopia and ptosis; with or without pain.

NOTE: Pain does not distinguish between microvascular infarction and compression.

Signs

(See Figures 10.5.1 to 10.5.4.)

FIGURE 10.5.1 Isolated right third cranial nerve palsy with complete ptosis.

FIGURE 10.5.2 Isolated right third cranial nerve palsy: Primary gaze showing right exotropia and dilated pupil.

FIGURE 10.5.3 Isolated right third cranial nerve palsy: Left gaze showing inability to adduct right eye.

FIGURE 10.5.4 Isolated right third cranial nerve palsy: Right gaze showing normal abduction of right eye.

Critical

1. External ophthalmoplegia.

• Complete palsy: Limitation of ocular movement in all fields of gaze except abduction.

 Incomplete palsy: Partial limitation of ocular movement.

 Superior division palsy: Ptosis and poor eye elevation.

 Inferior division palsy: Inability to adduct or depress the eye.

2. Internal ophthalmoplegia.

 Pupil-involving: A fixed, dilated, poorly reactive pupil.

 Pupil-sparing: Pupil not dilated and normally reactive to light.

 Relative pupil-sparing: Pupil partially dilated and sluggishly reactive to light.

Other. An exotropia or hypotropia. Aberrant regeneration. See 10.6, Aberrant Regeneration of the Third Cranial Nerve.

Differential Diagnosis

 Myasthenia gravis: Diurnal variation of symptoms and signs, pupil never involved, increased eyelid droop after sustained upgaze.

 Thyroid eye disease: Eyelid lag, eyelid retraction, injection over the rectus muscles, proptosis, positive forced duction testing. See 7.2.1, Thyroid Eye Disease.

 Chronic progressive external ophthalmoplegia (CPEO): Bilateral, slowly progressive ptosis and motility limitation. Pupil spared, often no diplopia. See 10.12, Chronic Progressive External Ophthalmoplegia.

 Idiopathic orbital inflammatory syndrome: Pain and proptosis common. See 7.2.2, Idiopathic Orbital Inflammatory Syndrome.

 Internuclear ophthalmoplegia (INO): Unilateral or bilateral adduction deficit with horizontal nystagmus of opposite abducting eye. No ptosis. See 10.13, Internuclear Ophthalmoplegia.

 Skew deviation: Supranuclear brainstem lesion producing asymmetric, mainly vertical ocular deviation not consistent with single cranial nerve defect. See Differential Diagnosis in 10.7, Isolated Fourth Cranial Nerve Palsy.

 Parinaud syndrome/dorsal midbrain lesion: Bilateral mid-dilated pupils that react poorly to light but constrict normally with convergence (not tonic). Associated with eyelid retraction (Collier sign), supranuclear upgaze paralysis, and convergence retraction nystagmus. No ptosis.

 GCA: Extraocular muscle ischemia due to involvement of the long posterior ciliary arteries. Any extraocular muscle may be affected, resulting in potentially complex horizontal and vertical motility deficits. Pupil typically not involved. Age >55 years. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

Etiology

 Pupil-involving:

 More common: Aneurysm, particularly posterior communicating artery aneurysm.

 Less common: Tumor, trauma, congenital, uncal herniation, cavernous sinus mass lesion, pituitary apoplexy, orbital disease, varicella zoster virus, ischemia (e.g., diabetic), GCA, and leukemia. In children, ophthalmoplegic migraine.

 Pupil-sparing: Ischemic microvascular disease; rarely cavernous sinus syndrome or GCA.

 Relative pupil-sparing: Ischemic microvascular disease; less likely compressive.

 Aberrant regeneration present: Trauma, aneurysm, tumor, congenital. Not microvascular. See 10.6, Aberrant Regeneration of the Third Cranial Nerve.

Workup

1. History: Onset and duration of diplopia? Recent trauma? Pertinent medical history (e.g., diabetes, hypertension, known cancer or central nervous system [CNS] mass, recent infections). If >55 years old, ask specifically about GCA symptoms.

2. Complete ocular examination: Check for pupillary involvement, the directions of motility restriction (in both eyes), ptosis, a visual field defect (visual fields by confrontation), proptosis, resistance to retropulsion, orbicularis muscle weakness, and eyelid fatigue with sustained upgaze. Look carefully for signs of aberrant regeneration. See 10.6, Aberrant Regeneration of the Third Cranial Nerve.

3. Neurologic examination: Carefully assess the other cranial nerves on both sides.

NOTE: The ipsilateral fourth cranial nerve can be assessed by focusing on a superior conjunctival blood vessel and asking the patient to look down. The eye should intort, and the blood vessel should turn down and toward the nose even if the eye cannot be adducted.

4. Immediate CNS imaging to rule out mass/aneurysm is indicated for all third cranial nerve palsies whether pupil-involving or pupil-sparing. One possible exception is a patient with complete sparing of the pupil and complete involvement of the other muscles (i.e., complete ptosis and complete paresis of extraocular muscles innervated by cranial nerve three).

NOTE: Most sensitive modality to identify aneurysm is contrast-enhanced CTA, though MRA is also very sensitive and can be done if CTA is contraindicated or unavailable. Gadolinium-enhanced MRI is most sensitive for identifying mass lesions and inflammatory etiologies. Choice of imaging should be made in conjunction with neuroradiology. If initial imaging studies are negative but clinical suspicion remains high, catheter angiography may be indicated.

5. Cerebral angiography is indicated for all patients >10 years of age with pupil-involving third cranial nerve palsies and whose imaging study is not definitively negative or shows a mass consistent with an aneurysm.

6. CBC with differential in children.

7. Ice test, rest test, or edrophonium chloride test when myasthenia gravis is suspected.

8. For suspected ischemic disease: Check blood pressure, fasting blood sugar, and hemoglobin A1c.

9. Immediate erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and platelet count if GCA is suspected. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

Treatment

1. Treat the underlying abnormality.

2. If the third cranial nerve palsy is causing symptomatic diplopia, an occlusion patch or prism may be placed over the involved eye. Patching is usually not performed in children <11 years of age because of the risk of amblyopia. Children should be monitored closely for the development of amblyopia in the deviated eye.

3. Strabismus surgery may be considered for persistent significant misalignment.

Follow Up

1. Follow-up intervals vary depending on underlying disorder and stability of examination findings. Comanagement with medicine, neurosurgery, and/or neurology may be necessary.

2. If secondary to ischemia, function should return within 3 months. Refer to internist for management of vasculopathic disease risk factors.

3. If pupil-involving and imaging/angiography are negative, an LP should be considered.

10.6 Aberrant Regeneration of the Third Cranial Nerve

Symptoms

See 10.5, Isolated Third Cranial Nerve Palsy.

Signs

(See Figures 10.6.1 and 10.6.2.)

FIGURE 10.6.1 Aberrant regeneration of right third cranial nerve showing rightsided ptosis in primary gaze.

FIGURE 10.6.2 Aberrant regeneration of right third cranial nerve showing right upper eyelid retraction on attempted left gaze.

The most common signs of aberrant third cranial nerve regeneration include the following:

 Eyelid-gaze dyskinesis: Elevation of involved eyelid on downgaze (Pseudo-von Graefe sign) or adduction.

 Pupil-gaze dyskinesis: Pupil constricts on downgaze or adduction.

 Other signs may include limitation of elevation and depression of eye, adduction of involved eye on attempted elevation or depression, absent optokinetic response, or pupillary light-near dissociation.

Etiology

Thought to result from misdirection of the third cranial nerve fibers from their original destination to alternate third cranial nerve controlled muscles (e.g., inferior rectus to the pupil).

 Aberrancy from congenital third cranial nerve palsies: Can be seen in up to two-thirds of these patients.

 Aberrancy from prior acquired third cranial nerve palsies: Seen most often in patients recovering from third cranial nerve damage by trauma or compression by a posterior communicating artery aneurysm.

 Primary aberrant regeneration: A term used to describe the presence of aberrant regeneration in a patient who has no history of a third cranial nerve palsy. Usually indicates the presence of a progressively enlarging parasellar lesion such as a carotid aneurysm or meningioma within the cavernous sinus.

Workup

1. Aberrancy from congenital: None. Document workup of prior congenital third cranial nerve palsy.

2. Aberrancy from acquired: See 10.5, Isolated Third Cranial Nerve Palsy. Document workup of prior acquired third cranial nerve palsy if previously obtained.

3. Primary aberrancy: All patients must undergo neuroimaging to rule out slowly compressive lesion or aneurysm.

NOTE: Ischemic third cranial nerve palsies DO NOT produce aberrancy. If aberrant regeneration develops in a presumed ischemic palsy, neuroimaging should be performed.

Treatment

1. Treat the underlying disorder.

2. Consider strabismus surgery if significant symptoms are present.

Follow Up

1. Aberrancy from congenital: Routine.

2. Aberrancy from acquired: As per the underlying disorder identified in the workup.

3. Primary aberrancy: As per neuroimaging and clinical examination findings. Patients are instructed to return immediately for any changes (e.g., ptosis, diplopia, sensory abnormality).

10.7 Isolated Fourth Cranial Nerve Palsy

Symptoms

Binocular vertical (or oblique) diplopia, difficulty reading, sensation that objects appear tilted; may be asymptomatic.

Signs

(See Figures 10.7.1 and 10.7.2.)

FIGURE 10.7.1 Isolated left fourth cranial nerve palsy: Primary gaze showing left hypertropia.

FIGURE 10.7.2 Isolated left fourth cranial nerve palsy: Right gaze with left inferior oblique overaction.

Critical. Deficient inferior movement of an eye when attempting to look down and in. The three-step test isolates a palsy of the superior oblique muscle (see #3 under Workup, Perform the three-step test).

Other. The involved eye is higher (hypertropic) in primary gaze. The hypertropia increases when looking in the direction of the uninvolved eye or tilting the head toward the ipsilateral shoulder. The patient often maintains a head tilt toward the contralateral shoulder to eliminate diplopia.

Differential Diagnosis

All of the following may produce binocular vertical diplopia, hypertropia, or both:

 Myasthenia gravis: Variable symptoms with fatigability. Ptosis common. Orbicularis oculi weakness often present.

 Thyroid eye disease: May have proptosis, eyelid lag, eyelid retraction, or injection over the involved rectus muscles. Positive forced duction test. See 7.2.1, Thyroid Eye Disease and Appendix 6, Forced Duction Test and Active Force Generation Test.

 Idiopathic orbital inflammatory syndrome: Pain and proptosis are common. See 7.2.2, Idiopathic Orbital Inflammatory Syndrome.

 Orbital fracture: History of trauma. Positive forced duction test. See 3.9, Orbital Blowout Fracture.

 Skew deviation: The three-step test does not isolate a particular muscle. Rule out a posterior fossa or brainstem lesion with neuroimaging. See 10.13, Internuclear Ophthalmoplegia.

 Incomplete third cranial nerve palsy: Inability to look down and in, usually with adduction weakness. Intorsion on attempted downgaze. Three-step test does not isolate the superior oblique. See 10.5, Isolated Third Cranial Nerve Palsy.

 Brown syndrome: Limitation of elevation in adduction due to restriction of superior oblique tendon. May be congenital or acquired (e.g., trauma, inflammation). Positive forced duction test. See 8.6, Strabismus Syndromes.

 GCA: Extraocular muscle ischemia causing nonspecific motility deficits or neural ischemia mimicking a cranial nerve palsy. Age ≥55 years, usually associated with systemic symptoms. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

Etiology

More Common. Trauma, vascular infarct (often the result of underlying diabetes or hypertension), congenital, or demyelinating disease.

Rare. Tumor, hydrocephalus, aneurysm, GCA.

Workup

1. History: Onset and duration of the diplopia? Misaligned eyes or head tilt since early childhood? Trauma? Stroke?

2. Examine old photographs to determine whether the head tilt is long-standing, indicating a chronic or congenital fourth cranial nerve palsy.

3. Perform the three-step test:

Step 1: Determine which eye is deviated upward in primary gaze. This is best seen with the cover-uncover test (see Appendix 3, Cover/Uncover and Alternate Cover Tests). The higher eye comes down after being uncovered.

Step 2: Determine whether the upward deviation is greater when the patient looks to the left or to the right.

Step 3: Determine whether the upward deviation is greater when tilting the head to the left shoulder or right shoulder.

• Patients with a superior oblique muscle paresis have a hyperdeviation that is worse on contralateral gaze and when tilting the head toward the shoulder ipsilateral to the affected eye.

 In addition to the findings on the three-step test, the hypertropia should be greater in downgaze than in upgaze.

 Patients with bilateral fourth cranial nerve palsies demonstrate hypertropia of the right eye when looking left, hypertropia of the left eye when looking right, and a "V"- pattern esotropia (the eyes cross more when looking down due to a decrease of the abducting effect of the superior oblique muscles in depression as well as overaction of the inferior oblique muscles).

4. Perform the double Maddox rod test if bilateral fourth cranial nerve palsies are suspected to measure total excyclotorsion.

 A white Maddox rod is placed before one eye and a red Maddox rod is placed before the other eye in a trial frame or phoropter, aligning the axes of each rod along the 90 degrees vertical mark. While looking at a white light in the distance, the patient is asked if both the white and red lines seen through the Maddox rods are horizontal and parallel to each other. If not, the patient is asked to rotate the Maddox rod(s) until they are parallel. If he or she rotates the top of this vertical axis outward (away from the nose) for more than 10 degrees total for the two eyes, then a bilateral superior oblique muscle paresis is likely present.

NOTE: The double Maddox rod test (or variations thereof) can be used to evaluate any suspected underlying strabismus and can help the practitioner measure ocular misalignment and subtle deviations.

5. Measure vertical fusional amplitudes with a vertical prism bar to distinguish a congenital from an acquired palsy.

 A patient with an acquired fourth cranial nerve palsy has a normal vertical fusional amplitude of 6 prism diopters or less. A patient with a congenital fourth cranial nerve palsy has greater than 6 prism diopters of fusional amplitude.

6. Ice test, rest test, or less commonly edrophonium chloride test if myasthenia gravis is suspected.

7. CT scan of head and orbits (axial, coronal, and parasagittal views) for suspected orbital disease.

8. Blood pressure measurement, fasting blood sugar, and hemoglobin A1c. Immediate ESR, CRP, and platelets if GCA is suspected.

9. MRI of the brain for:

 A fourth cranial nerve palsy accompanied by other cranial nerve or neurologic abnormalities.

 All patients <45 years of age with no history of significant head trauma, and patients aged 45 to 55 years with no vasculopathic risk factors or trauma.

Treatment

1. Treat the underlying disorder.

2. An occlusion patch may be placed over one eye or fogging plastic tape can be applied to one lens of patient’s spectacles to relieve symptomatic double vision. Patching is usually not performed in children <11 years of age because of the risk of amblyopia.

3. Prisms in spectacles may be prescribed for small, stable hyperdeviations.

4. Strabismus surgery may be indicated for bothersome double vision in primary or reading position or for a cosmetically significant head tilt. Defer surgery for at least 6 months after onset of the palsy to allow for deviation stabilization or possible spontaneous resolution.

Follow Up

1. Congenital fourth cranial nerve palsy: Routine.

2. Acquired fourth cranial nerve palsy: As per the underlying disorder. If the workup is negative, the lesion is presumed vascular or idiopathic and the patient is reexamined in 1 to 3 months. If the palsy does not resolve in 3 months or if an additional neurologic abnormality develops, appropriate imaging studies of the brain are indicated. Patients are instructed to return immediately for any changes (e.g., ptosis, worsening diplopia, sensory abnormality, pupil abnormality).

10.8 Isolated Sixth Cranial Nerve Palsy

Symptoms

Binocular horizontal diplopia, worse for distance than near, most pronounced in the direction of the paretic lateral rectus muscle.

Signs

(See Figures 10.8.1 and 10.8.2..)

FIGURE 10.8.1 Isolated right sixth cranial nerve palsy: Left gaze showing full adduction.

FIGURE 10.8.2 Isolated right sixth cranial nerve palsy: Right gaze showing limited abduction.

Critical. Deficient lateral movement of an eye with negative forced duction testing (see Appendix 6, Forced Duction Test and Active Force Generation Test).

Other. No proptosis.

Differential Diagnosis of Limited Abduction

 Thyroid eye disease: May have proptosis, eyelid lag, eyelid retraction, injection over the involved rectus muscles, and positive forced duction testing. See 7.2.1, Thyroid Eye Disease.

 Myasthenia gravis: Variable symptoms with fatigability. Ptosis common. Positive ice test, rest test, or less commonly edrophonium chloride test.

 Idiopathic orbital inflammatory syndrome: Pain and proptosis are common. See 7.2.2, Idiopathic Orbital Inflammatory Syndrome.

 Orbital trauma: Fracture causing medial rectus entrapment, positive forced duction testing. See 3.9, Orbital Blowout Fracture.

 Duane syndrome, type 1: Congenital; narrowing of the palpebral fissure and retraction of the globe on adduction (usually no diplopia). See 8.6, Strabismus Syndromes.

 Mobius syndrome: Congenital; bilateral facial paralysis present. See 8.6, Strabismus Syndromes.

 Convergence spasm: Intermittent, variable episodes of convergence and miosis. May appear to have abduction deficit when assessing versions; however, ductions are full. Miotic pupils help to differentiate since pupils are not affected in an isolated sixth cranial nerve palsy.

 Primary divergence insufficiency: Usually acquired and benign; esotropia and diplopia only at distance and single binocular vision at near. Symptoms may improve spontaneously without treatment or may be corrected with base-out prisms or surgery. If the history reveals sudden onset, trauma, infection (e.g., meningitis, encephalitis), MS, or malignancy, divergence paralysis should be considered and a neurologic workup with MRI of the brain and brainstem obtained. MRI rarely reveals pathology in true divergence-insufficiency.

 GCA: Less common; however, may occur with extraocular muscle ischemia in patients age >55 years. May be associated with systemic symptoms. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

Etiology

Adults

More Common. Vasculopathic (e.g., diabetes, hypertension, other atherosclerotic risk factors), trauma, idiopathic.

Less Common. Increased intracranial pressure, cavernous sinus mass (e.g., meningioma, aneurysm, metastasis), MS, sarcoidosis, vasculitis, after myelography or LP, stroke (usually with other neurologic deficits), meningeal inflammation/infection (e.g., Lyme disease, neurosyphilis), and GCA.

Children

Benign and usually self-limited after viral infection or vaccination, trauma, increased intracranial pressure (e.g., obstructive hydrocephalus), pontine glioma, and Gradenigo syndrome (petrositis causing sixth and often seventh cranial nerve involvement, with or without eighth and fifth cranial nerve involvement on the same side; associated with complicated otitis media).

Workup

Adults

1. History: Do the symptoms fluctuate during the day? Cancer, diabetes, or thyroid disease? Symptoms of GCA (in the appropriate age group)?

2. Complete neurologic and ophthalmic examinations; pay careful attention to the function of the other cranial nerves and the appearance of the optic disc. Because of the risk of corneal damage, it is especially important to evaluate the fifth cranial nerve. Corneal sensation (supplied by the first division) can be tested by touching a wisp of cotton or a tissue to the corneas before applying topical anesthetic. Ophthalmoscopy looking for papilledema is required because increased intracranial pressure from any cause can result in unilateral or bilateral sixth cranial nerve palsies.

3. Check blood pressure, fasting blood sugar, and hemoglobin A1c.

4. MRI of the brain is indicated for the following patients:

• Younger than 45 years of age (if MRI is negative, consider LP).

 Patients aged 45 to 55 years with no vasculopathic risk factors.

 Sixth cranial nerve palsy accompanied by severe pain or any other neurologic or neuro-ophthalmic signs.

 Any history of cancer.

 Bilateral sixth cranial nerve palsies.

 Papilledema is present.

5. Immediate ESR, CRP, and platelet count if GCA is suspected. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

6. Consider Lyme antibody.

Children

1. History: Recent illness or trauma? Neurologic symptoms, lethargy, or behavioral changes? Chronic ear infections?

2. Complete neurologic and ophthalmic examinations as described for adults.

3. Otoscopic examination to rule out complicated otitis media.

4. MRI of the brain in all children.

Treatment

1. Treat any underlying problem revealed by the workup.

2. An occlusion patch may be placed over one eye or fogging plastic tape applied to one spectacle lens to relieve symptomatic diplopia. In patients <11 years, patching is avoided, and these patients are monitored closely for the development of amblyopia. See 8.7, Amblyopia.

3. Prisms in glasses may be fit acutely for temporary relief or for chronic stable deviations (e.g., after stroke). Consider strabismus surgery for a stable deviation that persists >6 months.

Follow Up

Reexamine every 6 weeks after the onset of the palsy until it resolves. MRI of the head is indicated if any new neurologic signs or symptoms develop, the abduction deficit increases, or the isolated sixth cranial nerve palsy does not resolve in 3 to 6 months.

10.9 Isolated Seventh Cranial Nerve Palsy

Symptoms

Weakness or paralysis of one side of the face, inability to close one eye, excessive drooling.

Signs

(See Figures 10.9.1 and 10.9.2.)

FIGURE 10.9.1 Isolated peripheral left seventh cranial nerve palsy demonstrating lagophthalmos.

FIGURE 10.9.2 Isolated peripheral left seventh cranial nerve palsy demonstrating paralysis of upper facial muscles.

Critical. Unilateral weakness or paralysis of the facial musculature.

 Central lesion: Weakness or paralysis of lower facial musculature only. Upper eyelid closure and forehead wrinkling intact.

 Peripheral lesion: Weakness or paralysis of upper and lower facial musculature.

Other. Flattened nasolabial fold, droop of corner of the mouth, ectropion, and lagophthalmos. May have ipsilateral decreased taste on anterior two-thirds of tongue, decreased basic tear production, or hyperacusis. May have an injected eye with a corneal epithelial defect. Synkinesis, a simultaneous movement of muscles supplied by different branches of the facial nerve or simultaneous stimulation of visceral efferent fibers of facial nerve (e.g., corner of mouth contracts when eye closes, excessive lacrimation when eating [“crocodile” tears]), secondary to aberrant regeneration implying chronicity.

Etiology

Central Lesions

 Cortical: Lesion of contralateral motor cortex or internal capsule (e.g., stroke, tumor). Loss of voluntary facial movement; emotional facial movement sometimes intact. May also have ipsilateral hemiparesis.

 Extrapyramidal: Lesion of basal ganglia (e.g., parkinsonism, tumor, vascular lesion of basal ganglia). Loss of emotional facial movement; volitional facial movement intact. Not a true facial paralysis.

 Brainstem: Lesion of ipsilateral pons (e.g., MS, stroke, tumor). Often with ipsilateral sixth cranial nerve palsy, contralateral hemiparesis. Occasionally with cerebellar signs.

Peripheral Lesions

 Cerebellopontine angle (CPA) masses (e.g., acoustic neuroma, facial neuroma, meningioma, cholesteatoma, metastasis): Gradual progressive onset, although sometimes acute. May have facial pain, twitching, or a characteristic nystagmus. This is smallamplitude rapid jerk nystagmus in which the fast phase is directed away from the side of the lesion (peripheral vestibular) in conjunction with a slow, gaze-evoked nystagmus directed toward the side of the lesion (from brainstem compression). May have eighth cranial nerve dysfunction, including hearing loss, tinnitus, vertigo, or dysequilibrium.

 Temporal bone fracture: History of head trauma. May have Battle sign (ecchymoses over mastoid region), cerebrospinal fluid otorrhea, hearing loss, vertigo, or vestibular nystagmus.

 Other trauma: Accidental or iatrogenic (e.g., facial laceration, local anesthetic block, parotid or mastoid surgery).

 Acute or chronic suppurative otitis media.

 Malignant otitis externa: Pseudomonas infection in diabetic or elderly patients. Begins in external auditory canal but may progress to osteomyelitis, meningitis, or abscess.

 Ramsay-Hunt syndrome (varicella zoster virus oticus): Viral prodrome followed by ear pain; vesicles on pinna, external auditory canal, tongue, face, or neck. Progresses over 10 days. May have sensorineural hearing loss, tinnitus, or vertigo.

 Guillain-Barre syndrome: Viral syndrome followed by progressive motor weakness or paralysis or cranial nerve palsies or both. Loss of deep tendon reflexes. May have bilateral facial palsies.

 Lyme disease: May have rash, fever, fatigue, arthralgias, myalgias, or nausea. There may or may not be a history of tick bite. See 13.3, Lyme Disease.

 Sarcoidosis: May have uveitis, parotitis, skin lesions, or lymphadenopathy. May have bilateral facial palsies. See 12.6, Sarcoidosis.

 Parotid neoplasm: Slowly progressive paralysis of all or portion of facial musculature. Parotid mass with facial pain.

 Metastasis: History of primary tumor (e.g., breast, lung, prostate). Multiple cranial nerve palsies in rapid succession may be seen. Can be the result of basilar skull metastasis or carcinomatous meningitis.

 Bell palsy: Idiopathic seventh cranial nerve palsy. Most common, but other etiologies must be ruled out. May have viral prodrome followed by ear pain, facial numbness, decreased tearing or taste. Facial palsy may be complete or incomplete and progress over 10 days. May be recurrent, rarely bilateral. Possible familial predisposition.

 Others: Diabetes mellitus, botulism, human immunodeficiency virus, syphilis, Epstein-Barr virus, acute porphyrias, nasopharyngeal carcinoma, collagen-vascular disease, and others.

Workup

1. History: Onset and duration of facial weakness? First episode or recurrence? Facial or ear pain? Trauma? Stroke? Recent infection? Hearing loss, tinnitus, dizziness, or vertigo? History of sarcoidosis or cancer?

2. Examine old photographs to determine chronicity of facial droop.

3. Complete neurologic examination: Determine if facial palsy is central or peripheral, complete or incomplete. Look for motor weakness and cerebellar signs. Carefully assess other cranial nerves, especially the fifth, sixth, and seventh. Consider assessing taste on anterior two-thirds of the tongue on affected side.

4. Complete ocular examination: Check ocular motility and look for nystagmus. Assess orbicularis strength bilaterally, degree of ectropion, and Bell phenomenon. Examine cornea carefully for signs of exposure (superficial punctate keratopathy, epithelial defect, or ulcer). Perform Schirmer test (see 4.3, Dry Eye Syndrome) to assess basic tear production. Check for signs of uveitis.

5. Otolaryngologic examination: Examine ear and oropharynx for vesicles, masses, or other lesions. Palpate parotid for mass or lymphadenopathy. Check hearing.

6. CT scan if history of trauma to rule out basilar skull fracture: Axial, coronal, and parasagittal cuts with attention to temporal bone.

7. MRI or CT scan of the brain if any other associated neurologic signs, history of cancer, or duration >3 months. Sixth cranial nerve involvement warrants attention to the brainstem. Eighth cranial nerve involvement warrants attention to the CPA. Multiple cranial nerve involvement warrants attention to the skull base and cavernous sinus.

8. CT chest or chest radiograph and angiotensin-converting enzyme (ACE) level if sarcoidosis suspected.

9. Consider CBC with differential, Lyme antibody, FTA-ABS or treponemal-specific assay, and RPR or VDRL tests depending on suspected etiology.

10. Consider rheumatoid factor, ESR, antinuclear antibody, and antineutrophil cytoplasmic antibody if collagen-vascular disease suspected.

11. Echocardiogram, Holter monitor, and carotid noninvasive studies in patients with a history of stroke.

12. LP in patients with history of primary neoplasm to rule out carcinomatous meningitis (may repeat if negative to increase sensitivity).

Treatment

1. Treat the underlying disease as follows:

 Stroke: Refer to neurologist.

 CPA masses, temporal bone fracture, nerve laceration: Refer to neurosurgeon.

 Otitis: Refer to otolaryngologist.

 Ramsay-Hunt syndrome: If seen within 72 hours of onset, start acyclovir 800 mg five times per day for 7 to 10 days (contraindicated in pregnancy and renal failure). Refer to otolaryngologist.

 Guillain-Barre syndrome: Refer to neurologist. May require urgent hospitalization for rapidly progressive motor weakness or respiratory distress.

 Lyme disease: Refer to infectious disease specialist. May need LP. Treat with oral doxycycline, penicillin, or intravenous (i.v.) ceftriaxone. See 13.3, Lyme Disease.

 Sarcoidosis: Treat uveitis if present. Consider brain MRI, LP, or both to rule out CNS involvement; if present, refer to neurologist. Refer to internist for systemic evaluation. May require systemic prednisone for extraocular or CNS disease. See 12.6, Sarcoidosis.

 Metastatic disease: Refer to oncologist. Systemic chemotherapy, radiation, or both may be required.

2. Bell palsy: 86% of patients recover completely with observation alone within 2 months. Options for treatment include the following:

 Physical therapy with facial massage and/or electrical stimulation of facial musculature.

 For new-onset Bell palsy, steroids (e.g., prednisone 60 mg p.o. daily for 7 days, followed by a taper of 5 to 10 mg per day) have been shown to increase the likelihood of facial nerve recovery. Antiviral agents, in combination with prednisone, may be offered to patients although the benefit has not been well established.

3. The primary ocular complication of facial palsy is corneal exposure, which is managed as follows (also see 4.5, Exposure Keratopathy):

 Mild exposure keratitis: Artificial tears q.i.d. with lubricating ointment q.h.s.

 Moderate exposure keratitis: Preservative-free artificial tears, gel or ointment q1-2h or moisture chamber with lubricating ointment during the day; moisture chamber with lubricating ointment or tape tarsorrhaphy q.h.s. Consider a temporary tarsorrhaphy.

• Severe exposure keratitis: Temporary or permanent tarsorrhaphy. For expected chronic facial palsy, consider eyelid gold weight to facilitate eyelid closure.

Follow Up

1. Recheck all patients at 1 and 3 months and more frequently if corneal complications arise.

2. If not resolved after 3 months, order MRI of the brain to rule out mass lesion.

In nonresolving facial palsy with repeatedly negative workup, consider referral to neurosurgeon or plastic surgeon for facial nerve graft, cranial nerve reanastomosis, or temporalis muscle transposition for patients who desire improved facial motor function.

10.10 Cavernous Sinus and Associated Syndromes (Multiple Ocular Motor Nerve Palsies)

Symptoms

Double vision, eyelid droop, pain in the distribution of the V-1 and V2 branches of the ipsilateral trigeminal nerve, or numbness.

Signs

Critical

Limitation of eye movement corresponding to any combination of a third, fourth, or sixth cranial nerve palsy on one side; facial pain or numbness or both corresponding to first or second branches of the fifth cranial nerve; ptosis and a small pupil (Horner syndrome); the pupil also may be dilated if the third cranial nerve is involved. Any combination of the above may be present simultaneously because of the anatomy of the cavernous sinus. All signs involve the same side of the face when one cavernous sinus/superior orbital fissure is involved. The circular sinus connects the cavernous sinuses, and its involvement can cause contralateral signs. Consider orbital apex syndrome when proptosis and optic neuropathy are present.

Other

Proptosis may be present when the superior orbital fissure is involved.

Differential Diagnosis

 Myasthenia gravis: Fatigable ptosis, orbicularis weakness, and limited motility. Pupils never involved and never any sensory symptoms. No proptosis. See 10.11, Myasthenia Gravis.

 CPEO: Progressive, painless, bilateral motility limitation with ptosis. Normal pupils. Orbicularis always weak. See 10.12, Chronic Progressive External Ophthalmoplegia.

 Orbital lesions (e.g., tumor, thyroid disease, inflammation). Proptosis and increased resistance to retropulsion are usually present, in addition to motility restriction. Results of forced duction tests are abnormal (see Appendix 6, Forced Duction Test and Active Force Generation Test). May have an afferent pupillary defect if the optic nerve is involved.

NOTE: Orbital apex syndrome combines the superior orbital fissure syndrome with optic nerve dysfunction, and most commonly results from an orbital lesion.

• Brainstem disease: Tumors and vascular lesions of the brainstem produce ocular motor nerve palsies, particularly the sixth cranial nerve. MRI of the posterior fossa and brainstem is best for making this diagnosis.

 Carcinomatous meningitis: Diffuse seeding and infiltration of the leptomeninges by metastatic tumor cells can produce a rapidly sequential bilateral cranial nerve disorder. Workup includes neuroimaging and LP.

 Skull base tumors, especially nasopharyngeal carcinoma or clivus lesions: Most commonly affects the sixth cranial nerve, but the second, third, fourth, and fifth cranial nerves may be involved as well. Typically, one cranial nerve after another is affected by invasion of the skull base. The patient may have cervical lymphadenopathy, nasal obstruction, ear pain, or popping caused by serous otitis media or blockage of the Eustachian tube, weight loss, or proptosis.

Clivus tumors may produce fluctuating symptoms of double vision with an incomitant esotropia and only very mildly limited abduction deficits. These tumors also may produce relatively comitant esotropias due to involvement of both sixth cranial nerves as they ascend the clivus.

 Progressive supranuclear palsy (PSP): Vertical limitation of eye movements, typically beginning with downward gaze. Postural instability, dementia, and rigidity of the neck and trunk may be present. All eye movements are eventually lost. Significant cognitive impairment is often present and can progress rapidly. See 10.12, Chronic Progressive External Ophthalmoplegia.

 Rare: Myotonic dystrophy, bulbar variant of the Guillain-Barre syndrome (Miller-Fisher variant), intracranial sarcoidosis, others.

Etiology

 Arteriovenous fistula (AVF) (carotid-cavernous [“high-flow”] or dural-cavernous [“low-flow"]): Proptosis, chemosis, increased IOP, and dilated and tortuous (“corkscrew”) episcleral and conjunctival blood vessels are usually present (see Figure 10.10.1). Enhanced ocular pulsation (“pulsatile proptosis") may occur, usually discernible on slit lamp examination during applanation. A bruit may be heard in high flow fistulas by the physician, and sometimes by the patient, with auscultation around the globe or temple. Reversed, arterialized flow in the superior ophthalmic vein is detectable with orbital color Doppler US. Orbital CT or MRI may show an enlarged superior ophthalmic vein. MRA or CTA may occasionally reveal the fistula, but definitive diagnosis usually requires arteriography. High-flow fistulas have an abrupt onset, often following trauma or rupture of an intracavernous aneurysm. Low-flow fistulas have a more insidious presentation, most commonly in hypertensive women >50 years of age, and are due to dural arteriovenous malformations. The Barrow classification is used for preoperative planning and subdivides carotid-cavernous fistulas as follows:

A. Direct fistula.

B. Indirect with branches solely from internal carotid artery (rare).

C. Indirect with branches solely from external carotid artery.

D. Indirect with branches from both internal and external carotid arteries (most common).

• Tumors within the cavernous sinus: May be primary intracranial neoplasms with local invasion of the cavernous sinus (e.g., meningioma, pituitary adenoma, craniopharyngioma); or metastatic tumors to the cavernous sinus, either local (e.g., nasopharyngeal carcinoma, perineural spread of a periocular squamous cell carcinoma) or distant metastasis (e.g., breast, lung, lymphoma).

NOTE: Previously resected tumors may invade the cavernous sinus years after resection.

 Intracavernous aneurysm: Usually not ruptured. If aneurysm does rupture, the signs of a carotid-cavernous fistula develop.

 Zygomycosis (such as mucormycosis): Must be suspected in all diabetic patients, particularly those in ketoacidosis or recent poor sugar control and any debilitated or immunocompromised individual, especially patients on chemotherapy for cancer, with multiple cranial nerve palsies, with or without proptosis. Onset is typically acute. Bloody nasal discharge may be present, and nasal examination may reveal black, crusty material. This condition may produce massive hemispheric strokes and is always life threatening.

 Pituitary apoplexy: Acute onset of the critical signs listed previously; often bilateral with severe headache, decreased vision, and possibly bitemporal hemianopsia or blindness. A preexisting pituitary adenoma may enlarge during pregnancy and predispose to apoplexy. Peripartum hemorrhage/shock can cause an infarction of the pituitary gland, leading to apoplexy of a nontumorous pituitary gland (Sheehan syndrome). An enlarged sella turcica or an intrasellar mass, usually with acute hemorrhage, is seen on CT scan or MRI of the brain. Note that this may be clinically and radiographically indistinguishable from lymphocytic hypophysitis.

 Varicella zoster virus: Patients with the typical zoster rash may develop ocular motor nerve palsies as well as a mid-dilated pupil that reacts better to convergence than to light.

 Cavernous sinus thrombosis: Proptosis, chemosis, and eyelid edema. Usually bilateral. Fever, nausea, vomiting, and an altered level of consciousness often develop. May result from spread of infection from the face, mouth, throat, sinus, or orbit. Less commonly noninfectious, resulting from trauma or surgery. These patients are deathly ill.

 Tolosa-Hunt syndrome: Acute idiopathic inflammation of the superior orbital fissure or anterior cavernous sinus. Orbital pain often precedes restriction of eye movements. Recurrent episodes are common. This is a diagnosis of exclusion after high resolution MRI and CT scans with and without contrast of the cavernous sinus area. Lymphomas often are mis-diagnosed as Tolosa-Hunt syndrome.

 Others: Sarcoidosis, granulomatosis with polyangiitis (formerly Wegener granulomatosis), mucocele, tuberculosis, and other infectious and inflammatory conditions.

Work-Up

1. History: Diabetes? Hypertension? Recent significant head trauma? Prior cancer (including skin cancer)? Weight loss? Ocular bruit? Recent infection? Severe headache? Diurnal variation of symptoms?

2. Ophthalmic examination: Careful attention to pupils, extraocular motility, Hertel exophthalmometry, and resistance to retropulsion.

3. Examine the periocular skin for malignant or locally invasive lesions.

4. CT scan (axial, coronal, and parasagittal views) or MRI of the sinuses, orbit, and brain.

5. Orbital color doppler imaging is a dynamic evaluation, distinct from the static images of CT, MRI, and MRA. It is quick, painless, non-invasive and may be diagnostic when the other imaging studies are unrevealing. For some ateriovenous malformations (AVMs) and CCFs, cerebral angiography is required for diagnosis, and often for treatment.

6. LP to rule out carcinomatous meningitis in patients with a history of primary carcinoma. More than one LP might be required in some cases.

7. Nasopharyngeal examination with or without a biopsy to rule out nasopharyngeal carcinoma or infectious process.

8. Lymph node biopsy when lymphadenopathy is present.

9. CBC with differential, ESR, ANA, rheumatoid factor to rule out infection, malignancy, and systemic vasculitis. Antineutrophilic cytoplasmic antibody if granulomatosis with polyangiitis is suspected.

10. Cerebral arteriography is rarely required to rule out an aneurysm or AVM because most of these are seen by noninvasive imaging studies.

NOTE: Patients suspected of having dural arteriovenous fistulas are recommended to undergo arteriography to look for cortical venous drainage. If present, this puts the patient at greater risk for intracranial hemorrhage. These AVMs may present with a variable double vision syndrome involving partial paresis of the third, fourth and sixth cranial nerves. These lesions do not produce proptosis or any of the other external signs of cavernous sinus vascular lesions. The eyes are white and quiet. These lesions are especially difficult to diagnose and can produce large stroke syndromes.

11. If cavernous sinus thrombosis is being considered, obtain two to three sets of peripheral blood cultures and also culture the presumed primary source of the infection. Lemierre’s syndrome refers to an infectious thrombophlebitis of the internal jugular vein that is a result of spread from an oropharyngeal infection. This rare and potentially fatal entity may present in young, otherwise healthy individuals with neck pain, signs of sepsis, proptosis, and extraocular motility deficits.

Treatment and Follow-Up

Arteriovenous Fistula

1. Many dural fistulas close spontaneously or after arteriography. Others may require treatment via interventional neuroradiologic techniques.

2. Resolution of the fistula usually results in normalization of the intraocular pressure. However, medical treatment with aqueous suppressants for secondary glaucoma may be necessary. Drugs that increase outflow facility (e.g., latanoprost and pilocarpine) are usually not as effective because the intraocular pressure is increased as a result of increased episcleral venous pressure. See 9.1, Primary Open Angle Glaucoma.

Metastatic Disease to the Cavernous Sinus

Often requires systemic chemotherapy (if a primary is found) with or without radiation therapy to the metastasis. Refer to an oncologist.

Intracavernous Aneurysm

Refer to a neurosurgeon for work-up and possible treatment.

Zygomycosis (Mucormycosis)

1. Immediate hospitalization because this is a rapidly progressive, life-threatening disease.

2. Emergent CT scan of the sinuses, orbit, and brain.

3. Consult infectious disease, neurosurgery, otolaryngology, and endocrinology as indicated.

4. Begin amphotericin B 0.25 to 0.30 mg/kg i.v. in D5W slowly over 3 to 6 hours on the first day, 0.5 mg/kg i.v. on the second day, and then up to 0.8 to 1.0 mg/kg i.v. daily. The duration of treatment is determined by the clinical condition.

NOTE: Renal status and electrolytes must be checked before initiating therapy with amphotericin B and then monitored closely during treatment. Liposomal amphotericin has significantly less renal toxicity.

5. A biopsy should be obtained from any necrotic tissue (e.g., nasopharynx, paranasal sinuses) if zygomycosis/mucormycosis is suspected.

6. Early surgical debridement of all necrotic tissue (possibly including orbital exenteration), plus irrigation of the involved areas with amphotericin B, is often necessary to eradicate the infection.

7. Treat the underlying medical condition (e.g., diabetic ketoacidosis), with appropriate consultation as required.

Pituitary Apoplexy

These patients may be quite ill and require immediate systemic steroid therapy. Refer emergently to neurosurgery for surgical consideration.

Varicella Zoster Virus

See 4.16, Herpes Zoster Ophthalmicus/Varicella Zoster Virus.

Cavernous Sinus Thrombosis

1. For possible infectious cases (usually caused by Staphylococcus aureus), hospitalize the patient for treatment with intravenous antibiotics for several weeks. Consult infectious disease for antibiotic management.

2. Intravenous fluid replacement is usually required.

3. For aseptic cavernous sinus thrombosis, consider systemic anticoagulation (heparin followed by warfarin) or aspirin 325 mg p.o. daily in collaboration with a medical internist.

4. Exposure keratopathy is treated with preservative-free lubricating ointment or drops (see 4.5, Exposure Keratopathy).

5. Treat secondary glaucoma. See 9.1, Primary Open Angle Glaucoma.

Tolosa-Hunt Syndrome

Prednisone 80 to 100 mg p.o. daily for 1 week, and then decrease dose by 10 mg per week until discontinued. If pain persists after 72 hours, stop steroids and initiate reinvestigation to rule out other disorders. This condition requires a very gradual steroid taper.

NOTE: Other infectious or inflammatory disorders may also respond to steroids initially, so these patients need to be monitored closely.

10.11 Myasthenia Gravis

Symptoms

Painless, droopy eyelid or double vision that is variable throughout the day or worse when the individual is fatigued; may have weakness of facial muscles, proximal limb muscles, and difficulty swallowing or breathing.

Signs

Critical

Worsening of ptosis with sustained upgaze or diplopia with continued eye movements, weakness of the orbicularis muscle (cannot close the eyelids forcefully to resist examiner’s opening them). No pupillary abnormalities or pain.

Other

Upward twitch of ptotic eyelid when shifting gaze from inferior to primary position (Cogan eyelid twitch). Can have complete limitation of all ocular movements.

Differential Diagnosis

 Eaton-Lambert syndrome: A myasthenia-like paraneoplastic condition associated with carcinoma, especially lung cancer. Isolated eye signs do not occur, although eye signs may accompany systemic signs of weakness. Unlike myasthenia, muscle strength increases after exercise. Electromyography (EMG) distinguishes between the two conditions.

 Myasthenia-like syndrome due to medication (e.g., penicillamine, aminoglycosides).

 CPEO: No diurnal variation of symptoms or relation to fatigue; usually a negative intravenous edrophonium chloride test. Typically no diplopia. See 10.12, Chronic Progressive External Ophthalmoplegia.

 Kearns-Sayre syndrome: CPEO and retinal pigmentary degeneration in a young person; heart block develops. See 10.12, Chronic Progressive External Ophthalmoplegia.

 Third cranial nerve palsy: Pupil may be involved, no orbicularis weakness, no fatigability, no diurnal variation. See 10.5, Isolated Third Cranial Nerve Palsy.

NOTE: Myasthenia may mimic cranial nerve palsies, but the pupil is never involved.

 Horner syndrome: Miosis accompanies the ptosis. Pupil does not dilate well in darkness. See 10.2, Horner Syndrome.

 Levator muscle dehiscence or disinsertion: High eyelid crease on the side of the droopy eyelid, no variability of eyelid droop, no orbicularis weakness.

 Thyroid eye disease: No ptosis. May have eyelid retraction or eyelid lag, may or may not have exophthalmos, no diurnal variation of diplopia. Graves disease occurs in 5% of patients with myasthenia gravis. See 7.2.1, Thyroid Eye Disease.

 Idiopathic orbital inflammatory syndrome: Proptosis, pain, ocular injection. See 7.2.2, Idiopathic Orbital Inflammatory Syndrome.

 Myotonic dystrophy: May have ptosis and rarely, gaze restriction. After a handshake, these patients are often unable to release their grip (myotonia). Polychromatic lenticular deposits (“Christmas tree” cataract) and pigmentary retinopathy present.

Etiology

Autoimmune antibody-mediated disease; sometimes associated with underlying thyroid dysfunction. May be associated with thymic enlargement, representing either a benign thymoma or rarely a malignant thymoma. Increased incidence of other autoimmune disease (e.g., systemic lupus erythematosus, MS, rheumatoid arthritis). All age groups may be affected.

Work-Up

1. History: Do the signs fluctuate throughout the day and worsen with fatigue? Any systemic weakness? Difficulty swallowing, chewing, or breathing? Medications (worsened by beta-blockers, macrolides)?

2. Assess for presence of fatigability: Measure the degree of ptosis in primary gaze. Have the patient focus on your finger in upgaze for 1 minute. Observe whether the ptosis worsens.

3. Assess orbicularis strength by asking the patient to squeeze the eyelids shut while you attempt to force them open.

4. Test pupillary function. This will always be normal in myasthenia gravis.

5. Blood test for acetylcholine receptor antibodies (binding, blocking, and modulating). An elevated antibody titer establishes the diagnosis of myasthenia. However, values may be positive in only 60% to 88% of patients with myasthenia and are less likely to be positive in purely ocular myasthenia gravis. Anti musclespecific kinase (MUSK) antibodies are found in some patients who are negative for acetylcholine receptor antibodies, but those patients usually have systemic findings and have signs/symptoms that are not isolated to extraocular muscle function.

6. In adults, ice test (see later), rest test (see later), or, if cardiac monitoring present, edrophonium chloride or neostigmine test may confirm the diagnosis.

NOTE: Cholinergic crisis, syncopal episode, and respiratory arrest, although rare, may be precipitated by the edrophonium chloride test. Treatment includes atropine 0.4 mg i.v., while monitoring vital signs. Consider pretreating with atropine to prevent problems.

NOTE: Intramuscular neostigmine may be used instead of edrophonium chloride in children or in patients where injecting intravenous medication is problematic. The effect has a longer onset and lasts for approximately 2 to 4 hours.

7. For the ice test, an ice pack is placed over closed ptotic eye(s) for 2 minutes. Improvement of ptosis by at least 2 mm is a positive test for myasthenia gravis (see Figures 10.11.1 and 10.11.2).

8. In children, observation for improvement immediately after a 1- to 2-hour nap (sleep test) is a safe alternative. A similar rest test (keeping eyes closed) for 30 minutes in adults may be similarly diagnostic.

9. Check swallowing and breathing function as well as proximal limb muscle strength to rule out systemic involvement.

10. Thyroid function tests (including thyroid-stimulating hormone [TSH]).

11. CT scan of the chest to rule out thymoma.

12. Consider ANA, rheumatoid factor, and other tests to rule out other autoimmune disease.

13. A single-fiber EMG including the orbicularis muscle may be performed if other testing is negative and the diagnosis is still suspected. May be the most sensitive test for involvement of the ocular muscles.

Treatment

Refer to a neurologist familiar with this disease.

1. If the patient is having difficulty swallowing or breathing, urgent hospitalization for plasmapheresis, intravenous immunoglobulin (IVIG), neuromuscular disease specialist consult, and respiratory support may be indicated.

2. If the condition is mild, purely ocular, and is not disturbing to the patient, therapy need not be instituted (the patient may patch one eye as needed).

3. If the condition is disturbing or more severe, an oral anticholinesterase agent such as pyridostigmine should be given (often starting with 30 mg p.o. t.i.d. gradually increasing to an approximate dose of 60 mg p.o. q.i.d. for an adult). The dosage must be adjusted according to the response. Patients rarely benefit from >120 mg p.o. q3h of pyridostigmine. Overdosage may produce cholinergic crisis.

4. If symptoms persist, consider systemic steroids. There is no uniform agreement concerning the dosage. One option is to start with prednisone 20 mg p.o. daily, increasing the dose slowly until the patient is receiving 100 mg/d. These patients may require hospitalization for several days when a high-dose regimen of steroids is employed.

NOTE: Steroid use in myasthenia may precipitate respiratory crisis in the first 2 weeks of treatment. Therefore, in patients with systemic symptoms, hospitalization to begin steroids is required.

5. Azathioprine (2-3 mg/kg/d) may be helpful in older patients. Other medications to consider include mycophenolate mofetil and cyclosporine. Some patients with systemic myasthenia are treated with regularly scheduled IVIG or plasmapheresis.

6. Treat any underlying thyroid disease or infection.

7. Surgical removal of the thymus can be performed. This is indicated for anyone with thymoma. It may also improve symptoms in patients with generalized myasthenia without thymoma.

Follow-Up

1. If systemic muscular weakness is present, patients need to be monitored every 1 to 4 days by an appropriate medical specialist until improvement is demonstrated.

2. Patients who have had their isolated ocular abnormality for an extended time (e.g., months) should be seen every 4 to 6 months and if proven to be stable, every 6 to 12 months.

3. Patients should always be warned to return immediately if swallowing or breathing difficulties arise. After isolated ocular myasthenia has been present for 2 to 3 years, progression to systemic involvement is unlikely.

NOTE: Newborn infants of myasthenic mothers should be observed carefully for signs of myasthenia because acetylcholine receptor antibodies may cross the placenta. Poor sucking reflex, ptosis or decreased muscle tone may be seen.

10.12 Chronic Progressive External Ophthalmoplegia

Symptoms

Slowly progressive, symmetric ophthalmoplegia and droopy eyelids. Almost never have diplopia. Usually bilateral; there is no diurnal variation; there may be a family history.

Signs

Critical. Ptosis, limitation of ocular motility (sometimes complete limitation), normal pupils, and orthophoric.

Other. Weak orbicularis oculi muscles, weakness of limb and facial muscles, and exposure keratopathy.

Differential Diagnosis

The following syndromes must be ruled out when CPEO is diagnosed:

 Kearns-Sayre syndrome: Onset of CPEO before age 20 years associated with retinal pigmentary degeneration (classically exhibiting a salt-and-pepper appearance) and heart block that usually occurs years after the ocular signs and may cause sudden death. Other signs may include hearing loss, mental retardation, cerebellar signs, short stature, delayed puberty, nephropathy, vestibular abnormalities, increased cerebrospinal fluid protein, and characteristic “ragged red fiber” findings on muscle biopsy. Although some are inherited maternally, the vast majority are due to spontaneous mitochondrial deletions.

 Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): Rare progressive neurodegenerative disorder affecting the brainstem that causes early gait instability and ophthalmoplegia. Often downgaze affected first followed by other gaze limitations; vertical more than horizontal. Other eye movement problems include abnormalities in the saccadic and pursuit subsystems of horizontal gaze. Often the eyelids are held wide open resulting in a “staring" type of facial expression. Neck and axial rigidity is an important sign.

 Abetalipoproteinemia (Bassen-Kornzweig syndrome): Retinal pigmentary degeneration similar to retinitis pigmentosa, diarrhea, ataxia, and other neurologic signs. Acanthocytosis of red blood cells is seen on peripheral blood smear and LP demonstrates increased cerebrospinal fluid protein. See 11.28, Retinitis Pigmentosa and Inherited Chorioretinal Dystrophies.

 Refsum disease: Retinitis pigmentosa and increased blood phytanic acid level. May have polyneuropathy, ataxia, hearing loss, anosmia, and others. See 11.28, Retinitis Pigmentosa and Inherited Chorioretinal Dystrophies.

 Oculopharyngeal dystrophy: Difficulty swallowing, sometimes leading to aspiration of food; may have autosomal dominant inheritance.

• Mitochondrial myopathy and encephalopathy, lactic acidosis, and stroke-like episodes: Occurs in children and young adults. May have headache, transient hemianopsia, hemiparesis, nausea, and vomiting. Elevated serum and cerebrospinal fluid lactate levels and may have abnormalities on MRI.

Workup

1. Careful history: Determine the rate of onset (gradual versus sudden, as in cranial nerve disease).

2. Family history.

3. Carefully examine the pupils and ocular motility.

4. Test orbicularis oculi strength.

5. Fundus examination: Look for diffuse pigmentary changes.

6. Check swallowing function.

7. Ice test, rest test, or edrophonium chloride test to check for myasthenia gravis.

NOTE: Some patients with CPEO are supersensitive to edrophonium chloride which may precipitate heart block and arrhythmias.

8. Prompt referral to a cardiologist for full cardiac workup (including yearly electrocardiograms) if Kearns-Sayre syndrome is suspected.

9. If neurologic signs and symptoms develop, consult a neurologist for workup (including possible LP).

10. Lipoprotein electrophoresis and peripheral blood smear if abetalipoproteinemia suspected.

11. Serum phytanic acid level if Refsum disease suspected.

12. Consider genetic testing.

Treatment

There is no cure for CPEO, but associated abnormalities are managed as follows:

1. Treat exposure keratopathy with lubricants at night and artificial tears during the day. See 4.5, Exposure Keratopathy.

2. Single vision reading glasses or base-down prisms within reading glasses may help reading when downward gaze is restricted.

3. In Kearns-Sayre syndrome, a pacemaker may be required.

4. In oculopharyngeal dystrophy, dysphagia and aspirations may require cricopharyngeal surgery.

5. In severe ptosis, consider ptosis crutches or surgical repair, but watch for worsening exposure keratopathy.

6. Genetic counseling as needed.

Follow Up

Depends on ocular and systemic findings.

10.13 Internuclear Ophthalmoplegia

Definition

Ophthalmoplegia secondary to lesion in the medial longitudinal fasciculus (MLF).

Symptoms

Double vision, blurry vision, or vague visual complaints.

Signs

(See Figures 10.13.1 and 10.13.2.).

FIGURE 10.11.1 Left internuclear ophthalmoplegia: Left gaze showing full abduction.

FIGURE 10.11.2 Left internuclear ophthalmoplegia: Right gaze with severe adduction deficit.

Critical. Weakness or paralysis of adduction, with horizontal jerk nystagmus of the abducting eye.

NOTE: INO is localized to the side with the weak adduction.

Other. May be unilateral or bilateral (WEBINO: “wall-eyed,” bilateral INO). Upbeat nystagmus on upgaze may occur when INO is unilateral or bilateral. The involved eye can sometimes turn in when attempting to read (intact convergence). A skew deviation (relatively comitant vertical deviation not caused by neuromuscular junction disease or intraorbital pathology) may be present; brainstem and posterior fossa pathology should be ruled out. With skew deviation, the three-step test cannot isolate a specific muscle. See 10.7, Isolated Fourth Cranial Nerve Palsy. In addition, presence of other neurologic signs, including gaze-evoked nystagmus, gaze palsy, dysarthria, ataxia, and hemiplegia, favors skew deviation rather than fourth cranial nerve palsy.

Differential Diagnosis of Attenuated Adduction

 Myasthenia gravis: May closely mimic INO; however, ptosis and orbicularis oculi weakness are common. Nystagmus of INO is faster; myasthenia gravis is more gaze paretic. Symptoms vary throughout the day.

 Orbital disease (e.g., tumor, thyroid disease, idiopathic orbital inflammatory syndrome): Proptosis, globe displacement, or pain may be present. Nystagmus is usually not present. See 7.1, Orbital Disease.

 One-and-a-half syndrome: Pontine lesion that includes the ipsilateral MLF and horizontal gaze center (sixth cranial nerve nucleus). The only preserved horizontal movement is abduction of the eye contralateral to the lesion. This is because of an ipsilateral adduction deficit (from the MLF lesion) and a horizontal gaze paresis in the direction of the lesion (from the horizontal gaze center lesion). Causes include stroke and pontine neoplasia.

Etiology

 MS: More common in young patients, usually bilateral.

 Brainstem stroke: More common in elderly patients, usually unilateral.

 Brainstem mass lesion.

 Rare causes: CNS cryptococcosis, tuberculosis granuloma, pyoderma gangrenosum (all shown to cause WEBINO).

Workup

1. History: Age? Are symptoms constant or only toward the end of the day with fatigue? Prior optic neuritis, urinary incontinence, numbness or paralysis of an extremity, or another unexplained neurologic event (concerning for MS)?

2. Complete evaluation of eye movement to rule out other eye movement disorders (e.g., sixth cranial nerve palsy, skew deviation).

NOTE: Ocular motility can appear to be full, but a muscular weakness can be detected by observing slower saccadic eye movement in the involved eye compared with the contralateral eye. The adducting saccade is assessed by having the patient fix on the examiner’s finger held laterally and then asking the patient to make a rapid eye movement from lateral to primary gaze. If an INO is present, the involved eye will show a slower adducting saccade than the uninvolved eye. The contralateral eye may be tested in a similar fashion.

3. Ice test, rest test, or edrophonium chloride test when the diagnosis of myasthenia gravis cannot be ruled out.

4. MRI of the brainstem and midbrain.

Treatment/Follow Up

1. If an acute stroke is diagnosed, admit to the hospital for neurologic evaluation and observation.

2. If concern for demyelinating disease, consider treatment recommendations described in 10.14, Optic Neuritis.

3. Patients are managed by physicians familiar with the underlying disease.

10.14 Optic Neuritis

Symptoms

Typical optic neuritis associated with MS causes vision loss over hours to days, with the nadir approximately 1 week after onset. Visual loss may be subtle or profound. Usually unilateral, rarely bilateral. Age typically 18 to 45 years. Retro-orbital pain, especially with eye movement. Acquired loss of color vision. Reduced perception of light intensity. May have other focal neurologic symptoms (e.g., weakness, numbness, tingling in extremities). May have antecedent flulike viral syndrome. Occasionally altered perception of moving objects (Pulfrich phenomenon) or a worsening of symptoms with exercise or increase in body temperature (Uhthoff sign).

More recently, immune-mediated disorders of the CNS, such as neuromyelitis optica spectrum disorder (NMOSD), have been described as causes of atypical optic neuritis. Atypical features include advanced patient age, severe vision loss with poor recovery, and simultaneous or rapidly sequential bilateral optic neuritis.

Signs

Critical. Relative afferent pupillary defect in unilateral or asymmetric cases; decreased color vision; central, cecocentral, or arcuate visual field defects.

Other. Swollen disc (in one-third of patients) usually without peripapillary hemorrhages (papillitis most commonly seen in children and young adults) or a normal disc (in two-thirds of patients; retrobulbar optic neuritis more common in adults). Posterior vitreous cells possible.

Differential Diagnosis

 Ischemic optic neuropathy: Visual loss is sudden but in up to 35% of patients may progress over 4 weeks. Typically, no pain with ocular motility, though pain may be present in 10% of cases (compared to 92% of patients with optic neuritis). Optic nerve swelling due to nonarteritic ischemic optic neuropathy (NAION) is initially hyperemic and then becomes pale. Optic nerve swelling in GCA is diffuse and chalk white. Patients tend to be older (40 to 60 for NAION and >55 in arteritic ischemic optic neuropathy). See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis) and 10.18, Nonarteritic Ischemic Optic Neuropathy.

 Acute papilledema: Bilateral disc edema, usually no decreased color vision, minimal to no decreased visual acuity, no pain with ocular motility, and no vitreous cells. See 10.15, Papilledema.

 Severe systemic hypertension: Bilateral disc edema, increased blood pressure, flame-shaped retinal hemorrhages, and cottonwool spots. See 11.10, Hypertensive Retinopathy.

 Orbital tumor compressing the optic nerve: Unilateral and usually associated with proptosis, resistance to retropulsion, and/or restriction of extraocular motility. See 7.4, Orbital Tumors.

 Intracranial mass compressing the afferent visual pathway: Normal or pale disc, afferent pupillary defect, decreased color vision, and mass evident on CT scan or MRI of the brain.

 Leber hereditary optic neuropathy: Usually occurs in males in the second or third decade of life. Patients may have a family history and present with rapid visual loss of one and then the other eye within days to months. Early examination of the disc may reveal peripapillary telangiectasias followed by optic atrophy.

 Toxic or metabolic optic neuropathy: Progressive painless bilateral visual loss that may be secondary to alcohol, malnutrition, various toxins (e.g., ethambutol, chloroquine, isoniazid, chlorpropamide, heavy metals), anemia, and others.

Etiology

 MS: Frequently optic neuritis is the initial manifestation of MS.

 NMOSD should be considered in all first-time optic neuritis patients.

 Childhood infections or vaccinations: Measles, mumps, chickenpox, and others.

 Other viral infections: Mononucleosis, varicella zoster, encephalitis, and others.

 Contiguous inflammation of the meninges, orbit, or sinuses.

 Granulomatous inflammations/infections: Tuberculosis, syphilis, sarcoidosis, cryptococcus, and others.

 Idiopathic.

Workup

FIGURE 10.12.1 MRI of optic neuritis showing enhancement of the right optic nerve.

1. History: Determine the patient’s age and rapidity of onset of the visual loss. Previous episode? Pain with eye movement? Intractable hiccups, nausea/vomiting, and severe itching are features strongly suggestive of NMOSD.

2. Complete ophthalmic and neurologic examinations, including pupillary and color vision assessment, evaluation for vitreous cells, and dilated retinal examination with attention to the optic nerve.

3. For all cases, MRI of the brain and orbits with gadolinium and fat suppression should be obtained (see Figure 10.14.1). While a short segment of optic nerve is involved in typical optic neuritis, lesions in NMOSD may be longitudinally extensive. In addition, patients with NMOSD should have MRI of the spine to look for signs of transverse myelitis. Antibodies for anti-aquaporin 4 (anti-AQP4) and anti-myelin oligodendrocyte glycoprotein (anti-MOG) should be drawn.

4. Check blood pressure.

5. Visual field test, preferably automated (e.g., Humphrey).

6. Consider the following: CBC, ESR, anti-AQP4 and anti-MOG antibodies for NMOSD, ACE level, Lyme antibody, FTA-ABS or treponemal-specific assay and RPR or VDRL tests, and chest x-ray or CT.

Treatment

Typical Optic Neuritis

If patient seen acutely with no prior history of MS or optic neuritis:

1. Offer pulsed i.v. steroid in the following regimen within 14 days of decreased vision:

 Methylprednisolone 1 g/day i.v. for 3 days, then

 Prednisone 1 mg/kg/d p.o. for 11 days, then

 Taper prednisone over 4 days (20 mg on day 1, 10 mg on days 2 through 4).

 Antiulcer medication (e.g., omeprazole 20 mg p.o. daily or ranitidine 150 mg p.o. b.i.d.) for gastric prophylaxis.

NOTE: The Optic Neuritis Treatment Trial (ONTT) found steroid treatment reduced initial progression to clinically definite multiple sclerosis (CDMS) for 2 years. Steroid therapy only increases the rapidity of visual return but does not improve final visual outcome.

2. If MRI shows two or more characteristic demyelinating lesions, treat with the aforementioned steroid regimen and refer to neurologist or neuro-ophthalmologist for further management. Currently, there are fourteen drugs that have been FDA approved for treatment of MS. These include agents that are given orally, by injection, or by infusion. The most commonly used medications include interferon-beta, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, alemtuzumab, natalizumab, ocrelizumab, and dalfampridine.

3. Patients with one or more typical signal changes on MRI have a 72% chance of developing CDMS over 15 years.

NOTE: NEVER use oral prednisone as a primary treatment because of increased risk of recurrence found in ONTT. Disease-modifying drugs as listed above have been shown to reduce probability of progression to CDMS in high-risk patients.

4. With a negative MRI, the risk of MS is low, 25% at 15 years. Thus, observation was an acceptable option in the past. However, in the current era of NMOSD, negative MRI should arouse suspicion for this condition. Pulsed i.v. steroid should be administered in all patients, and additional serological studies for antibodies should be obtained.

In a patient with a diagnosis of prior MS or typical optic neuritis:

1. Observation or pulsed i.v. steroids, as above. We usually treat with i.v. pulsed steroids.

Atypical Optic Neuritis

NMOSD (anti-AQP4 positive, anti-MOG positive, or seronegative disease):

1. For acute optic neuritis, high-dose i.v. steroids are used first.

2. Plasmapheresis should be performed if response to steroids is poor.

3. Referral to a neurologist/neuroimmunologist for long-term immunosuppression with agents such as rituximab, azathioprine, or mycophenolate. Eculizumab was recently approved by the FDA for anti-AQP4 positive NMOSD.

Follow Up

Diagnosis of Prior MS or Typical Optic Neuritis

1. Reexamine the patient approximately 4 to 6 weeks after presentation and then every 3 to 6 months.

2. Clinically isolated syndromes without features of MS need repeat MRI brain every 6 months initially and then annually to monitor for development of MS lesions.

3. Patients at high risk for MS, including patients with CNS demyelination on MRI or a positive neurologic examination, should be referred to a neurologist or neuro-ophthalmologist for evaluation and management of possible MS.

Atypical Optic Neuritis

NMOSD: Even closer follow up initially may be necessary due to frequency of relapses and severity of vision loss. Follow up within 2 weeks of initial treatment with rapid referral to neurologist experienced in treating NMOSD.

REFERENCES

Beck RW, Cleary PA, Anderson MM Jr, et al. A randomized, controlled trial of corticosteroids in the treatment of acute optic neuritis. The Optic Neuritis Study Group. N Engl J Med. 1992;326:581-588.

Beck RW, Cleary PA, Trobe JD, et al. The effect of corticosteroids for acute optic neuritis on the subsequent development of multiple sclerosis. The Optic Neuritis Study Group. N Engl J Med. 1993;329:1764-1769.

Chen J, Pittock S, Flanagan E, et al. Optic neuritis in the era of biomarkers. Surv Ophthalmol. 2020;65(1):12-17.

Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med. 2000;343:898-904.

Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis: final follow-up from the Optic Neuritis Treatment Trial. Arch Neurol. 2008;65:727-732.

10.15 Papilledema

Definition

Optic disc swelling produced by increased intracranial pressure.

Symptoms

Episodes of transient, usually bilateral visual loss (lasting seconds), often precipitated after rising from a lying or sitting position (altering intracranial pressure); headache; double vision; nausea; vomiting; and, rarely, a decrease in visual acuity (a mild decrease in visual acuity can occur in the acute setting if associated with a macular disturbance). Visual field defects and severe loss of central visual acuity occur more often with chronic papilledema.

Signs

(See Figure 10.15.1.)

FIGURE 10.13.1 Swollen optic disc with obscured blood vessels and blurring of the disc margin. Flame-shaped hemorrhages may occur.

Critical. Bilaterally swollen, hyperemic discs (in early papilledema, disc swelling may be asymmetric) with nerve fiber layer edema causing blurring of the disc margin, often obscuring the blood vessels.

Other. Papillary or peripapillary retinal hemorrhages (often flame shaped); loss of venous pulsations (20% of the normal population do not have venous pulsations); dilated, tortuous retinal veins; normal pupillary response and color vision; an enlarged physiologic blind spot or other visual field defects by formal visual field testing.

In chronic papilledema, the hemorrhages and cotton-wool spots resolve, disc hyperemia disappears, and the disc becomes gray in color. Peripapillary gliosis and narrowing of the peripapillary retinal vessels occur, and optociliary shunt vessels may develop on the disc. Loss of color vision, loss of central visual acuity, and visual field defects (especially inferonasally) may be observed.

NOTE: Unilateral or bilateral sixth cranial nerve palsy may result from increased intracranial pressure.

Differential Diagnosis of Disc Edema or Elevation

 Pseudopapilledema (e.g., optic disc drusen or congenitally anomalous disc): Not true disc swelling. Vessels overlying the disc are not obscured, the disc is not hyperemic, and the surrounding nerve fiber layer is normal. Spontaneous venous pulsations (SVPs) are often present. Buried drusen may be present and can be identified with B-scan ultrasonography or autofluorescence; will also be visible on CT imaging.

 Papillitis: An afferent pupillary defect and decreased color vision are present; decreased visual acuity occurs in most cases, usually unilateral. See 10.14, Optic Neuritis.

 Hypertensive optic neuropathy: Extremely high blood pressure, narrowed arterioles, arteriovenous crossing changes, hemorrhages with or without cotton-wool spots extending into the peripheral retina. See 11.10, Hypertensive Retinopathy.

 Central retinal vein occlusion: Hemorrhages extend far beyond the peripapillary area; dilated and tortuous veins, generally unilateral; acute loss of vision in most cases. See 11.8, Central Retinal Vein Occlusion.

 Ischemic optic neuropathy: Disc swelling is pale but may be hyperemic; initially unilateral unless due to GCA, with sudden visual loss. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis) and 10.18, Nonarteritic Ischemic Optic Neuropathy.

 Infiltration of the optic disc (e.g., sarcoid or tuberculous granuloma, leukemia, metastasis, other inflammatory disease or tumor): Other ocular or systemic abnormalities may be present.

Usually unilateral.

 Leber hereditary optic neuropathy: Usually occurs in males in the second or third decade of life. Patients may have a family history and present with rapid visual loss of one and then the other eye within days to months. Early examination of the disc may reveal peripapillary telangiectasias followed by optic atrophy.

 Orbital optic nerve tumors: Unilateral disc swelling, may have proptosis.

 Diabetic papillopathy: Benign disc edema in one or both eyes of a diabetic patient, most commonly with mild visual loss. No correlation with diabetic retinopathy. In addition to disc edema, disc hyperemia due to telangiectasias of the disc vessels may occur, simulating neovascularization. More common in patients with juvenile-onset diabetes. No treatment is indicated. Spontaneous resolution usually occurs after 3 to 4 months but may take even longer.

 Thyroid-related optic neuropathy: May have eyelid lag or retraction, ocular misalignment, resistance to retropulsion. See 7.2.1, Thyroid Eye Disease.

 Uveitis (e.g., syphilis or sarcoidosis): Pain or photophobia, anterior chamber/vitreous cells. See 12.3, Posterior Uveitis.

 Amiodarone toxicity: May present with subacute visual loss and disc edema.

NOTE: Optic disc swelling in a patient with leukemia is often a sign of leukemic optic nerve infiltration. Urgent initiation of therapy including corticosteroids and chemotherapy/radiation is required to achieve best visual outcomes.

Etiology

 Primary and metastatic intracranial tumors.

 Hydrocephalus.

 Idiopathic intracranial hypertension: Often occurs in young, overweight females. See 10.16, Idiopathic Intracranial

Hypertension/Pseudotumor Cerebri.

 Subdural and epidural hematomas.

 Subarachnoid hemorrhage: Severe headache, may have preretinal hemorrhages (Terson syndrome).

 Arteriovenous malformation.

 Brain abscess: Often produces high fever and mental status changes.

 Meningitis: Fever, stiff neck, headache (e.g., syphilis, tuberculosis, Lyme disease, bacterial, inflammatory, neoplastic).

 Encephalitis: Often produces mental status abnormalities.

 Cerebral venous sinus thrombosis.

Workup

1. History and physical examination, including blood pressure measurement.

2. Ocular examination, including a pupillary examination and assessment for dyschromatopsia, posterior vitreous evaluation for white blood cells, and a dilated fundus examination. The optic disc is best examined with a slit lamp and a 60-diopter (or equivalent), Hruby, or fundus contact lens.

3. Emergency MRI with gadolinium and magnetic resonance venography (MRV) of the head are preferred. CT scan (axial, coronal, and parasagittal views) may be done if MRI not available emergently.

4. If MRI/MRV or CT is unrevealing, perform LP with CSF analysis and opening pressure measurement if no contraindication.

Treatment

Treatment should be directed at the underlying cause of the increased intracranial pressure.

10.16 Idiopathic Intracranial Hypertension/Pseudotumor Cerebri

Definition

A syndrome in which patients present with symptoms and signs of elevated intracranial pressure, the nature of which may be either idiopathic or due to various causative factors.

Symptoms

Headache, transient episodes of visual loss (typically lasting seconds) often precipitated by changes in posture, double vision, pulsatile tinnitus, nausea, or vomiting accompanying the headache. Occurs predominantly in obese women.

Signs

Critical. By definition, the following findings are present:

 Papilledema due to increased intracranial pressure.

 Negative MRI/MRV of the brain.

 Increased opening pressure on LP with normal CSF composition.

Other. See 10.15, Papilledema. Unilateral or bilateral sixth cranial nerve palsy may be present. There are no other neurologic signs on examination aside from possible sixth cranial nerve palsy.

Differential Diagnosis

See 10.15, Papilledema.

Associated Factors

Obesity, significant weight gain, and pregnancy are often associated with the idiopathic form. Possible causative factors include various medications such as oral contraceptives, tetracyclines (including semisynthetic derivatives, e.g., doxycycline), cyclosporine, vitamin A (>100,000 U/d), amiodarone, sulfa antibiotics, lithium, and historically nalidixic acid (now rarely used). Systemic steroid intake and withdrawal may also be causative.

Workup

1. History: Inquire specifically about medications.

2. Ocular examination, including pupillary examination, ocular motility, assessment for dyschromatopsia (e.g., color plates), and optic nerve evaluation.

3. Systemic examination, including blood pressure and temperature.

4. MRI/MRV of the orbit and brain. Any patient with papilledema needs to be imaged immediately. If normal, the patient should have an LP, to rule out other causes of optic nerve edema and to determine the opening pressure (see 10.15, Papilledema).

5. Visual field test is the most important method for following these patients (e.g., Humphrey).

Treatment

Idiopathic intracranial hypertension may be a self-limited process. Treatment is indicated in the following situations:

• Severe, intractable headache.

 Evidence of progressive decrease in visual acuity or visual field loss.

 Some ophthalmologists suggest treating all patients with papilledema.

Methods of treatment include the following:

1. Weight loss if overweight.

2. Acetazolamide 250 mg p.o. q.i.d. initially, building up to 500 to 1000 mg q.i.d. if tolerated. Use with caution in sulfa-allergic patients.

3. Discontinuation of any causative medication.

4. Consider short course of systemic steroids, especially if any plans for surgical intervention.

If treatment by these methods is unsuccessful, consider a surgical intervention:

1. A neurosurgical shunt (ventriculoperitoneal or lumboperitoneal) or venous sinus stenting procedure should be considered if intractable headache is a prominent symptom.

2. Optic nerve sheath decompression surgery or neurosurgical shunt (ventriculoperitoneal or lumboperitoneal) is often effective if vision is threatened.

Special Circumstances

1. Pregnancy: Incidence of idiopathic intracranial hypertension does not increase during pregnancy beyond what would be expected from the weight gain. No increased risk of fetal loss. Acetazolamide may be used after 20 weeks of gestation (in consultation with OB/GYN). Intense weight loss is contraindicated during pregnancy. Without visual compromise, close observation with serial visual fields is recommended. With visual compromise, consider steroids, optic nerve sheath decompression, shunting, or repeat LPs.

2. Children/adolescents: A secondary cause is identifiable in 50% patients.

Follow Up

1. If acute, patients can be monitored every 3 months in the absence of visual field loss. If chronic, initially follow patient every 3 to 4 weeks to monitor visual acuity and visual fields and then every 3 months depending on the response to treatment.

2. In general, the frequency of follow up depends on the severity of visual loss. The more severe, the more frequent the follow up.

10.17 Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis)

Symptoms

Sudden, painless visual loss. Initially unilateral, but may rapidly become bilateral. Occurs in patients >55 years of age. Antecedent or simultaneous headache, jaw claudication (pain with chewing), scalp tenderness especially over the superficial temporal arteries (e.g., tenderness with hair combing), proximal muscle and joint aches (polymyalgia rheumatica), anorexia, weight loss, or fever may occur.

Signs

(See Figure 10.17.1.)

FIGURE 10.15.1 Chalky, pale, swollen optic disc with flame-shaped hemorrhages in giant cell arteritis.

Critical. Afferent pupillary defect; visual loss (often counting fingers or worse); pale, swollen disc, at times with flame-shaped hemorrhages. Later, optic atrophy and cupping occur as the edema resolves. The ESR, CRP, and platelet count may be markedly increased.

Other. Visual field defect (commonly altitudinal or involving the central field); a palpable, tender, and often nonpulsatile temporal artery; and a central retinal artery occlusion or a cranial nerve palsy (especially a sixth cranial nerve palsy) may occur.

Differential Diagnosis

• NAION: Patients may be younger. Visual loss often less severe, do not have the accompanying symptoms of GCA listed previously, and usually have a normal ESR and CRP. See 10.18,

Nonarteritic Ischemic Optic Neuropathy.

 Inflammatory optic neuritis: Younger age group. Pain with eye movements. Optic disc swelling, if present, is more hyperemic. See 10.14, Optic Neuritis.

 Compressive optic nerve tumor: Optic nerve pallor or atrophy may be seen; disc heme unlikely. Slowly progressive visual loss. Few to no symptoms common with GCA.

 Central retinal vein occlusion: Severe visual loss may be accompanied by an afferent pupillary defect and disc swelling, but the retina shows diffuse retinal hemorrhages extending out to the periphery. See 11.8, Central Retinal Vein Occlusion.

 Central retinal artery occlusion: Sudden, painless, severe visual loss with an afferent pupillary defect. No disc swelling. Retinal edema with a cherry-red spot frequently observed. See 11.6, Central Retinal Artery Occlusion.

Workup

1. History: GCA symptoms present? Age is critical.

2. Complete ocular examination, particularly pupillary assessment, dyschromatopsia evaluation (e.g., color plates), dilated retinal examination to rule out retinal causes of severe visual loss, and optic nerve evaluation.

3. Immediate ESR (Westergren is the most reliable method), CRP (does not rise with age), and platelet count (may have thrombocytosis). A guideline for top-normal ESR calculation: men, age/2; women, (age + 10)/2. ESR may not be increased. CRP and platelet upper limit values are based on laboratory-specific standards.

4. Perform a temporal artery biopsy if GCA is suspected.

NOTE: The biopsy should be performed within 1 week after starting systemic steroids, but a positive result may be seen up to 1 month later. Biopsy is especially important in patients in whom steroids are relatively contraindicated (e.g., diabetics).

Treatment

1. Systemic steroids should be given immediately once GCA is suspected. Methylprednisolone 250 mg i.v., q6h for 12 doses, and then switch to prednisone 80 to 100 mg p.o. daily. A temporal artery biopsy specimen should be obtained within 1 week of systemic steroid initiation.

2. If the temporal artery biopsy is positive for GCA (or clinical presentation/therapeutic response warrants continued therapy), the patient must be maintained on prednisone, about 1 mg/kg initially. Oral steroids are tapered on an individual basis with the goal of using the lowest required dose necessary for disease suppression (see below).

3. If the biopsy is negative on an adequate (2 to 3 cm) section, the likelihood of GCA is small. However, in highly suggestive cases, biopsy of the contralateral artery is performed.

4. Steroids are usually discontinued if the disease is not found in adequate biopsy specimens, unless the clinical presentation is classic and a response to treatment has occurred.

NOTE:

1. Without steroids (and occasionally on adequate steroids), the contralateral eye can become involved within 1 to 7 days.

2. Concurrent antiulcer (e.g., proton-pump inhibitor [e.g., omeprazole 20 mg p.o. daily] or histamine type 2 receptor blocker [e.g., ranitidine 150 mg p.o. b.i.d.]) should be used for gastrointestinal prophylaxis while on steroids.

3. A medication to help prevent osteoporosis should be used as directed by an internist, particularly given the long-term need for steroids.

Follow Up

1. Patients suspected of having GCA must be evaluated and treated immediately.

2. After the diagnosis is confirmed by biopsy, the initial oral steroid dosage is maintained until the symptoms resolve and lab values normalize. The dosage is then tapered slowly, repeating bloodwork with each dosage change and/or monthly (whichever appropriate based on disease stability) to ensure that the new steroid dosage is enough to suppress the disease.

3. If the ESR or CRP increase or symptoms return, the dosage must be increased.

4. Treatment should last at least 6 to 12 months. The smallest steroid dose that suppresses disease is used.

Tocilizumab, a novel humanized IL-6 receptor antagonist, has been recently approved by the FDA for long-term management of GCA. Addition of subcutaneous tocilizumab to standardized steroid regimens helps achieve remission faster and significantly reduces the dose and toxicity of corticosteroids.

10.18 Nonarteritic Ischemic Optic Neuropathy

Symptoms

Sudden, painless visual loss of moderate degree, initially unilateral, but may become bilateral. Typically occurs in patients 40 to 60 years of age, but well-documented cases have been reported in patients in their teenage years. In younger patients, NAION should be suspected when painless visual loss develops with a contralateral “disc at risk” (i.e., crowded disc with small or absent optic cup [cup:disc ratio less than 0.3]) and normal MRI scan. The visual deficit may improve. Hyperlipidemia, labile hypertension, and sleep apnea are the common risk factors for younger patients.

Signs

(See Figure 10.18.1.)

FIGURE 10.16.1 Nonarteritic ischemic optic neuropathy with segmental disc edema and hemorrhage.

Critical. Afferent pupillary defect, pale disc swelling (often segmental), flame-shaped hemorrhages, normal ESR and CRP.

 Nonprogressive NAION: Sudden initial decrease in visual acuity and visual field, which stabilizes.

 Progressive NAION: Sudden initial decrease in visual acuity and visual field followed by worsening in visual acuity or visual field days to weeks later. As many as 35% of NAION cases may be progressive.

Other. Reduced color vision, altitudinal or central visual field defect, optic atrophy without cupping (segmental or diffuse) after the edema resolves. Crowded or congenitally anomalous disc with small or absent cup in fellow eye.

Differential Diagnosis

See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

Etiology

Idiopathic: Arteriosclerosis, diabetes, hypertension, hyperlipidemia, hyperhomocysteinemia, anemia, and sleep apnea are associated risk factors, but causation has never been proven. Relative nocturnal hypotension may play a role, especially in patients taking antihypertensive medication. Nocturnal hypotension may be related to sleep apnea.

NOTE: Currently, phosphodiesterase-5 inhibitors (e.g., sildenafil, vardenafil, and tadalafil) often used for erectile dysfunction have not been proven to cause NAION. However, the FDA has issued a warning regarding a possible association with these medications and NAION. It is recommended that patients with risk factors for NAION (listed previously) be counseled against the use of these medications.

Workup

1. Same as 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

2. Consult internist to rule out cardiovascular disease, diabetes, hypertension, and sleep apnea.

Treatment

1. Observation.

2. Cardiovascular risk factor modification.

3. Consider avoiding blood pressure medication at bedtime to help avoid nocturnal hypotension.

Follow Up

1. One month.

2. Up to 40% of patients show mild improvement in vision over 3 to

6 months in some studies. Optic nerve edema resolves within 8 weeks.

3. Patients should be counseled of risk to the contralateral eye (variable).

10.19 Posterior Ischemic Optic Neuropathy

Symptoms

Painless visual loss. Most commonly occurs in the postoperative setting at any time from upon awakening from anesthesia to 4 to 7 days thereafter. May be unilateral or bilateral, with a partial or complete deficit.

Signs

See 10.18, Nonarteritic Ischemic Optic Neuropathy. Optic discs may appear normal initially in acute posterior ischemic optic neuropathy, but eventually pale disc edema, followed by pallor, develops.

Etiology

• Postoperative: May occur after head and neck surgery, spinal surgery, gastrointestinal surgery, open heart surgery, or any procedure associated with hypotension, anemia, increased surgical time, large amounts of blood loss, increased central venous pressure, or positioning of head in a dependent, down-tilt position. History of peripheral vascular disease, diabetes, and anemia may increase risk.

NOTE: Operative planning in high-risk patients should include attention to head positioning and length of surgical time, balance of risk and benefits of hypotensive anesthesia, aggressive replacement of blood loss, monitoring vision early in the postoperative period, and prompt ophthalmic consultation if patient describes visual disturbances.

• Inflammatory/infectious: GCA, varicella zoster virus, systemic lupus erythematosus, and others.

Treatment

1. Although no controlled studies exist for postoperative posterior ischemic optic neuropathy, it has been suggested that prompt blood transfusion with correction of hypotension and anemia may be beneficial and should be considered.

2. Treat any inflammatory or infectious etiology as appropriate.

10.20 Miscellaneous Optic Neuropathies

TOXIC/METABOLIC OPTIC NEUROPATHY

Symptoms

Painless, progressive, bilateral loss of vision.

Signs

Critical. Bilateral cecocentral or central visual field defects, signs of alcoholism, tobacco/substance use, certain medication use, heavy metal exposure, or poor nutrition.

Other. Visual acuity of 20/50 to 20/200, reduced color vision, temporal disc pallor, optic atrophy, or normal-appearing disc initially.

Etiology

 Tobacco/alcohol or other substance abuse.

 Severe malnutrition with thiamine (vitamin B1) deficiency.

 Pernicious anemia: Usually due to vitamin B12 malabsorption.

 Toxic: Exposure to medications such as chloramphenicol, ethambutol, linezolid, isoniazid, digitalis, streptomycin, chlorpropamide, ethchlorvynol, disulfiram, amiodarone, and lead. Methanol can cause an acute optic neuropathy.

Workup

 History: Drug or substance abuse? Medications? Diet?

 Complete ocular examination, including pupillary assessment, dyschromatopsia evaluation, and optic nerve examination.

• Formal visual field test.

 CBC with differential and peripheral smear.

 Serum vitamin B1, B12, and folate levels.

 Consider a heavy metal (e.g., lead, thallium) screen.

 If disc is swollen, consider blood test for Leber hereditary optic neuropathy.

Treatment

 Thiamine 100 mg p.o. b.i.d.

 Folate 1.0 mg p.o. daily.

 Multivitamin tablet daily.

 Eliminate any causative agent (e.g., alcohol, medication).

 Coordinated care with an internist, including vitamin B12 1,000 mg intramuscularly every month for pernicious anemia.

Follow Up

Every month at first and then every 6 to 12 months.

COMPRESSIVE OPTIC NEUROPATHY

Symptoms

Slowly progressive visual loss, although occasionally acute or noticed acutely.

Signs

Critical. Central visual field defect, relative afferent pupillary defect.

Other. The optic nerve can be normal, pale, or, occasionally, swollen; proptosis; optociliary (collateral) shunt vessels. Collateral vessels occur only with intrinsic lesions of the nerve (never with extrinsic lesions).

Etiology

 Optic nerve glioma: Age usually <20 years, often associated with neurofibromatosis.

 Optic nerve meningioma: Usually adult women. Orbital imaging may show an optic nerve mass, diffuse optic nerve thickening, or a railroad-track sign (increased contrast of the periphery of the nerve).

 Any intraorbital or intracranial mass (e.g., hemangioma, schwannoma).

Workup

All patients with progressive visual loss and optic nerve dysfunction should have an MRI of the orbit and brain.

Treatment

1. Depends on the etiology.

2. Treatment for optic nerve glioma is controversial. These lesions are often monitored unless there is evidence of intracranial involvement, at which point surgical excision may be indicated. Most of these patients are young children, who are very susceptible to cognitive complications of radiotherapy. Chemotherapy may be considered if there is progressive visual loss.

3. For optic nerve sheath meningiomas, fractionated stereotactic radiotherapy treatment should be considered. Serial MRIs may be used to monitor tumor control.

LEBER HEREDITARY OPTIC NEUROPATHY

Symptoms

Painless progressive visual loss in one and then the other eye within days to months of each other. Visual loss is bilateral at onset in approximately 25% of cases.

Signs

Critical. Mild swelling of optic disc progressing over weeks to optic atrophy; small, telangiectatic blood vessels near the disc that do not leak on i.v. fluorescein angiography often present acutely; usually occurs in young men aged 15 to 30 years, and less commonly in women who are often older.

Other. Visual acuity 20/200 to counting fingers, cecocentral visual field defect.

Transmission

By mitochondrial DNA (transmitted by mothers to all offspring). However, 50% to 70% of sons and 10% to 15% of daughters manifest the disease. All daughters are carriers, and none of the sons can transmit the disease.

Workup

Genetic testing is available for the most frequent base-pair nucleotide substitutions at positions 11778, 3460, and 14484 in the mitochondrial gene for the NADH dehydrogenase protein.

Treatment

1. Idebenone is used in Canada and the United Kingdom but is not available in the United States. Studies thus far have shown variable results regarding its effectiveness. Phase 3 clinical trials of gene replacement are ongoing.

2. Tobacco (or exposure to smoke) and alcohol avoidance are recommended.

3. Genetic counseling should be offered.

4. Consider cardiology consult because of increased incidence of cardiac conduction defects.

DOMINANT OPTIC ATROPHY

Mild-to-moderate bilateral visual loss (20/40 to 20/200) usually presenting at approximately age 4 years old. Slow progression, temporal disc pallor, cecocentral visual field defect, tritanopic (blueyellow) color defect on Farnsworth-Munsell 100-hue test, strong family history, and no nystagmus. OPA1 and other mutations are responsible.

COMPLICATED HEREDITARY OPTIC ATROPHY

Bilateral optic atrophy with spinocerebellar degenerations (e.g., Friedreich, Marie, Behr), polyneuropathy (e.g., Charcot-Marie-Tooth), or inborn errors of metabolism.

RADIATION OPTIC NEUROPATHY

Delayed effect (usually 1 to 5 years) after radiation therapy to the eye, orbit, sinus, nasopharynx, and brain with acute or gradual stepwise visual loss that is commonly severe. Disc swelling, radiation retinopathy, or both may be present. Enhancement of optic nerve or chiasm on MRI.

10.21 Nystagmus

Nystagmus is divided into congenital and acquired forms.

Symptoms

Congenital and acquired nystagmus may be symptomatic with decreased visual acuity. The environment may be noted to oscillate horizontally, vertically, or torsionally in cases of acquired nystagmus, but only occasionally in congenital cases.

Signs

Critical. Repetitive, rhythmic oscillations of the eye horizontally, vertically, or torsionally.

 Jerk nystagmus: The eye repetitively slowly drifts in one direction (slow phase) and then rapidly returns to its original position (fast phase).

 Pendular nystagmus: Drift occurs in two phases of equal speed, giving a smooth back-and-forth slow movement of the eye.

CONGENITAL FORMS OF NYSTAGMUS

INFANTILE NYSTAGMUS

Onset by age 2 to 3 months with wide, swinging eye movements. At age 4 to 6 months, small pendular eye movements are added. At age 6 to 12 months, jerk nystagmus and a null point (a position of gaze where the nystagmus is minimized) develop. Compensatory head positioning may develop at any point up to 20 years of age. Infantile nystagmus is usually horizontal and uniplanar (same direction in all gazes) and typically dampens with convergence. May have a latent component (worsens when one eye is occluded).

Differential Diagnosis

Opsoclonus/saccadomania: Repetitive, conjugate, multidirectional rapid saccadic eye movements associated with cerebellar or brainstem disease, postviral encephalitis, visceral carcinoma, or neuroblastoma.

 Spasmus nutans: Head nodding and head turn with vertical, horizontal, or torsional nystagmus appearing between 6 months and 3 years of age and resolving between 2 and 8 years of age. Unilateral or bilateral (but asymmetric) rapid “shimmering nystagmus.” Spasmus nutans is a benign condition; however, gliomas of the anterior visual pathway may produce an identical clinical picture and need to be ruled out with MRI.

 Latent nystagmus (see below).

 Nystagmus blockage syndrome (see below).

Etiology

 Idiopathic.

 Albinism: Iris transillumination defects and foveal hypoplasia. See 13.8, Albinism.

 Aniridia: Bilateral, near-total congenital iris absence. See 8.12, Developmental Anterior Segment and Lens Anomalies/Dysgenesis.

 Leber congenital amaurosis: Markedly abnormal or flat electroretinogram (ERG).

 Others: Bilateral optic nerve hypoplasia, bilateral congenital cataracts, rod monochromatism, or optic nerve or macular disease.

Workup

1. History: Age of onset? Head nodding or head positioning? Known ocular or systemic abnormalities? Medications? Family history?

2. Complete ocular examination: Observe the head position and eye movements, perform iris transillumination, and carefully inspect the optic disc and macula.

3. Consider obtaining an eye movement recording if the diagnosis is uncertain.

4. If opsoclonus is present, obtain abdominal and chest imaging (e.g., ultrasound, CT, MRI) to rule out neuroblastoma and visceral carcinoma. Refer to primary medical doctor or pediatrician for additional workup (e.g., urinary vanillylmandelic acid) as appropriate.

5. In selected cases and in all cases of suspected spasmus nutans, obtain an MRI of the brain (axial, coronal, and parasagittal views) to rule out an anterior optic pathway lesion.

Treatment

1. Maximize vision by refraction.

2. Treat amblyopia if indicated.

3. If small face turn: Prescribe prism in glasses with base toward direction of face turn.

4. If large face turn: Consider muscle surgery.

LATENT NYSTAGMUS

Occurs when only one eye is viewing. Conjugate horizontal nystagmus with fast phase beating toward viewing eye.

Manifest latent nystagmus occurs in children with strabismus or decreased vision in one eye, in whom the nonfixating or poorly seeing eye behaves as an occluded eye.

NOTE: When testing visual acuity in one eye, fog (e.g., add plus lenses in front of) rather than occlude the opposite eye to minimize

induction of latent nystagmus.

Treatment

1. Maximize vision by refraction.

2. Treat amblyopia if indicated.

3. Consider muscle surgery if symptomatic strabismus or cosmetically significant head turn exists.

NYSTAGMUS BLOCKAGE SYNDROME

Any nystagmus that decreases when the fixating eye is in adduction and demonstrates an esotropia to dampen the nystagmus.

Treatment

For large face turn, consider muscle surgery.

ACQUIRED FORMS OF NYSTAGMUS

Etiology

 Visual loss (e.g., dense cataract, trauma, cone dystrophy): Usually monocular and vertical nystagmus (Heimann-Bielschowsky phenomenon).

 Toxic/metabolic: Alcohol intoxication, lithium, barbiturates, phenytoin, salicylates, benzodiazepines, phencyclidine, other anticonvulsants or sedatives, Wernicke encephalopathy, and thiamine deficiency.

 CNS disorders in brainstem or cerebellum: Hemorrhage, tumor, stroke, trauma, MS, and others.

 Peripheral vestibular disease: Typically worsened by head movements and positional, often accompanied by tinnitus, hearing loss. Fast phase is contralateral to pathology.

 Nonphysiologic: Voluntary, rapid, horizontal, small oscillatory movements of the eyes that usually cannot be sustained >30 seconds without fatigue.

Nystagmus With Localizing Neuroanatomic Significance

 Seesaw: One eye rises and intorts while the other descends and extorts. Lesion typically involves the parasellar region and chiasm. Typically pendular when chiasmal region involved and jerk if involving the midbrain. One proposal suggests a unilateral lesion of the interstitial nucleus of Cajal or its connections are responsible for this nystagmus subtype. May have a bitemporal hemianopsia resulting from chiasmal compression. May be congenital or associated with septo-optic dysplasia.

 Convergence retraction: Not a true nystagmus, but convergence movements accompanied by globe retraction when the patient attempts an upward saccade. May be associated with limitation of upward gaze, eyelid retraction, and bilateral mid-dilated pupils that react poorly to light but constrict better with convergence. Usually, a pineal region tumor or other dorsal midbrain abnormality is responsible. See 10.4, Adie (Tonic) Pupil.

 Downbeat: The fast phase of nystagmus is down and most prominent looking down and to the right and left. Most commonly, either a manifestation of cerebellar degeneration or associated with a lesion at the cervicomedullary junction (e.g., Arnold-Chiari malformation).

 Periodic alternating: In primary position, fast eye movements are in one direction for 60 to 90 seconds and then reverse direction for 60 to 90 seconds. The cycle repeats continuously. Patients may attempt to minimize nystagmus with periodic head turning. May be congenital. Acquired forms are most commonly the result of lesions of the cervicomedullary junction and posterior fossa. Other causes include MS, medication side effects, and rarely blindness.

 Gaze evoked: Absent in primary gaze, but appears as the eyes look to the side. Nystagmus increases when looking in the direction of fast phase. Slow frequency. Most commonly the result of alcohol intoxication, sedatives, and cerebellar or brainstem disease.

 Peripheral vestibular: Horizontal or horizontal-rotary nystagmus. May be accompanied by vertigo, tinnitus, or deafness. May be due to dysfunction of vestibular end organ (inner ear disease), eighth cranial nerve, or eighth cranial nerve nucleus in brainstem. Destructive lesions produce fast phases opposite to lesion. Irritative lesions (e.g., Meniere disease) produce fast phase in the same direction as the lesion. Vestibular nystagmus associated with interstitial keratitis is called Cogan syndrome.

 Spasmus nutans: See above.

 Others: Rebound nystagmus (cerebellar lesions), Bruns nystagmus (CPA), oculomasticatory myorhythmia (Whipple disease), oculopalatal myoclonus (prior brainstem stroke).

Differential Diagnosis

 Superior oblique myokymia: Small, unilateral, vertical, and torsional movements of one eye can be seen with a slit lamp or ophthalmoscope. Patients complain of unilateral oscillopsia. Symptoms and signs are more pronounced when the involved eye looks inferonasally. Usually benign, resolving spontaneously, but rarely due to a mass lesion so requires neuroimaging. Consider treating with carbamazepine.

 Opsoclonus/saccadomania: Rapid, chaotic conjugate saccades in multiple directions. Etiology in children is a paraneoplastic effect of neuroblastoma or encephalitis. In adults, in addition to paraneoplastic or infectious, it can be seen with drug intoxication or following infarction.

Workup

1. History: Nystagmus, strabismus, or amblyopia in infancy? Oscillopsia? Drug or alcohol use? Vertigo? Episodes of weakness, numbness, or decreased vision in the past? MS?

2. Family history: Nystagmus? Albinism? Eye disorder?

3. Complete ocular examination: Careful motility examination. Slit lamp or optic disc observation may be helpful in subtle cases. Iris transillumination should be performed to rule out albinism.

4. Consider an eye movement recording if diagnosis unclear.

5. Visual field examination, particularly with seesaw nystagmus.

6. Consider a drug/toxin/nutritional screen of the urine, serum, or both.

7. CT scan or MRI as needed with careful attention to appropriate area of interest.

NOTE: The cervicomedullary junction and cerebellum are best evaluated with sagittal MRI.

Treatment

1. The underlying etiology must be treated.

2. The nystagmus of periodic alternating nystagmus may respond to baclofen. Baclofen is not recommended for pediatric use. Other medications may be tried empirically for other nystagmus types.

3. Severe and disabling nystagmus can rarely be treated with retrobulbar injections of botulinum toxin.

Follow Up

Appropriate follow-up time is dictated by the condition responsible for the nystagmus.

10.22 Transient Visual Loss/Amaurosis Fugax

Symptoms

Monocular visual loss that usually lasts seconds to minutes, but may last up to 1 to 2 hours. Vision returns to normal.

Signs

Critical. May see an embolus within an arteriole or the ocular examination may be normal.

Other. Signs of ocular ischemic syndrome (see 11.11, Ocular Ischemic Syndrome/Carotid Occlusive Disease), an old branch retinal artery occlusion (sheathed arteriole), or neurologic signs and symptoms caused by cerebral ischemia (e.g., transient ischemic attacks [TIAs] with contralateral arm or leg weakness).

Differential Diagnosis of Transient Visual Loss

 Papilledema: Optic disc swelling is evident. Visual loss lasts seconds, is usually bilateral, and is often associated with postural change or Valsalva maneuver. See 10.15, Papilledema.

 GCA: ESR, CRP, and platelet count typically elevated. GCA symptoms often present. Transient visual loss may precede an ischemic optic neuropathy or central retinal artery occlusion. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

 Impending central retinal vein occlusion: Dilated, tortuous retinal veins are observed, though the fundus may be normal. See 11.8, Central Retinal Vein Occlusion.

 Migraine with aura: Visual loss/disturbance from 10 to 50 minutes, often with history of carsickness or migraine headache (personal or family). Vision loss is associated with “positive phenomena (e.g., scintillating scotoma).” See 10.27, Migraine.

 Acephalgic migraine: Visual aura without migraine headache. Usually a diagnosis of exclusion. Often have recurrent episodes. See 10.27, Migraine.

 Vertebrobasilar artery insufficiency: Transient, bilateral blurred vision. Associated with vertigo, dysarthria or dysphasia, perioral numbness, and hemiparesis or hemisensory loss. History of drop attacks. See 10.23, Vertebrobasilar Artery Insufficiency.

 Basilar artery migraine: Mimics vertebrobasilar artery insufficiency. Bilateral blurring or blindness, vertigo, gait disturbances, formed hallucinations, and dysarthria or dysphasia in a patient with migraine. See 10.23, Vertebrobasilar Artery Insufficiency and 10.27, Migraine.

 Vertebral artery dissection: After trauma or resulting from atherosclerotic disease.

 Intermittent intraocular hemorrhage (e.g., vitreous hemorrhage, uveitis-glaucoma-hyphema [UGH] syndrome).

 Others: Optic nerve head drusen, intermittent angle closure, intermittent pigment dispersion.

Etiology

1. Embolus from the carotid artery (most common), heart, or aorta.

2. Vascular insufficiency as a result of arteriosclerotic disease of vessels anywhere along the path from the aorta to the globe causing hypoperfusion often precipitated by a postural change or cardiac arrhythmia.

3. Hypercoagulable/hyperviscosity state.

4. Rarely, an intraorbital mass may compress the optic nerve or a nourishing vessel in certain gaze positions, causing gaze-evoked transient visual loss.

5. Vasospasm.

Workup

1. Amaurosis fugax is considered by the American Heart Association to be a form of TIA. Current guidelines recommend MRI with diffusion weighted imaging, urgent carotid and cardiac studies, and neurology consultation. If patient is seen within days of the event, emergent referral to a stroke center or emergency room is required.

2. Immediate ESR, CRP, and platelet count when GCA is suspected.

3. History: Monocular visual loss or homonymous hemianopsia (verified by covering each eye)? Duration of visual loss? Previous episodes of transient visual loss or TIA? Cardiovascular disease risk factors? Oral contraceptive use? Smoker? Vascular surgeries?

4. Ocular examination, including a confrontation visual field examination and a dilated retinal evaluation. Look for an embolus or signs of other aforementioned disorders.

5. Medical examination: Cardiac and carotid auscultation.

6. Noninvasive carotid artery evaluation (e.g., duplex Doppler US). Consider orbital color Doppler US, if available, which may reveal a retrolaminar central retinal artery stenosis or embolus proximal to the lamina cribrosa. MRA or CTA may also be considered, but cannot evaluate flow like a duplex Doppler US.

7. CBC with differential, fasting blood sugar, hemoglobin A1c, and lipid profile (to rule out polycythemia, thrombocytosis, diabetes, and hyperlipidemia).

8. Cardiac evaluation including an echocardiogram.

Treatment

1. Carotid disease.

 Consider aspirin 81 mg or 325 mg p.o. daily.

 Consult vascular surgery in select patients if a surgically accessible, high-grade carotid stenosis is present for consideration of carotid endarterectomy or endovascular stent.

 Control hypertension, diabetes, and dyslipidemia (follow up with a medical internist).

 Lifestyle modification (e.g., smoking cessation).

2. Cardiac disease.

 Consider aspirin 325 mg p.o. daily.

 In presence of a thrombus, coordinate care with internal medicine and/or cardiology with likely hospitalization and anticoagulation (e.g., heparin therapy).

 Consider referral to cardiac surgery as needed.

 Control arteriosclerotic risk factors (follow up with medical internist).

3. If carotid and cardiac diseases are ruled out, a vasospastic etiology can be considered (extremely rare). Treatment with a calcium channel blocker may be beneficial.

10.23 Vertebrobasilar Artery Insufficiency

Symptoms

Transient, bilateral blurred vision, sometimes accompanied by flashing lights. Ataxia, vertigo, dysarthria or dysphagia, perioral numbness, and hemiparesis or hemisensory loss may accompany the visual symptoms. History of drop attacks (the patient suddenly falls to the ground without warning or loss of consciousness). Recurrent attacks are common.

Signs

May have a hemianopsia, ocular motility deficits, or nystagmus, but often presents with a normal ocular examination.

Differential Diagnosis of Transient Visual Loss

See Differential Diagnosis in 10.22, Transient Visual Loss/Amaurosis Fugax.

Workup

1. History: Associated symptoms of vertebrobasilar insufficiency? History of carsickness or migraine? Symptoms of GCA? Smoker?

2. Dilated fundus examination to rule out retinal emboli or papilledema.

3. Blood pressure in each arm to rule out subclavian steal syndrome.

4. Cardiac auscultation to rule out arrhythmia.

5. CBC to rule out anemia and polycythemia, with immediate ESR, CRP, and platelet count if GCA is considered.

6. Electrocardiography, echocardiography, and cardiac monitoring to rule out dysrhythmia.

7. Consider noninvasive carotid flow studies.

8. MRA, CTA, or transcranial/vertebral artery Doppler US to evaluate posterior cerebral blood flow.

Treatment

1. Coordinated care with internal medicine or neurology with initiation of antiplatelet and/or anticoagulation therapy.

2. Consult internist for hypertension, diabetes, and dyslipidemia control if present.

3. Lifestyle modification (e.g., smoking cessation).

4. Correct any underlying problem revealed by the workup.

Follow Up

If outpatient, 1 week to check test results. Thereafter follow-up time is dictated by identified underlying causative condition(s).

10.24 Cortical Blindness

Symptoms

Bilateral complete or severe loss of vision. Patients may deny they are blind (Anton syndrome) or may perceive moving targets but not stationary ones (Riddoch phenomenon).

Signs

Critical. Markedly decreased vision and visual field in both eyes (sometimes no light perception) with normal pupillary responses.

Etiology

• Most common: Bilateral occipital lobe infarctions.

 Other: Toxic, postpartum (amniotic embolus), posterior reversible encephalopathy syndromes.

 Rare: Neoplasm (e.g., metastasis, meningioma), incontinentia pigmenti.

Workup

1. Test vision at distance (patients with bilateral occipital lobe infarcts may appear completely blind, but actually have a very small residual visual field). Patients will do much worse with near-card testing than distance if only a small island remains.

2. Complete ocular and neurologic examinations.

3. MRI of the brain.

4. Rule out nonphysiologic visual loss by appropriate testing (see 10.25, Nonphysiologic Visual Loss).

5. Cardiac auscultation and electrocardiography to rule out arrhythmia.

6. Check blood pressure.

7. Consult neurologist or internist for evaluation of stroke risk factors.

Treatment

1. Patients diagnosed with a stroke within 72 hours of symptom onset are admitted to the hospital for neurologic evaluation and observation.

2. If possible, treat the underlying condition.

3. Arrange for services to help the patient optimize function at home and their surrounding environment.

Follow Up

As per the internist or neurologist.

10.25 Nonphysiologic Visual Loss

Symptoms

Loss of vision. Malingerers frequently are involved with an insurance claim or are looking for other forms of financial gain. Those with psychogenic visual loss truly believe they have lost vision.

Signs

Critical. No ocular or neuro-ophthalmic findings that would account for the decreased vision. Normal pupillary light reaction.

Differential Diagnosis

 Amblyopia: Poor vision in one eye since childhood, rarely both eyes. Patient often has strabismus or anisometropia. Vision is no worse than counting fingers, especially in the temporal periphery of an amblyopic eye. See 8.7, Amblyopia.

 Cortical blindness: Bilateral complete or severe visual loss with normal pupils. See 10.24, Cortical Blindness.

 Retrobulbar optic neuritis: Afferent pupillary defect is present. See 10.14, Optic Neuritis.

 Cone-rod or cone dystrophy: Positive family history, decreased color vision, abnormal results on dark adaptation studies and multifocal ERG. See 11.29, Cone Dystrophies.

 Chiasmal tumor: Visual loss may precede optic atrophy. Pupils usually react sluggishly to light, and an afferent pupillary defect is often present. Visual fields are abnormal.

• Cancer-associated retinopathy or melanoma-associated retinopathy: Immune-mediated attack of photoreceptors. Fundus often appears normal. Abnormal macular ocular coherence tomography (OCT) and ERG.

Workup

The following tests may be used to diagnose a patient with nonphysiologic visual loss (to prove the malingerer or hysteric can see better than he or she admits).

Two codes are used in the list below:

1. U: This test may be used in patients feigning unilateral decreased vision.

2. B: This test may be used in patients feigning bilateral vision loss.

Patients Claiming No Light Perception

Determine whether each pupil reacts to light (U or B): The presence of a normal pupillary reaction suggests that anterior visual pathways are intact but do not prove nonorganic visual loss (pupillary response is maintained in cortical blindness). When only one eye has no light perception, its pupil will not react to light. The pupil should not appear dilated unless the patient has bilateral lack of light perception or third cranial nerve involvement. If a patient responds aversely to light stimulus, one can establish some level of afferent input.

Patients Claiming Counting Fingers to No Light Perception

1. Test for an afferent pupillary defect (U): A defect should be present in unilateral or asymmetric visual loss to this degree. If not, the likelihood of nonphysiologic visual loss substantially increases.

2. Mirror test (U or B): If the patient claims unilateral visual loss, cover the better-seeing eye; with bilateral complaints leave both eyes uncovered. Ask the patient to hold eyes still and slowly tilt a large mirror from side to side in front of the eyes, holding it beyond the patient’s range of hand motion vision. If the eyes move, the patient can see better than hand motion.

3. Optokinetic test (U or B): Patch the uninvolved eye when unilateral visual loss is claimed. Ask the patient to look straight ahead and slowly move an optokinetic tape in front of the eyes (or rotate an optokinetic drum). If nystagmus can be elicited, vision is better than counting fingers. Note: Some patients can purposely minimize or suppress an ocular response by diverting focus past the drum.

4. Base-out prism test (U): Place a 4 to 6 diopter prism base-out in front of the supposedly poorly seeing eye. If there is an inward shift of the eye (or a convergent movement of the opposite eye), this indicates vision better than what the patient claims.

5. Vertical prism dissociation test (U): Hold a 4 diopter prism basedown or base-up in front of the supposedly good-seeing eye. If the patient sees two separate images (one above another), this suggests nearly symmetric vision in both eyes.

6. Worth four-dot test (U): Place red-green glasses on patient and quickly turn on four-dot pattern and ask the patient how many dots are seen. If the patient closes one eye (cheating), try reversing the glasses and repeating test. If all four dots are seen, vision is better than hand motion.

Patients Claiming 20/40 to 20/400 Vision

1. Visual acuity testing (U or B): Start with the 20/10 line and ask the patient to read it. When the patient claims inability to read it, look amazed and then offer reassurance. Inform the patient you will go to a larger line and show the 20/15 line. Again, force the patient to work to see this line. Slowly proceed up the chart, asking the patient to read each line as you pass it (including the three or four 20/20 lines). It may help to express disbelief that the patient cannot read such large letters. By the time the 20/30 or 20/40 lines are reached, the patient may in fact read one or two letters correctly. The visual acuity can then be recorded.

2. Fog test (U): Dial the patient’s refractive correction into the phoropter. Add +4.00 to the normally seeing eye. Put the patient in the phoropter with both eyes open. Tell the patient to use both eyes to read each line, starting at the 20/15 line and working up the chart slowly, as described previously. Record visual acuity with both eyes open (this should be visual acuity of supposedly poorly seeing eye) and document the vision of the “good eye” through the +4.00 lens to prove the vision obtained was from the "bad eye.”

3. Retest visual acuity in the supposedly poorly seeing eye at 10 feet from the chart (U or B): Vision should be twice as good (e.g., a patient with 20/100 vision at 20 feet should read 20/50 at 10 feet). If it is better than expected, record the better vision. If the vision is worse, this suggests nonphysiologic visual loss.

4. Test near vision (U or B): If normal near vision can be documented, nonphysiologic visual loss or myopia has been documented.

5. Visual field testing (U or B): Goldmann visual field tests often reveal inconsistent responses and nonphysiologic field losses.

Children

1. Tell the child that there is an eye abnormality, but the strong drops about to be administered will cure it. Dilate the child's eyes (e.g., tropicamide 1%) and retest the visual acuity after approximately 30 minutes. Children, as well as adults, sometimes need a "way out.” Provide a reward (bribe them).

2. Test as described previously.

Treatment

1. Patients are usually told that no ocular abnormality can be found that accounts for their decreased vision. In general, they should not be told that they are faking the visual loss.

2. Hysterical patients often benefit from being told that their vision can be expected to return to normal by their next visit. Psychiatric referral is sometimes indicated.

Follow Up

1. If nonphysiologic visual loss is highly suspected but cannot be proven, reexamine in 1 to 2 weeks.

2. Consider obtaining an ERG, visual-evoked response, macular OCT, or an MRI of the brain.

3. If functional visual loss can be documented, have the patient return as needed.

NOTE: Always try to determine the patient’s actual visual acuity if possible and carefully document your findings.

10.26 Headache

Most headaches are not dangerous or ominous; however, they can be symptoms of a life-threatening or vision-threatening problem. Accompanying signs and symptoms that may indicate a lifethreatening or vision-threatening headache and some of the specific signs and symptoms of various headaches are listed below.

Warning Symptoms and Signs of a Serious Disorder

 Scalp tenderness, weight loss, pain with chewing, muscle pains, or malaise in patients at least 55 years of age (GCA).

 Optic nerve swelling.

 Fever.

 Altered mentation or behavior.

 Stiff neck.

 Decreased vision.

 Neurologic signs.

 Subhyaloid (preretinal) hemorrhages on fundus examination.

Suggestive Symptoms and Signs

 Onset in a previously headache-free individual.

 A different, more severe headache than the usual headache.

 A headache that is always in the same location.

 A headache that awakens the person from sleep.

 A headache that does not respond to pain medications that previously relieved it.

 Nausea and vomiting, particularly projectile vomiting.

 A headache followed by migraine-like visual symptoms (abnormal time course of events).

Etiology

Life or Vision Threatening

 GCA: Age >55 years. May have high ESR, CRP, and platelet count. See 10.17, Arteritic Ischemic Optic Neuropathy (Giant Cell Arteritis).

 Acute angle closure glaucoma: Decreased vision, painful eye, fixed mid-dilated pupil, and high intraocular pressure. See 9.4, Acute Angle Closure Glaucoma.

 Ocular ischemic syndrome: Periorbital eye pain. See 11.11, Ocular Ischemic Syndrome/Carotid Occlusive Disease.

 Malignant hypertension: Marked increase of blood pressure, often accompanied by retinal cotton-wool spots, hemorrhages, and, when severe, optic nerve swelling. See 11.10, Hypertensive Retinopathy.

 Increased intracranial pressure: May have papilledema and/or a sixth cranial nerve palsy. Headaches usually worse in the morning and with Valsalva. See 10.15, Papilledema.

 Infectious CNS disorder (meningitis or brain abscess): Fever, stiff neck, mental status changes, photophobia, and neurologic signs.

 Structural abnormality of the brain (e.g., tumor, aneurysm, arteriovenous malformation): Mental status change, signs of increased intracranial pressure, or neurologic signs during, and often after, the headache episode.

 Subarachnoid hemorrhage: Extremely severe headache, stiff neck, mental status change; rarely, subhyaloid hemorrhages seen on fundus examination, usually from a ruptured aneurysm.

 Epidural or subdural hematoma: Follows head trauma; altered level of consciousness; may produce anisocoria or cranial neuropathy.

Others

 Migraine (see 10.27, Migraine).

 Cluster headache (see 10.28, Cluster Headache).

 Tension headache.

 Varicella zoster virus: Headache or pain may precede the herpetic vesicles (see 4.16, Herpes Zoster Ophthalmicus/Varicella Zoster Virus).

 Sinus disease.

NOTE: A “sinus” headache may be a serious headache in diabetic patients and immunocompromised hosts given the possibility of zygomycosis infection (e.g., mucormycosis).

 Tolosa-Hunt syndrome.

 Cervical spine disease.

 Temporomandibular joint syndrome.

 Dental disease.

 Trigeminal neuralgia (tic douloureux).

 Anterior uveitis: See 12.1, Anterior Uveitis (Iritis/Iridocyclitis).

 Status post LP.

 Paget disease.

 Depression/psychogenic.

 Convergence insufficiency: See 13.4, Convergence Insufficiency.

 Accommodative spasm: See 13.5, Accommodative Spasm.

Workup

1. History: Location, intensity, frequency, possible precipitating factors, and timing? Determine age of onset, exacerbating/relieving factors, and whether there are any associated signs or symptoms. Specifically ask about concerning symptoms and signs listed above. Also ask about trauma, medications including birth-control pills, personal or family history of migraine, and motion sickness or cyclic vomiting as a child?

2. Complete ocular examination, including pupillary, motility, and visual field evaluation; intraocular pressure measurement, optic disc and venous pulsation assessment, and a dilated retinal examination. Manifest and cycloplegic refractions may be helpful.

NOTE: The presence of SVPs classically indicates a normal intracranial pressure. However, about 20% of normal individuals do not have SVPs and thus their absence has little significance.

3. Neurologic examination (check neck flexibility and other meningeal signs).

4. Palpate the temporal arteries for tenderness, swelling, and hardness. Ask specifically about fever, jaw claudication, scalp tenderness, temporal headaches, and unexpected weight loss. Immediate ESR, CRP, and platelet count when GCA is suspected (see 10.17, Arteritic Ischemic Optic Neuropathy [Giant Cell Arteritis]).

5. Temperature and blood pressure.

6. Refer the patient to a neurologist, neurosurgeon, otolaryngologist, or internist, as indicated.

Treatment/Follow Up

See individual sections.

10.27 Migraine

Symptoms

Typically unilateral (although it may occur behind both eyes or across the entire front of the head), throbbing or boring head pain accompanied at times by nausea, vomiting, mood changes, fatigue, photophobia, or phonophobia. An aura with visual disturbances, including flashing (zig-zagging or kaleidoscopic) lights, blurred vision, or a visual field defect lasting 15 to 50 minutes, may precede the migraine. May experience temporary or rarely permanent neurologic deficits, such as paralysis, numbness, tingling, or others. A family history is common. Motion sickness or cyclic vomiting as a child is also common. Migraine in children may be seen as recurrent abdominal pain and malaise. Of these patients, 60% to 70% are girls.

Migraine prevalence is highest between ages 30 and 39 years and progressively declines after age 40. Migraine attacks may be shorter and less typical with advancing age. New-onset migraines are uncommon after the age of 50, and these patients should be worked up for secondary causes such as vascular lesions, intracranial hemorrhages, infarcts, masses, or GCA.

NOTE: Most unilateral migraine headaches at some point change sides of the head. Headaches always on the same side of the head may have another cause of headache (e.g., intracranial structural lesions).

Determine if headache precedes visual symptoms, which is more common with arteriovenous malformations, mass lesions with cerebral edema, or seizure foci.

Signs

Usually none. Complicated migraines may have a permanent neurologic or ocular deficit (see the following discussion).

Differential Diagnosis

See 10.26, Headache.

International Classification

Consult International Classification of Headache Disorders, 3rd edition, for further information.

 Migraine without aura (common migraine; 80%): Lasts 4 to 72 hours. Unilateral location, pulsating quality, moderate-to-severe pain, and/or aggravation by physical activity. Nausea, vomiting, photophobia, and/or phonophobia are the characteristics.

 Migraine with typical aura (classic migraine; 10%): Fully reversible binocular visual symptoms that may be perceived as monocular (e.g., flickering lights, spots, lines, loss of vision) or fully reversible unilateral sensory symptoms (e.g., numbness, “pins and needles”). Symptoms gradually develop over 5 minutes and last between 5 and 60 minutes. No motor symptoms are present.

 Typical aura without headache (acephalgic migraine): Visual or sensory symptoms as above without accompanying or subsequent headache.

 Familial hemiplegic and sporadic hemiplegic migraine: Migraine with aura as above with accompanying motor weakness with (familial) or without (sporadic) history in a first-degree or second- degree relative. Sporadic cases always require neuroimaging.

 Retinal migraine: Fully reversible monocular visual phenomenon (e.g., scintillations, scotoma, blindness) accompanied by headache fulfilling migraine definition. Appropriate investigations to exclude other causes of transient monocular blindness should be completed. Existence of retinal migraine is controversial.

 Basilar-type migraine: Aura symptoms mimic vertebrobasilar artery insufficiency in a patient with migraine. See 10.23,

Vertebrobasilar Artery Insufficiency.

• Ophthalmoplegic migraine: Onset in childhood. Headache with third cranial nerve palsy. Likely an inflammation, rather than migraine, as MRI shows enhancement of CNIII.

Associations or Precipitating Factors

Birth control or other hormonal pills, puberty, pregnancy, menopause, foods containing tyramine or phenylalanine (e.g., aged cheeses, wines, chocolate, cashew nuts), nitrates or nitrites, monosodium glutamate, alcohol, aspartame, caffeine withdrawal, weather changes, fatigue, emotional stress, or bright lights.

Workup

See 10.26, Headache, for a general headache workup.

1. History: May establish the diagnosis.

2. Ocular and neurologic examinations, including refraction.

3. CT scan or MRI of the head is indicated for:

 Atypical migraines: New onset migraines in patients over 50 years old. Migraines that are always on the same side of the head or those with an unusual sequence such as visual disturbances persisting into or occurring after the headache phase.

 Complicated migraines.

4. Consider checking for uncontrolled blood pressure or low blood sugar (hypoglycemic headaches are almost always precipitated by stress or fatigue).

Treatment

1. Avoid agents that precipitate the headaches (e.g., stop using birth

control pills; avoid alcohol and any foods that may precipitate attacks; reduce stress).

2. Referral to neurologist or internist for pharmacologic management.

a. Abortive therapy: Medications used at onset of the headache. Best for infrequent headaches.

i. Initial therapy: Aspirin or nonsteroidal anti-inflammatory agents.

ii. More potent therapy (when initial therapy fails): Ergotamines or selective serotonin receptor agonists (triptans). More recently FDA-approved medications include rimegepant and ubrogepant (calcitonin gene-related peptide [CGRP] antagonists) and lasmiditan (selective serotonin agonist without vasoconstrictor activity). Check contraindications for specific agents.

NOTE: Opioid drugs should be avoided.

b. Prophylactic therapy: Used in patients with frequent or severe headache attacks (e.g., two or more headaches per month) or those with neurologic changes. Includes beta-blockers, calcium channel blockers, antidepressants, anti-CGRP monoclonal antibodies, and others.

c. Antinausea medication as needed during an acute episode.

Follow Up

Reevaluate in 4 to 6 weeks to assess the efficacy of the therapy.

10.28 Cluster Headache

Symptoms

Typically unilateral, very painful (stabbing), periorbital, frontal, or temporal headache associated with ipsilateral tearing, rhinorrhea, sweating, nasal stuffiness, and/or a droopy eyelid. Usually lasts for minutes to hours. Typically recurs once or twice daily for several weeks, followed by a headache-free interval of months to years. The cycle may repeat. Predominantly affects men. Headache awakens patients, whereas migraine does not.

Signs

Ipsilateral conjunctival injection, facial flush, or Horner syndrome (third-order neuron etiology) may be present. Ptosis may become permanent.

Precipitating Factors

Alcohol, nitroglycerin.

Differential Diagnosis

 Migraine headache: Typically unilateral headache possibly associated with visual and neurologic symptoms. See 10.27, Migraine.

 Chronic paroxysmal hemicrania: Several attacks of pain and cranial autonomic features (e.g., tearing, ocular injection, rhinorrhea) occurring throughout the day and typically lasting no more than 30 minutes. Patients have dramatic improvement with indomethacin.

 Idiopathic stabbing “ice pick” headache: Episodic, momentary sharp pain, or stabbing sensations lasting less than a second that may occur in patients with preexisting migraine or cluster headache history. Lack the classic autonomic features of cluster headaches.

 Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing: A trigeminal autonomic cephalgia that presents with burning or stabbing pain felt unilaterally, primarily around the eye. Pain lasts for seconds to minutes and may occur >100 times per day. May have tearing, ptosis, eyelid edema, and conjunctival injection. Episodes last days to months and often recur. Distinguish from cluster headaches due to shorter duration, increased frequency, and more prominent autonomic findings.

• Others: See 10.26, Headache.

Workup

1. History and complete ocular examination.

2. Neurologic examination, particularly a cranial nerve evaluation.

3. If Horner syndrome present, consider imaging studies to eliminate other causes. See 10.2, Horner Syndrome.

4. Obtain an MRI of the brain when the history is atypical or a neurologic abnormality is present.

Treatment

1. Avoid alcoholic beverages or cigarette smoking during a cluster cycle.

2. Refer patient to neurologist to help coordinate pharmacologic therapy.

3. Abortive therapy for acute attack:

 Oxygen, 5 to 8 L/min by face mask for 10 minutes at onset of attack. Relieves pain in 70% of adults.

 Sumatriptan used subcutaneously (6 mg) or intranasally (20 mg) is often effective in relieving pain.

 Zolmitriptan 5 or 10 mg intranasally also appears to be effective.

 Less frequent medications used include ergotamine inhalation, dihydroergotamine, or corticosteroids.

4. When headaches are moderate to severe and are unrelieved by nonprescription medication, one of the following drugs may be an effective prophylactic agent during cluster periods:

 Calcium channel blockers (e.g., verapamil 360 to 480 mg/day p.o. in divided doses).

 Lithium 600 to 900 mg p.o. daily is administered in conjunction with the patient’s medical doctor. Baseline renal (blood urea nitrogen, creatinine, urine electrolytes) and thyroid function tests (triiodothyronine, thyroxine, TSH) are obtained. Lithium intoxication may occur in patients using indomethacin, tetracycline, or methyldopa.

 Ergotamine 1 to 2 mg p.o. daily.

 Methysergide 2 mg p.o. b.i.d. with meals. Do not use for longer than 3 to 4 months because of the significant risk of retroperitoneal fibrosis. Methysergide is not recommended in patients with coronary artery or peripheral vascular disease, thrombophlebitis, hypertension, pregnancy, or hepatic or renal disease.

 Oral steroids (e.g., prednisone 40 to 80 mg p.o. for 1 week, tapering rapidly over an additional week if possible) and an antiulcer agent (e.g., omeprazole 20 mg p.o. daily or ranitidine 150 mg p.o. b.i.d.).

 Galcanezumab is a monoclonal antibody to CGRP, which received FDA approval for prevention of cluster headaches and migraines.

5. If necessary, an acute, severe attack can be treated with i.v. diazepam.

Follow Up

1. Patients started on systemic steroids are seen within a few days and then every several weeks to evaluate the effects of treatment and monitor intraocular pressure.

2. Patients taking methysergide or lithium are reevaluated in 7 to 10 days. Plasma lithium levels are monitored in patients taking this agent.