Double vision, eyelid droop, pain in the distribution of the V-1 and V-2 branches of the ipsilateral trigeminal nerve, or numbness.

• 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.
• 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.

NOTE:

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

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–Barré syndrome (Miller–Fisher variant), intracranial sarcoidosis, others.

• 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:
  1. Direct fistula.
  2. Indirect with branches solely from internal carotid artery (rare).
  3. Indirect with branches solely from external carotid artery.
  4. 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).
• 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 pre-existing 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.

NOTE:

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

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.
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.

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.

Treatment and Follow-Up

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.
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.

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.

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.