Neuro-Ophthalmology & Neuro-Otology
Toxic and nutritional deficiency optic neuropathies
Nov. 20, 2023
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Diplopia is a common complaint in patients with diseases of the central nervous system and is usually helpful for localization of pathology. A minority of patients complaining of diplopia have signs that indicate involvement of multiple ocular motor nerve palsies. These must be differentiated from single ocular motor nerve palsies, neuromuscular junction, myopathic disorders, and supranuclear disorders. Their recognition is important because the differential diagnosis includes a higher frequency of mass and inflammatory lesions in the vicinity of the orbital apex or cavernous sinus, which may require urgent therapy.
• Ophthalmoplegia can be caused by multiple ocular motor nerve palsies (combined third, fourth, and/or sixth nerve palsies), single ocular motor nerve palsies, supranuclear gaze disorders, neuromuscular junction disorders, and myopathy.
• Cavernous sinus lesions can affect combinations of third (oculomotor), fourth (trochlear), V1 (ophthalmic), V2 (maxillary), sixth (abducens), and postganglionic sympathetic nerve fibers and can cause orbital congestion.
• Orbital apex lesions can affect combinations of second (optic nerve), third (oculomotor), fourth (trochlear), V1 (ophthalmic), sixth (abducens), and postganglionic sympathetic nerve fibers and can cause orbital congestion.
By definition, multiple ocular motor palsies are present when eye muscle weakness, with or without anisocoria and ptosis, indicates dysfunction of more than one ocular motor nerve. These may be unilateral or bilateral. They should be distinguished from supranuclear disorders of ocular motility, which often show dissociations between different types of eye movements (ie, limited saccades but full vestibulo-ocular range of eye movements). In contrast, the ocular defects in multiple ocular motor palsies always affect all types of eye movements. Non-selective palsies are also found with diffuse disorders of the muscle, neuromuscular junction, or nerve (eg, Graves ophthalmopathy, myasthenia gravis, and Miller-Fisher syndrome) and may be difficult to distinguish from multiple ocular motor palsies.
“Ocular motor nerves” refers to cranial nerves 3, 4, and 6. “Oculomotor nerve” refers solely to cranial nerve 3.
The cardinal symptom is binocular diplopia (that is, double vision only when both eyes are open). When multiple nerves are affected, this is usually a combination of horizontal and vertical deviations; therefore, the images are oblique to each other. Associated torsional deviations will often cause one image to be tilted with respect to the other. Diplopia is almost always noticed suddenly, either because the disorder is truly sudden in onset or because the patient only becomes aware of a chronically progressive problem. More helpful is the description of whether the diplopia has been static or progressive following its discovery, in terms of either the distance between the images at a fixed distance in a specific direction of gaze or the range of gaze in which diplopia is present.
Eye movement testing will reveal limited range of eye movements when palsies are severe. More subtle effects require assessment of ocular alignment, with either subjective or objective tests. Subjective tests include the red glass, Maddox-rod, and Hess screen tests. Objective tests include the cover, alternate cover, and prism cover tests. Familiarity with the patterns produced by single nerve palsies is critical to discovering multiple nerve involvement. Combinations of third and sixth, third and fourth, and all three ocular motor nerves (third, fourth, and sixth) are most likely. Combined fourth and sixth nerve palsies extremely rare.
The combination of third and sixth nerve palsy is not difficult to perceive. In addition to the third nerve palsy characteristics of ptosis, mydriasis, and impaired supraduction, infraduction, and adduction, there is a failure of abduction of the same eye.
The addition of a fourth nerve palsy to a third palsy is more difficult. There are two main signs. One is a defect in the depression of the eye that varies between adduction and abduction. If there is more depression in adduction, the fourth nerve is probably working. However, this can be subtle because the sixth nerve only generates 15% of the depression in adduction normally. More obvious is a deficit in the fourth nerve’s primary function, intorsion of the eye. This is best shown by abducting the eye maximally, then having the patient look down. If the superior oblique muscle is working, the eye will intort because this action is not opposed by the normal extorsion of the inferior rectus during depression, given the third nerve palsy. This intorsion is seen as a downward twist of the scleral vessels nasal to the cornea. If intorsion is not seen, an additional fourth nerve palsy is confirmed.
Ptosis is common when the third nerve is a component of multiple nerve palsies. Pupillary signs are also important. Unilateral mydriasis is useful in confirming a component of third nerve palsy and excluding myopathic disease (179). Horner syndrome with miosis and mild ptosis indicates the involvement of sympathetic fibers. Involvement of both third nerve and sympathetic pupillary pathways can produce alternating anisocoria in which the affected pupil is the smaller one in the dark due to impaired dilation and the larger one in the light due to impaired constriction.
Examination of facial sensation is critical as V1 and V2 numbness indicates a cavernous sinus lesion in the setting of multiple ocular motor palsies. V1 numbness alone can occur in an orbital apex lesion or an incomplete cavernous sinus lesion.
Ipsilateral headache and periorbital pain are other common symptoms. There are multiple sources of pain, including involvement of the trigeminal nerve (V1), increased intracranial or cavernous sinus pressure, or inflammation in the retroorbital or subarachnoid space.
Blurred vision may be due to a mild diplopia if it goes away with covering either eye, but if not, it could indicate involvement of the optic nerve, with lesions of orbital apex or optic chiasm, with lesions of the cavernous sinus.
Proptosis can occur to a mild degree with ocular motor nerve palsies alone; however, more severe exophthalmos points to an intraorbital mass or venous congestion from cavernous sinus or orbital apex pathology.
These depend on the etiology of the combined cranial nerve palsy.
The natural history of intracarotid aneurysms varies, with either gradual improvement or worsening over months to years (107). Rarely, rupture occurs, causing high-flow carotid cavernous fistulae (08). Subarachnoid hemorrhage is more likely with aneurysms that arise from the anterior genu of the carotid siphon or erode the sella turcica (106). Most patients do not die from these (111; 106).
In high-flow carotid fistulae, vision may be lost immediately due to a secondary acute glaucoma (58). Intracranial hemorrhage or epistaxis occurs in 10%, causing death in 30% (58). Hemorrhage tends to occur within the first week but may be delayed up to 3 weeks. A vascular steal may cause cerebral infarction (75). In low-flow cavernous fistulae, bleeding and death are unlikely, but 30% have visual loss from a secondary glaucoma (131; 58), and some develop central retinal vein occlusion (92).
For septic thrombosis, death is nearly universal and rapid in untreated cases. In many the disorder quickly progresses over a few days to bilateral ophthalmoplegia (33) and if untreated to meningitis, sepsis or multiple brain abscesses (180).
In Tolosa-Hunt syndrome, most patients never develop other neurologic or systemic defects (90), but there are rare reports of pituitary hypofunction, diabetes insipidus (67), and thyroiditis (165).
For zoster, there is usually significant recovery over 2 months (19), though complete resolution may take up to 18 months.
Combined cranial nerve palsies secondary to the SARS-CoV-2 virus typically resolve over a period of weeks to months. However, in rare cases, permanent cranial nerve palsies exist (34).
A 56-year-old woman had pain for several weeks that was followed by oblique diplopia, which became worse looking down. When seen 3 weeks after onset of diplopia, the pain was improving. She had a right hypertropia worse in left gaze and with right head tilt, indicating a right fourth nerve palsy. Because of the pain, unusual for fourth nerve palsies, she had imaging with MR sella and MR angiogram, which were normal. One month later she was seen elsewhere with a right partial third nerve palsy in addition to the fourth palsy. Edrophonium test was negative. She returned another month later with red eye, mild proptosis, and a partial third and sixth palsy on the right. She also complained of dysesthesia over the right V1 distribution, mainly over the vertex. Carotid cavernous sinus fistula was suspected and confirmed with repeat MR angiography. T2-weighted MRI showed an enlarged superior ophthalmic vein and the engorged muscles of the orbit. Lateral view of her formal angiogram shows the blood in the cavernous sinus and superior ophthalmic vein. She was treated with neuroradiologic particle embolization, with rapid improvement in her signs. She did have mild inferior arcuate visual field loss from glaucoma in that eye that resolved several months later. After 6 months, her only signs were a mild right sixth nerve palsy and Horner syndrome on the right.
The cavernous sinus is the main site of pathology of multiple ocular motor palsies until proven otherwise; however, an orbital mass, inflammatory process, or, rarely, a brainstem syndrome also can present with multiple ocular motor palsies. Ischemia and idiopathic lesions are less common and compressive lesions more common than with isolated single ocular motor nerve palsies. Combinations of third, fourth, and sixth nerves are due to tumors in 20% to 40% (63; 134; 83). Superior cerebellar artery aneurysms can cause combined third and fourth nerve palsies.
Brainstem syndromes. These are not common, though hemorrhage, infarction, and tumors have been reported as causes of combined ocular motor nerves palsies (24; Rush and Young 1981; 82; 137). These may damage the nuclei or fascicles of the nerves. There may also be supranuclear signs. Other neurologic signs include ipsilateral limb ataxia, contralateral involuntary movements, contralateral hemiparesis, and ipsilateral facial nerve palsy.
Cavernous sinus syndromes. Lesions of the cavernous sinus can affect any or all ocular motor nerves, the ophthalmic (V1) nerve, the maxillary (V2) nerve, and the sympathetic fibers to the eye. Venous hypertension in the cavernous sinus can cause orbital congestion. There have been attempts to sub-localize cavernous sinus syndromes (anterior, middle, posterior, middle, complete) based on involvement of trigeminal and optic nerves for the purposes of differential diagnosis. However, the sensitivity and specificity are insufficient to guide clinical practice (11). Seventy percent of cavernous sinus lesions are tumors, 35% primary and 35% metastatic. Aneurysms account for another 20% (159; 42). Unlike the Western world, a prospective series of 73 cases of cavernous sinus syndrome from a tertiary care center in India reported the following etiologies: 29% neoplastic, 25% fungal, 23% Tolosa-Hunt syndrome, 4% other infection, 7% other inflammatory, 7% vascular, and 2% diabetic (10).
The most common primary tumors are pituitary adenoma, followed by schwannoma of cranial nerves III, IV, V1, and V2, meningioma, craniopharyngioma, and chondroma (118). Pituitary apoplexy can cause sudden involvement of one or both cavernous sinuses and is a medical emergency. Local spread from nasopharyngeal carcinoma is a common cause, and more distant metastases occur commonly with breast, lung, and prostate carcinoma (187; 18; 145); however, rare cases of metastatic colon carcinoma (122; 120) and hepatocellular carcinoma metastasizing to the skull base (88; Carey and Sudhakar 2015) and involving ocular nerve palsy have been reported. Lymphoma and multiple myeloma also occur. Primary tumors present more with painless and gradually progressive ophthalmoplegia, whereas secondary tumors are more likely to have subacute painful onset (159; 162; 118).
Intracavernous aneurysms. These only account for 2% to 9% of intracranial aneurysms but are a frequent cause of cavernous sinus syndromes. These occur in older adults (111; 162; 153; 28). Half present with painless, slowly progressive ophthalmoplegia, half with acute painful diplopia (162; 153). The sixth nerve is most commonly affected followed by fifth nerve sensory loss or pain. The third nerve, fourth nerve, optic nerve, and oculosympathetics are injured in some (162; 107; 153; 28).
Carotid-cavernous fistulae. These are abnormal acquired arteriovenous communications. Although arteriovenous malformations can occur anywhere in dura matter covering the brain, they occur most frequently in the cavernous and transverse sigmoid sinus. Patients may be asymptomatic or may experience symptoms from mild symptoms to fatal hemorrhage. Incidence of ocular symptoms has been between 80% and 97% of patients with cavernous sinus fistula (89; 132). A case series of 40 patients over 11 years at a single institution reported 60% to have diplopia (78). Diagnosis is typically confirmed on the basis of digital subtraction angiography. Noninvasive imaging has a high incidence of false-negative findings. Superior ophthalmic vein enlargement is a frequent finding on noninvasive imaging, though Jacobs and colleagues reported 27% of patients lacked this finding (78).
There are two kinds of carotid-cavernous fistulae. One is a high-flow direct shunt between the internal carotid and the cavernous sinus. Head trauma or spontaneous rupture of an intracavernous aneurysm is usually responsible (08; 66). It may complicate carotid endarterectomy (98; 123), trigeminal gangliolysis (96; 47), and maxillofacial surgery (66), or, in young women, inherited vascular defects, such as Ehlers-Danlos type IV (144; 109) and fibromuscular dysplasia (69; 189). Direct fistulae present with sudden, severe painful pulsatile proptosis with periorbital edema and chemosis. The patients may have pulsatile tinnitus, audible also to the examiner as an ocular bruit. Ocular motility is reduced both from both nerve palsies and orbital congestion. Anterior draining fistulas are more likely to cause ocular problems.
The other kind is a low-flow shunt between the cavernous sinus and dural branches of the internal or external carotid artery. The low-flow dural fistula occurs spontaneously, with 85% of patients older than 55 and 90% female (131; 08; 84; 70). It can be a rare congenital anomaly in infants (94; 56). Usually, a red eye develops over a few weeks with minimal pain, diplopia, and subtle proptosis (131; 127), often mistaken for conjunctivitis. In addition to the ocular motor signs, dilated scleral and conjunctival veins, slight exophthalmos, mildly increased intraocular pressure (131; 127), and secondary glaucoma (57) have been reported. If the fistula drains posteriorly, orbital signs will be absent. Instead, neurologic symptoms such as confusion and expressive aphasia are more often seen (176).
Septic cavernous sinus thrombosis. This occurs with infections of the midface, paranasal sinuses, orbital cellulitis, dental abscess, and otitis media or externa (33; 48). It may complicate trauma (25) transsphenoidal craniotomy with CSF leakage (142), or cervical spinal fusion (48). In 65% of cases, the causal organism is Staphylococcus aureus. Streptococci (20%), pneumococci (5%), and anaerobic bacteria (5%) make up the remaining organisms (158; 180; 164; 117; 48). Meningovascular neurosyphilis (139; 157) and tuberculosis pachymeningitis (100) can cause multiple ocular motor nerve palsies and orbital fissure syndromes and should be considered in the list of differential diagnoses of cranial nerve palsies.
Fungal thrombosis with mucormycosis (40), aspergillus, and coccidiomycosis. Aspergillus is most common, followed by mucormycosis and coccidiomycosis (48). Mucormycosis is mainly seen in the diabetic patient, whereas aspergillus and coccidiomycosis are more often seen in patients with chronic renal failure, chronic myelocytic leukemia, immunosuppression (146; 163; 48), or secondary to the SARS-CoV-2 virus (38). Fungi spread from the sinuses or palate to the orbital apex and cavernous sinus. Early visual loss or retinal arterial occlusion is common (01). A black necrotic crust of the nasal or palatal mucosa or black orbital pus point to mucormycosis (101).
Tolosa-Hunt syndrome. This presents at any age with acute painful ophthalmoplegia, sometimes with nausea and vomiting lasting days to weeks (90). Most commonly the third and sixth are involved, with fourth nerve and V1 sensory loss also in some. The optic nerve is affected in 20% of cases, and there is V2 sensory loss in 10% (90). Horner syndrome, V3 sensory loss, and seventh nerve palsy are unusual (90). Proptosis, chemosis, and periorbital edema are rare. Tolosa-Hunt syndrome is caused by idiopathic nonspecific inflammation. Pathology shows a noncaseating granulomatous inflammation (49). Some cases with antineutrophil cytoplasmic antibodies may be a localized form of granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) (114). It is theorized that Tolosa-Hunt syndrome is part of the autoimmune spectrum as it has also been associated with systemic lupus erythematosus (185), sarcoidosis (14), and the SARS-CoV-2 virus (22). The International Classification of Headache Disorders, third edition beta (ICHD-3 beta), includes updated diagnostic criteria for Tolosa-Hunt syndrome that require granulomatous inflammation of the cavernous sinus or superior orbital fissure or orbit demonstrated by MRI or biopsy. However, this definition may lead to false negatives in cases that lack MRI findings and false positives in cases in which the MRI finding is caused by something other than granulomatous inflammation (116). A more traditional definition is painful ophthalmoplegia with exclusion of other diseases. Zhang and colleagues found the ICHD-3 beta criteria to be only 52% sensitive in patients diagnosed under the traditional definition (painful ophthalmoplegia and exclusion of other diseases) (188).
Orbital apex syndromes. Lesions of the orbital apex can affect the ocular motor nerves, sympathetic fibers, optic nerve, and V1. Involvement of only one branch of cranial nerve 3 (superior supplying superior rectus and levator or inferior supplying medial rectus, inferior rectus, inferior oblique, and ciliary ganglion) or sparing of V2 should invite consideration of this anatomical location. Sparing of the optic nerve can occur if only the superior orbital fissure is involved. Orbital apex lesions can also cause orbital congestion through compromise of orbital venous outflow. Etiologies include benign and malignant tumors and inflammatory lesions originating in the orbit or gaining entry via the superior orbital fissure or optic canal. Extension of pathologies from the paranasal sinuses is an important cause of orbital apex syndromes, especially in the case of invasive fungal sinusitis, which can be elusive to confirm and fatal if not treated in a timely manner (160). Penetrating injury, orbital fracture, and sinus mucocele can also affect the orbital apex (182).
SARS-CoV-2 virus. The neuro-ophthalmic manifestations of the SARS-CoV-2 virus (COVID-19) are becoming more frequently recognized (32). Cranial nerve palsies have appeared in conjunction with respiratory symptoms or, rarely, as isolated findings in patients with COVID-19 (32; 167). It is theorized that the SARS-CoV-2 virus causes hyperstimulation of the immune system, which results in overproduction of autologous antibodies in genetically predisposed patients. Additionally, heptapeptide sharing exists between SARS-CoV-2 spike glycoproteins and mammalian proteins, suggesting that molecular mimicry may play a part in the stimulation of secondary autoimmune conditions (36).
Other causes of multiple unilateral ocular motor palsies. The skin lesions of Herpes zoster ophthalmicus can be followed in 1 to 2 weeks by single or multiple ocular motor palsies on the same side, sometimes even complete ophthalmoplegia (Marsh and Kelly 1977; 19; 121; 124). The pathophysiology may be either vasculitis or inflammatory neuritis.
Diabetes can cause combined ocular motor nerve palsies (44; 147) and also may cause simultaneous or sequential multiple neuropathies, sometimes with ischemic optic neuropathy (77; 39). Recovery over 2 to 3 months is typical.
Temporal arteritis also can cause simultaneous cranial neuropathies, and in elderly patients with history of headache, mild anemia, jaw and fascial pain, and arthritis should be in consideration (159).
Orbital infarction syndrome is defined as ischemia of all intraorbital and intraocular structures. This rare acute orbital perfusion failure can occur from postoperative complications of intracranial aneurysms, systemic vasculitis, and orbital cellulitis, including from mucormycosis (178).
Finally, trauma is the most common cause of unilateral multiple ocular motor palsies in children (72).
Bilateral ophthalmoplegia secondary to multiple ocular nerves palsies. Partial bilateral ophthalmoplegia is more common than complete ophthalmoplegia (82). Many of the same diagnostic considerations as for unilateral ophthalmoplegia apply. The examination must distinguish if the pattern is one of multiple bilateral ocular motor neuropathies, supranuclear gaze palsies, or myopathic or neuromuscular junction disorders.
Diabetes and vasculitis can cause multiple bilateral cranial neuropathies, as can cavernous sinus disease, as the two cavernous sinuses have interconnecting channels. Midline skull base and sellar lesions cause bilateral, multiple ocular motor nerve palsies through invasion into both cavernous sinuses. Pituitary apoplexy is a cause of acute bilateral ocular motor palsies that must be diagnosed and treated emergently.
Unusual central lesions include occasional focal midbrain lesions such as hematoma (161). This may represent bilateral III nerve palsies with a transient bi-directional horizontal gaze palsy (177), or combined midbrain and pontine damage. This would involve not only descending pursuit and saccadic tracts but also possibly facilitatory pathways to the medial vestibular nuclei, to explain the loss of horizontal vestibuloocular reflex (07).
The differential diagnosis includes non-mononeuropathy causes of extraocular motility disturbance, including myopathy, neuromuscular junction disease, and supranuclear causes.
Graves ophthalmopathy can mimic multiple ocular motor palsies. A number of other eye signs such as chemosis, eyelid and conjunctival congestion, lid retraction and lag, and exophthalmos are clues to Graves disease. Ophthalmoparesis in Graves disease is a combination of weakness and restriction due to edema, inflammation and fibrosis of the extra ocular muscles and periorbital tissues. The forced duction test can confirm restriction: with topical anesthesia, the eye is placed as far into the limited range as possible. Then the examiner determines if the eye can be moved further with using tweezers or a cotton swab. If no resistance is met as the examiner pulls or pushes the eye in the direction of limited active motion, then the eye is not restricted. Orbital imaging including ultrasound, CT scan, and MRI can show the muscle enlargement characteristic of Graves ophthalmopathy. The pupils are not involved in Graves ophthalmopathy. The optic nerve can be affected due to compression by enlarged extraocular muscles.
Myasthenia gravis can produce any ocular motor pattern and ptosis. It is usually bilateral but asymmetric. Variability and fatigability are key signs. The edrophonium ocular drop test (71% sensitive), repetitive nerve conduction studies (50% sensitive), and assays for antibodies to acetylcholine receptors are useful but have low sensitivities when myasthenia is confined to the eye muscles (169; 41; 115; 143). Hence, negative test results do not reliably exclude myasthenia. Although no longer routinely used, the Tensilon test used to be highly diagnostic (92% sensitive and 97% specific). Currently, the single fiber EMG test is highly sensitive for ocular myasthenia gravis and is widely used as more than 50% of patients with ocular myasthenia gravis are seronegative for myasthenia gravis markers (37). The pupils, optic nerves, and trigeminal nerve are not involved in myasthenia.
Botulism is another neuromuscular junction disorder. Signs of cholinergic autonomic hypofunction such as dilated unreactive pupils, urinary retention, and decreased bowel sounds are important clues that differentiate it from myasthenia.
Miller-Fisher syndrome is a triad of ophthalmoplegia, ataxia, and areflexia, sometimes following an upper respiratory or gastrointestinal tract infection by a few weeks (09). The pattern of ophthalmoparesis is highly variable. The CSF usually has moderately elevated protein with cytoalbuminologic dissociation, though 8% of patients may have a pleocytosis (09). Nerve conduction studies can show absent sensory nerve action potentials, slowed motor or sensory conduction, or abnormal H and F wave latencies (80; 183; 128; 03; 52). However, normal conduction studies are not uncommon (21; 04; 113) and may occur in 30% (09). The serum autoantibodies to GQ1b-ganglioside are a marker for the syndrome (21; 20; 174). A few patients with isolated acute or chronic bilateral partial ophthalmoplegia have anti-GQ1b antibodies, without the typical course or other associated signs of Miller-Fisher syndrome (156; 133).
Chronic progressive external ophthalmoplegia is a myopathy that causes slowly progressive bilateral ptosis and symmetric extraocular limitation, usually without diplopia. It usually spares the pupils, but involvement of the orbicularis is the rule (102). It begins in childhood or adolescence and can be associated with cardiac conduction defects and pigmentary retinopathy (Kearns Sayre syndrome). Other features include short stature, hearing loss, and endocrine and bone abnormalities. Deletions in mitochondrial DNA also occur, and muscle biopsy shows ragged-red fibers (135).
Bilateral partial and total ophthalmoplegia also have been rarely reported with administration of drugs such as phenytoin (151; 46), phenobarbital, primidone, carbamazepine, and amitriptyline. These are likely supranuclear disorders, possibly due to increased GABA-minergic inhibition in the vestibulocerebellum. Paraneoplastic brainstem encephalitis associated with anti-Hu antibodies can progress over a few months from upgaze paresis with slowed horizontal saccades and gaze-paretic nystagmus, to bilateral ptosis and complete external ophthalmoplegia (186). Some patients undergoing cardiovascular bypass surgery with deep hypothermia emerge with a horizontal and vertical supranuclear ophthalmoplegia that spares vestibuloocular movements, which can slowly recover partially over weeks to months (27; 31). MRI in such cases often shows diffuse white matter lesions. The origin of this syndrome is unclear but may reflect diffuse damage to cerebral ocular motor areas.
Orbital congestion with partial or total ophthalmoplegia can rarely occur with other vascular states, including noncavernous sinus cerebral arteriovenous malformations (171; 103).
MRI of the orbit and sella, including cavernous sinus and MR angiography are the diagnostic procedures of choice (29; 79; 119). These should include axial and coronal sections of the orbit and cavernous sinus, with fat suppression pulse sequences and gadolinium. Biopsies of imaged lesions may be required. Blood cultures or nasal biopsies are indicated if infection is suspected.
If an intracavernous aneurysm is detected, some advocate a formal conventional cerebral angiography because it remains the gold standard for aneurysm detection and can detect secondary aneurysms. However, it is an invasive procedure and has widely been replaced by noninvasive MRA and CT angiograms. MR and CT angiograms have a 95% specificity and 90% sensitivity and can reliably diagnose aneurysms 3 mm or greater in diameter 90% to 95% of the time (107; 136).
Investigation of carotid-cavernous fistulae can use several imaging modalities. In office procedures, including orbital ultrasound, show shunting, exclude other causes of red proptotic eyes like Graves disease and orbital pseudotumor, and differentiate high- and low-flow fistulae (131; 150; 66; 70). Color Doppler imaging has a 97% sensitivity and 42% specificity, making negative color Doppler imaging more diagnostic than positive color Doppler imaging (152). However, it can show arterialized blood flow in an enlarged superior ophthalmic vein in anterior draining fistulae (43; 168). Although not routinely used, a difference in ocular pulse amplitude of 1.6 mmHg seen between the two eyes on pneumotonometry is 100% sensitive and 93% specific for carotid-cavernous fistulae (66). Patients with suspected carotid-cavernous fistula require more advanced neuroimaging. MRI reveals shunted blood in the cavernous sinus and superior ophthalmic vein as well as increased volume of the cavernous sinus (93; 02). Digital subtraction angiography remains the gold standard for the classification and diagnosis of carotid-cavernous fistulae and is both diagnostic and therapeutic (78; 175; 66).
In septic bacterial thrombosis, blood cultures are typically positive in 70% (158; 23). Also, blood tests such as complete blood count, ESR, C-reactive protein, ACE level, P-ANCA, C-ANCA, ANA, and protein electrophoresis can help in cases suspicious for temporal arteritis, sarcoidosis, Wegener granulomatosis, Churg-Strauss syndrome, systemic lupus erythematosus, rheumatoid arthritis, multiple myeloma, and lymphoma (91; 48).
For fungal thrombosis, biopsy of the nasopharynx or intracranial mass makes the diagnosis of mucormycosis and aspergillosis (73). A definite diagnosis frequently requires histologic examination of tissue. If paranasal sinus or orbital involvement is present, transsphenoidal (146) or orbital (85; 86) biopsy may establish the diagnosis. The fine-needle aspiration techniques with CT guidance may also be employed safely and effectively for lesions of the anterior cavernous sinus (138).
Regardless of the origin of the infecting agent, imaging should be conducted using contrast-enhanced MRI and CT in order to examine the cavernous sinus. Specifically, MR and CT venograms are highly sensitive and specific for identifying cavernous sinuous thrombosis (48).
In the ICHD-III beta, diagnosis of Tolosa-Hunt syndrome requires demonstration of granulomatous inflammation by MRI or biopsy. However, few patients ever receive a biopsy, and critiques of these criteria suggest that they exclude cases with normal MRI (62; 05) and that they have high sensitivity but low specificity for Tolosa-Hunt syndrome diagnosis (74; 05). MRI can show signal changes and enlargement of the cavernous sinus, with convex bowing of its lateral wall (184; 55). CT imaging may show occlusion of the superior ophthalmic vein and intraorbital changes that may represent either contiguous orbital inflammation or secondary effects of vascular occlusion (54). Imaging is also important to exclude masses because Tolosa-Hunt accounts for only 3% of cavernous sinus syndromes and is only a diagnosis of exclusion (159; 140; 87). Atypical imaging is both sensitive and specific for diagnoses other than Tolosa-Hunt syndrome (74; 05).
Carotid aneurysms smaller than 12 mm in diameter generally do not require intervention can be observed through serial CT or MRI imaging (118). Reasons for intervention include epistaxis, subarachnoid hemorrhage, progression of ophthalmoplegia, visual loss, or large radiologic size (107). Treatment options include open surgery, coil embolization, or endovascular flow diversion (16; 118). Endovascular flow diversion has increased in popularity as it has been shown to decrease patient morbidity when compared to coil embolization (28).
For high-flow carotid fistulae, urgent therapy is needed for progressive proptosis, visual loss, transient ischemic attacks, and angiographic signs, including a cavernous sinus varix, more distal thrombosis, or cortical venous drainage from the fistula (58). Endovascular intervention with transarterial balloon embolization is the preferred approach (15; 105; 154). Alternatives include direct surgical repair and ligation of the internal carotid artery. Treatment options for dural low-flow cavernous fistula include observation, manual carotid compression, drugs to lower intraocular pressure, and endovascular intervention. Observation is preferred unless high-risk symptoms are present as up to 70% of all dural cavernous fistulae close spontaneously (66). Treatment is determined by visual loss, diplopia, pain, or exposure keratitis. Drugs or filtering procedures treat glaucoma (131). Endovascular coiling using the transvenous approach is still the preferred method for fistula closure (130). The fistula can be alternatively treated through a transarterial approach with glue or particle embolization (170; 08; 66). Over the past few years, the direct orbital approach has been utilized at increasing rates and has had similar rates of success (130). Stroke is a potential side effect of both angiography and intraarterial embolization. Transvenous coil embolization is 80% effective and may be safer, with frequent and durable effect (112; 51; 130). Radiotherapy has been shown to result in complete remission anywhere from 50% to 100% of the time (12; 181; 68; 125). There have been small trials of electrothrombosis (76).
For septic cavernous sinus thrombosis, immediate intravenous broad-spectrum antibiotics are mandatory. If fungal infection is suspected, amphotericin B should be added to the medication regiment (73; 48). The role of anticoagulation is unclear. Some suggest it may improve antibiotic access, remove clot acting as culture media, and help recanalization (158). Others say it increases intracranial bleeding and hematogenous spread (180). The available empiric data are not helpful and have yielded mixed results (149; 104; 172; 48). At the least, anticoagulation seems relatively safe, and patients should have individualized anticoagulation treatment plans. Anticoagulation is, however, contraindicated in patients with concomitant meningitis (104; 190; 166).
Treatment of deep-seated aspergillosis is difficult and by no means always successful. Aggressive attempts to treat the infections are warranted, particularly because of the risk of septic arterial occlusion, resulting in thrombosis (65), rupture (146), or mycotic aneurysm formation (126). Medication and surgical debridement of necrotic tissue are first-line therapies (73). Amphotericin B alone is liable to fail but may be more effective when combined with flucytosine and possibly rifampin. Wide surgical excision is recommended but frequently is not practicable. Ethmoidectomy, sphenoidotomy, maxillary antrostomy, or orbital decompression may be required depending on the extent of fungal spread (73).
For Tolosa-Hunt syndrome, steroids are the mainstay of therapy. However, response is not diagnostic because steroids can improve signs in neoplasia, infections, and aneurysms (159; 45; 35; 26). Successful clinical remission of recurrent Tolosa-Hunt syndrome was noted after treatment with steroids followed by methotrexate (99). Adalimumab, a subcutaneous TNFi, also appears to be an effective treatment for corticosteroid-dependent Tolosa-Hunt syndrome in adult and pediatric populations (173).
For zoster, the efficacy of the standard treatment of intravenous steroids or acyclovir is unknown.
For SARS-CoV-2, there are no differences in the diagnosis and treatments for cranial nerve palsies secondary to the virus. Patients can receive additional supportive care with or without antiviral treatments to resolve the underlying COVID-19 infection.
Some advocate that during the period of prolonged recovery of ocular motility, botulinum toxin injection to the antagonist muscles should be used to protect against contracture (141; 95), though this is not standard practice. If recovery is incomplete, one may continue symptomatic treatment with monocular patching or prisms or consider surgery for strabismus or ptosis, once it is clear that the magnitude of the deficit has been stable for at least 1 year.
Following successful treatment for any of the above, there may be residual nerve palsy. Bhatkar and colleagues reported improvement in 94% of patients with Tolosa-Hunt versus less than 25% of patients with neoplasm-based cavernous sinus syndrome (10). Though a majority (69%) of patients with fungal cavernous sinus syndromes had improvement, 25% of patients with this etiology expired. In some patients these may take up to 3 years to recover completely (53). Recovery initially begins with improvement in eyelid elevation, followed by pupillary contraction and, lastly, extraocular eye movements (110).
The recovery of ocular motor nerve palsies from aneurysmal compression depends on size of the aneurysm, the interval between the onset of palsy and surgery, and the degree of deficit (60; 155; 61). Treatment within 2 weeks of palsy onset has a more favorable outcome compared to delayed intervention (50). Treatment methodology was not associated with degree of cranial neuropathy recovery (16). Recovery of compressive lesions may continue up to a year after treatment but may be complicated by aberrant regeneration (60; 61).
For cavernous carotid fistulae, some cases improve after angiography without intervention. Effects of balloon embolization appear long-lasting, and initial intervention has been shown to be 80% effective. There is a 20% complication rate. Complications include cerebral ischemia, sometimes delayed for months, iatrogenic cranial nerve palsies, trigeminal sensory neuropathy, embolization, and significant intraocular pressure elevation (105; 71). Ehlers-Danlos syndrome has a 12% mortality and 36% morbidity rate for angiography (144), and treatment of such patients is difficult (59; 81). Carotid ligation may increase the risk of a subsequent contralateral aneurysm (30).
For septic cavernous sinus thrombosis, mortality with treatment with increasingly effective antibiotic regiments is only around 20% (180; 149; 33; 48). In the early era of antibiotics, 87% of patients treated for septic cavernous sinus thrombosis had residual cranial nerve deficits. However, only 10% to 15% of patients have lasting neurologic deficits (166). Late complications include ocular neuromyotonia (64), Korsakoff syndrome (13), and panhypopituitarism (129).
As fungi become more resistant to modern medicine, the mortality rate from fungus continues to increase. Early on, amphotericin B reduced mortality from mucormycosis from 90% to 15% (101). However, in a modern case series of mucormycosis in which 53% of patients had cavernous sinus or orbital apex involvement and all received aggressive antifungal and surgical treatment, mortality was 50% (97).
For Tolosa-Hunt syndrome, pain responds within 48 to 72 hours of starting either oral or intravenous steroids, mainly prednisone and dexamethasone (148; 87). Recovery from cranial nerve palsy has been shown to take anywhere from 2 to 8 weeks (62). The prognosis for complete recovery from an attack following steroid therapy is good (35), but a few patients can have residual ocular motor paresis. Painful ophthalmoplegia recurs in patients 20% to 40% of the time, at intervals varying from months to years, on either the same or the opposite side. Patients who received steroid-sparing agents had a significantly lower recurrence (62; 06; 87).
For SARS-CoV-2, the cranial nerve palsies typically dissipate within 1 month of symptom onset with only symptomatic treatment of the virus (34). No antiviral treatment has been shown to decrease the mortality of SARS-CoV-2. However, there has been limited research to this point on how antiviral administration can affect the duration and severity of cranial nerve palsies.
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Heather E Moss MD PhD
Dr. Moss of Stanford University has no relevant financial relationships to disclose.See Profile
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