Neuro-Ophthalmology & Neuro-Otology

Updated 07.17.2024
Released 01.08.2003
Expires For CME 07.17.2027

Combined third, fourth, and sixth nerve palsies

Authors: Ricky Paramo BS, Lakshmi Leishangthem MD

Editor: Jonathan D Trobe MD

Introduction

Overview

Patients complaining of diplopia may 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.

Key points

	• Multiple ocular motor nerve palsies (combined third, fourth, or sixth nerve palsies) produce clinical manifestations that must be distinguished from extraocular muscle dysfunction, myasthenia gravis, and brainstem syndromes.
	• Cavernous sinus lesions are responsible for most multiple ocular motor palsies; they often also cause Horner syndrome and trigeminal neuropathy affecting the first two divisions.
	• Cavernous sinus lesions often extend into the orbital apex to cause an ipsilateral optic neuropathy.

Historical note and terminology

Multiple ocular motor palsies are present when ocular ductional deficits, with or without anisocoria and ptosis, lie in the domain of more than one ocular motor nerve. The manifestations may be unilateral or bilateral. The differential diagnosis includes lesions that arise in the brainstem, neuromuscular junction, or extraocular muscles.

“Ocular motor nerves” refers to cranial nerves 3, 4, and 6. “Oculomotor nerve” refers to cranial nerve 3.

Clinical manifestations

Presentation and course

The cardinal symptom of ocular motor palsies is binocular diplopia, which disappears when either eye is occluded. The diplopia may consist of seeing the second image as displaced horizontally, vertically, or obliquely. Eliciting whether the image displacement has been static or progressive is helpful in diagnosis. That is, has the diplopia proceeded from intermittent to persistent since onset? Has it spread from being present in one position of gaze to more than one position of gaze? Has image separation increased, decreased, or remained stable?

Eye movement testing may reveal a reduced range of ocular ductions, but diplopia can be present even when ductions appear to be full. In that case, assessment must include measurement of ocular alignment with subjective or objective tests. Subjective tests include the red glass, Maddox-rod, and Hess screen tests; objective tests include the cover test, alternate cover test, and prism-and-cover test.

The manifestations of a combination of complete third and sixth nerve palsy are not difficult to recognize. In addition to deficits in adduction, supraduction, and infraduction, there will be a deficit in abduction, as well as ptosis and often mydriasis. Incomplete palsies are more difficult to discern.

The combination of a third and fourth palsy is challenging to diagnose. In addition to the typical third nerve-related deficits, there will be a deficit in infraduction and intorsion, primarily when the eye is in the adducted position.

Discovering unilateral mydriasis is useful in excluding myopathic and neuromuscular junction disease (180). The addition of Horner syndrome (ipsilateral miosis and mild ptosis) suggests a lesion of the cavernous sinus. A caution here: third nerve palsy and Horner syndrome produce opposing effects on pupil size, so the combination of third nerve palsy and Horner syndrome may manifest with isocoria. The diagnosis is established by finding reduced constriction to light and a positive apraclonidine test.

Examination of facial sensation is critical as the V1 and V2 segments of the trigeminal nerve course near the ocular motor nerves in the middle cranial fossa. Multiple ocular motor palsies with facial numbness suggest a cavernous sinus lesion. Numbness limited to V1 can occur in an orbital apex lesion or an incomplete cavernous sinus lesion.

Ipsilateral headache and periocular pain are other common symptoms that suggest trigeminal nerve involvement in the orbit, superior orbital fissure, cavernous sinus, retrocavernous region, or floor of the middle cranial fossa.

Blurred vision may be due to mild diplopia if it goes away with covering either eye, or it may indicate optic nerve involvement caused by lesions of the optic nerve or optic chiasm.

Proptosis suggests an orbital mass or venous congestion from cavernous sinus or orbital apex pathology.

Prognosis and complications

The natural history of intracavernous carotid aneurysms can include either gradual improvement or worsening over months to years (103). Rarely, rupture of the aneurysm causes a high-flow carotid cavernous fistula (10). Subarachnoid hemorrhage is more likely when intracavernous aneurysms arise from the anterior genu of the carotid siphon or erode the sella turcica to extend intradurally (107; 102).

In high-flow carotid-cavernous fistula, vision may be lost immediately due to steal from the arterial supply to the optic nerve or retrograde venous flow into the orbit and an acute rise in intraocular pressure (54). Intracranial hemorrhage or epistaxis occurs in 10% of patients with high-flow carotid-cavernous fistula, causing death in 30% (54). Hemorrhage tends to occur within the first week but may be delayed up to 3 weeks. Retrograde venous flow may also extend toward the cerebrum to cause venous infarction (70). In low-flow carotid-cavernous fistula, bleeding and death are unlikely, but 30% have visual loss from high intraocular pressure (126; 54) or central retinal vein occlusion (91; 127). The combination of optic disc hyperemia, retinal vein dilation, and intra-retinal hemorrhage is touted as predictive of vision loss in carotid-cavernous fistula, with 75% visual impairment in high-flow fistula and 25% visual impairment in low-flow fistula (04).

In septic cavernous sinus thrombosis, death is nearly universal and rapid in untreated cases. There may be rapid progression over several days to bilateral ophthalmoplegia (30), systemic sepsis, meningitis, and brain abscess (181).

In idiopathic inflammation of the cavernous sinus or orbital apex region (Tolosa-Hunt syndrome), most patients never develop other neurologic or systemic defects (89), but there are rare reports of pituitary hypofunction, diabetes insipidus (63; Hama 1996; 179; 88), and thyroiditis (165; 83).

In herpes zoster infection of the cavernous sinus, there is usually substantial recovery, but it may take more than a year (141).

In SARS-CoV-2 infection, the ocular motor palsies typically resolve over a period of weeks to months, but deficits may persist (31).

Clinical vignette

A 56-year-old woman had pain for several weeks followed by oblique diplopia that became worse when she looked downward. When she was examined 3 weeks after the onset of diplopia, the pain was improving. She had a right hypertropia (worse in left gaze) and right head tilt, indicating a right fourth nerve palsy. Because of the pain, unusual for fourth nerve palsies, she underwent MRI and MRA, the results of which were normal. One month later, an examiner noted a right partial third nerve palsy in addition to the fourth nerve palsy. An intravenous edrophonium test was negative. One month later, an examination disclosed that the right eye had developed surface vascular congestion, mild proptosis, and a partial third and sixth palsy. She reported dysesthesia in the right V1 distribution, mainly over the vertex. A carotid-cavernous fistula was confirmed with imaging. MRI showed engorged extraocular muscles on the right. Lateral view of the digital angiogram showed rapid flow into the cavernous sinus and a dilated superior ophthalmic vein. She was treated with particle embolization. The clinical features regressed within days. Six months later, the only signs were a mild right sixth nerve palsy and Horner syndrome on the right.

Cavernous sinus and superior ophthalmic vein in pretreatment angiogram (lateral view)

Angiogram shows arterial blood entering the cavernous sinus and dilating the superior ophthalmic vein. (Contributed by Dr. Jason Barton.)
Fistula and superior ophthalmic vein (posttreatment angiogram)

Angiogram shows the material placed around the fistula as well as the disappearance of the blood in the superior ophthalmic vein. (Contributed by Dr. Jason Barton.)

Biological basis

Etiology and management

Inflammation and compressive lesions are the most likely causes of multiple ocular motor palsies. In several series, tumors accounted for 20% to 40% of unilateral third, fourth, and sixth nerve palsies (59; 129; 79). In other series, tumors accounted for 70% of cavernous sinus lesions (35% primary and 35% metastatic), and intracavernous aneurysms for 20% (158; 40; 113). Among 73 cases of cavernous sinus lesions from a tertiary care center in India, 29% of lesions were neoplastic, 25% were fungal, 23% were idiopathic inflammation (Tolosa-Hunt syndrome), 4% were infections, 7% other inflammatory, 7% vascular, and 2% diabetic (12).

Many lesions that cause cavernous sinus syndromes can also extend into the nearby orbital apex or be limited to that region. They differ from cavernous sinus lesions clinically by causing damage to the optic nerve and sparing the second trigeminal division (183; 159; 186).

Although brainstem lesions are rare causes of multiple ocular motor palsies, they must be considered, particularly if the ophthalmoplegia involves both eyes (24; Rush and Young 1981; 78; 133). Accompanying signs include ipsilateral limb ataxia, contralateral involuntary movements, contralateral hemiparesis, and ipsilateral facial nerve palsy.

Tumors. Among the tumors that cause multiple ocular motor nerve palsies are pituitary adenomas, schwannomas, meningiomas, craniopharyngiomas, and chondromas (113). Pituitary apoplexy is a medical emergency that can cause sudden involvement of one or both cavernous sinuses. Local spread from nasopharyngeal carcinoma is also a common cause, as are metastases from breast, lung, and prostate carcinoma (190; 18; 144). Metastatic colon carcinoma (117; 115) and hepatocellular carcinoma are rare causes (86; Carey and Sudhakar 2015). Lymphoma and multiple myeloma also occur. Primary tumors present more with painless and gradually progressive ophthalmoplegia, whereas metastatic tumors are more likely to have a subacute painful onset (158; 161; 113).

Aneurysms. Intracavernous aneurysms occur in older adults (107; 161; 151; 27). About 50% present with slowly progressive painless ophthalmoplegia, and the remainder present with acute pain and diplopia (161; 151). The sixth nerve is most commonly affected, followed by trigeminal pain or hypesthesia. The third nerve, fourth nerve, optic nerve, and oculosympathetic fibers may also be injured (161; 103; 151; 27).

Intracavernous aneurysms smaller than 12 mm in diameter can be observed through serial CT or MRI imaging (113). Reasons for intervention include epistaxis, subarachnoid hemorrhage, ophthalmoplegia progression, visual loss, or large aneurysm size (103). Treatment options include coil embolization or endovascular flow diversion (16; 113). Endovascular flow diversion has increased in popularity as it has been shown to decrease patient morbidity when compared to coil embolization (27).

The recovery of ocular motor nerve palsies from aneurysmal compression depends on the size of the aneurysm, the interval between the onset of palsy and surgery, and the degree of deficit (56; 152; 57; 77). Treatment within 2 weeks of palsy onset has a more favorable outcome than delayed intervention (46; 108). Recovery after compressive lesions may continue up to a year following treatment but may be complicated by aberrant regeneration (56; 57).

Fistulas. Carotid-cavernous fistulas occur frequently in the cavernous sinus and transverse sigmoid sinus. Patients may be asymptomatic, mildly symptomatic, or experience fatal hemorrhage. A case series of 40 patients over 11 years at a single institution reported 60% to have diplopia (72). Ophthalmic manifestations are present in 80% to 97% of patients (131). They are attributed to ischemia from the diversion of arterial blood supplying ocular motor nerves or from venous congestion.

Superior ophthalmic vein enlargement is a frequent finding on noninvasive imaging, but one publication reported that 27% of patients lacked this finding (72). Diagnosis is typically confirmed by digital angiography, as noninvasive imaging is often negative.

High-flow (“direct’) carotid-cavernous fistulas are arteriovenous shunts between the internal carotid artery and the cavernous sinus. Head trauma or spontaneous rupture of an intracavernous aneurysm is usually responsible (10; 62), but such fistulas may also arise after carotid endarterectomy (96; 118), trigeminal gangliolysis (94; 43), maxillofacial surgery (62), and inherited vascular defects such as Ehlers-Danlos type IV (143; 105) and fibromuscular dysplasia (65; 191). They present with sudden, severe, and painful pulsatile proptosis, periocular edema, and chemosis. Pulsatile tinnitus is often audible to the patient and to an examiner placing a stethoscope on the cheek, brow, temporal bone, or eye. Ocular motility is reduced either because of ocular motor palsies or orbital congestion. Fistulas that drain predominantly anteriorly into the orbit are more likely to produce ophthalmic manifestations than those that drain posteriorly, superiorly, or inferiorly.

Low-flow (“indirect,” “dural”) carotid-cavernous fistulas consist of arteriovenous shunts between dural branches of the internal or external carotid artery and the cavernous sinus. They occur spontaneously. Some 85% of patients are older than 55 years, and 90% are women (126; 10; 80; 66). They may rarely appear as congenital anomalies in infants (92; 52). A red eye develops over a few weeks with mild periocular pain, diplopia, and subtle proptosis (126; 122; 173), often mistaken for conjunctivitis. In addition to the ocular motor palsies, dilated scleral and conjunctival veins, slight exophthalmos, mildly increased intraocular pressure (126; 122), and secondary glaucoma (53; 84) have been reported. If the fistula drains posteriorly, orbital signs will be absent. Confusion and expressive aphasia may be seen if flow is directed toward the cerebrum (177).

In carotid-cavernous fistulas, urgent intervention is needed for progressive proptosis, visual loss, transient ischemic attacks, or angiographic signs of a cavernous sinus varix or cortical venous drainage (54). Endovascular intervention with coil embolization into the carotid defect is the preferred approach for direct fistulas. For dural low-flow fistulas, the options are observation, manual carotid compression, medications to lower intraocular pressure, and transvenous coiling (125; 05). Observation is preferred unless high-risk symptoms are present because up to 70% of all dural carotid-cavernous fistulas will close spontaneously (62). Treatment is indicated for visual loss, diplopia, pain, or exposure keratitis. High intraocular pressure is treated with medications or filtering procedures (126). If transvenous embolization cannot be performed, the alternative is using the transarterial approach to deposit glue or particles in the dural feeder vessels (169; 10; 62). The cavernous sinus can also be accessed via the superior ophthalmic vein or by direct transorbital puncture (125). Transvenous coil embolization is 80% effective in closing the fistula (109; 47; 125). Radiotherapy has been shown to result in complete remission 50% to 100% of the time (64; 120; 15).

Balloon embolization, formerly a common approach, is no longer practiced because complications occurred so frequently, including stroke, cranial nerve palsies, trigeminal sensory neuropathy, and intractable intraocular pressure elevation (101; 170; 67). Ehlers-Danlos syndrome has a 12% mortality and 36% morbidity rate for angiography (143), and fistula closure is challenging (55; 76). Novel approaches have included transvenous embolization via the superior ophthalmic vein (155).

Septic cavernous sinus thrombosis. This devastating condition occurs following infections of the midface, paranasal sinuses, orbit, teeth, and external or middle ear (30; 44). It may complicate minor head trauma (87), transsphenoidal craniotomy with CSF leakage (137), and cervical spinal fusion (44). In 65% of cases, the causal organism is Staphylococcus aureus. Streptococci (20%), pneumococci (5%), and anaerobic bacteria (5%) make up the remaining organisms (156; 181; 164; 112; 44).

For the management of septic cavernous sinus thrombosis, immediate intravenous broad-spectrum antibiotics are mandatory. If a fungal infection is suspected, amphotericin B should be added to the medication regimen (69; 44). The role of anticoagulation is unclear. Some suggest it may improve antibiotic access, remove clots that act as a culture media, and promote recanalization (156). But anticoagulation increases the risk of intracranial bleeding and hematogenous spread (181; 149; 100; 171; 44). It is contraindicated in patients with concomitant meningitis (100; 192; 166). In children with meningitis, there is no strong evidence against anticoagulation (140).

Among intensively treated patients, mortality is only 20% (181; 149; 30; 44). Only 10% to 15% of patients have lasting neurologic deficits (166). Late complications include ocular neuromyotonia (60), Korsakoff syndrome (13), and panhypopituitarism (124).

Idiopathic polycranial neuritis (Fisher syndrome). This condition consists of a triad of ophthalmoplegia, ataxia, and areflexia, sometimes following an upper respiratory or gastrointestinal tract infection by a few weeks (11). The pattern of ophthalmoparesis is highly variable. Spinal fluid examination usually discloses a moderately elevated protein with a normal cell count (“cytoalbuminous dissociation”), although 8% of patients may have a pleocytosis (11; 176). Nerve conduction studies can show absent sensory nerve action potentials, slowed motor or sensory conduction, or abnormal H and F wave latencies (74; 184; 03; 48; 75). However, normal conduction studies occur in up to 30% of cases (11; 07; 35). This condition is now considered an autoimmune antiganglioside antibody disorder. Serum autoantibodies to GQ1b-ganglioside are often positive, as they are in Bickerstaff brainstem encephalitis and acute ophthalmoplegia without ataxia (20; 19; 174; 42). Anti-GQ1b antibodies are also present in some patients with isolated acute or chronic bilateral partial ophthalmoplegia (153; 188).

Syphilis. Meningovascular syphilis (135; 154) and tuberculous pachymeningitis (98) are emerging causes of multiple ocular motor nerve palsies.

Fungal infection. Fungal infection is a rare cause of multiple ocular motor palsies (38). Aspergillus is the most common organism, followed by mucormycosis and coccidioidomycosis (44). Mucormycosis is encountered mainly in patients with diabetes mellitus, whereas aspergillosis and coccidioidomycosis are more often seen in patients with chronic renal failure, chronic myelocytic leukemia, SARS-CoV-2 infection (36) and other conditions associated with immunosuppression (145; 163; 44). Fungi spread from the sinuses or palate to the orbital apex and cavernous sinus. Early visual loss and retinal arterial occlusion are common (01; 123). A black necrotic crust of the nasal or palatal mucosa or black orbital pus suggests mucormycosis (99; 157).

Aggressive treatment is warranted, particularly because of the risk of septic arterial occlusion resulting in cavernous sinus thrombosis (61), hemorrhage (145), or mycotic aneurysm formation (121). Medication and surgical debridement of necrotic tissue are first-line therapies (69). Amphotericin B alone is likely to fail but may be more effective when combined with flucytosine and possibly rifampin. Wide surgical excision is recommended but frequently not feasible. Ethmoidectomy, sphenoidotomy, maxillary antrostomy, or orbital decompression may be required, depending on the extent of fungal spread (69).

As fungi become more resistant to pharmaceuticals, mortality continues to increase. Amphotericin B treatment formerly reduced mortality in mucormycosis from 90% to 15% (99). However, in a modern case series in which 53% of patients had cavernous sinus or orbital apex involvement and all received aggressive antifungal and surgical treatment, mortality was 50% (95).

Tolosa-Hunt syndrome. Idiopathic cavernous sinus or orbital apex inflammation (Tolosa-Hunt syndrome) presents at any age with acute painful ophthalmoplegia, sometimes with nausea and vomiting lasting days to weeks (89). Most commonly, the third and sixth cranial nerves are involved. The optic nerve is affected in 20% of cases, and there is second division trigeminal sensory loss in 10% (89). Horner syndrome, third-division trigeminal sensory loss, and seventh nerve palsy are other features (89; 162). Proptosis, chemosis, and periocular edema are rare. Pathology shows noncaseating granulomatous inflammation (45). Some cases may represent a localized form of granulomatosis with polyangiitis (110). This condition has also been associated with systemic lupus erythematosus (185), sarcoidosis (14), SARS-CoV-2 infection (22), and tuberculosis (142).

For management of Tolosa-Hunt syndrome, corticosteroids are the mainstay of therapy. However, the response is not diagnostic because steroids can improve signs in neoplasia, infections, and aneurysms (158; 41; 32; 25; 146). Successful clinical remission of recurrent Tolosa-Hunt syndrome was noted after treatment with corticosteroids followed by methotrexate (97). Adalimumab, a TNF inhibitor, also appears to be an effective treatment for corticosteroid-dependent disease (172).

In Tolosa-Hunt syndrome, pain responds within 48 to 72 hours of starting either oral or intravenous corticosteroids, mainly methylprednisone and dexamethasone (148; 85). Recovery from cranial nerve palsy takes 2 to 8 weeks (58). The prognosis for complete recovery from a single attack is favorable (32), but a few patients can have residual ocular motor paresis. Painful ophthalmoplegia recurs ipsilaterally or contralaterally in 20% to 40% of patients at intervals varying from months to years. In three studies, patients who received corticosteroid-sparing agents had a significantly lower recurrence rate (58; 08; 85).

SARS-CoV-2 infection. Cranial nerve palsies have appeared in conjunction with respiratory symptoms or, rarely, as isolated findings in patients with COVID-19 infection (29; 167). The SARS-CoV-2 virus causes hyperstimulation of the immune system, which results in the 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 (33). Typically, the ocular motor cranial nerve palsies of SARS-CoV-2 spontaneously resolve within 1 month of onset (31).

Herpes zoster infection. The skin lesions may be followed in 1 to 2 weeks by single or multiple ocular motor palsies ipsilateral to the skin lesion, sometimes even leading to complete ophthalmoplegia (104; 116; 119). The pathophysiology may be either vasculitis or inflammatory neuritis. The efficacy of treatment with corticosteroids or acyclovir is unresolved.

Diabetes mellitus. Diabetes mellitus may very rarely cause simultaneous multiple ocular motor cranial neuropathies, sometimes together with ischemic optic neuropathy (71; 37). Spontaneous recovery within 2 to 3 months is typical.

Temporal arteritis. Temporal arteritis can also cause simultaneous cranial neuropathies, and in elderly patients with a history of headache, mild anemia, jaw and facial pain, and arthritis, it should be a consideration (158).

Blunt head trauma. Blunt head trauma may cause multiple ocular motor palsies and is the most common cause in children (68).

Brainstem lesions. Brainstem lesions are unusual causes of multiple ocular motor palsies (160; 178; El Ouail 2012; 09). The lesions damage the intraparenchymal segments of the nerves. The distinctive features are that other neurologic manifestations, including nystagmus, skew deviation, and ataxia, are usually present.

Some authors advocate botulinum toxin injection into the antagonist extraocular muscles to protect against contracture during the period of prolonged recovery from ocular motor palsy (93). 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.

Ocular motor palsies may linger after the apparent resolution of many causes. One series reported improvement in 94% of patients with Tolosa-Hunt but in only 25% of patients with neoplasm-based cavernous sinus syndrome (12). Although 69% of patients with fungal cavernous sinus syndromes had improvement, 25% of patients died of their disease. In some patients, it may take 3 years to recover fully (49). Ptosis recovers first, followed by iris sphincter function, and finally by ocular ductions (106).

Differential diagnosis

Extraocular muscle disorders, myasthenia gravis, and brainstem lesions can present with clinical manifestations that imitate those of multiple ocular motor palsies.

Inflammation of extraocular muscles. This condition may mimic multiple ocular motor palsies. Graves ophthalmopathy can be distinguished by producing chemosis, eyelid and conjunctival congestion, lid retraction and lag, and exophthalmos. Ophthalmoparesis is based on a combination of weakness and restriction due to edema, inflammation, and fibrosis of the extraocular muscles and periorbital tissues. The forced duction test can confirm restriction. Under topical anesthesia, the eye is placed as far into the limited range as possible. Then, the examiner determines if the eye can be moved farther by using forceps, a cotton-tipped applicator, or a suction duction plunger similar to that used to remove contact lenses. 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 compressed by enlarged extraocular muscles.

Chronic progressive external ophthalmoplegia. Chronic progressive external ophthalmoplegia is a mitochondrial myopathy that causes slowly progressive bilateral ptosis and symmetric extraocular limitation, usually without diplopia. It spares the pupils, but orbicularis involvement is common (187). 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 are often present, and muscle biopsy shows ragged-red fibers (130; 147).

Brainstem syndromes. Brainstem syndromes can cause ophthalmoplegia in stroke or cancer and following medication use. In dorsal midbrain lesions (Parinaud syndrome), the defining ophthalmologic features include fixed pupils, convergence-retraction nystagmus, lid retraction (Collier’s sign), light-near dissociation, and paralysis of upward gaze. Midbrain tegmental syndromes (designated by eponyms such as Claude, Benedict, Nothnagel, and Weber) usually cause single ocular motor palsies. They can be distinguished by their additional neurologic features, such as tremor in Claude syndrome, tremor and chorea in Benedict syndrome, ataxia in Nothnagel syndrome, and hemiparesis in Weber syndrome. Lesions affecting the base of the pons that involve the corticospinal tracts cause contralateral hemiparesis and ipsilateral facial nerve palsy. These presentations are part of the Millard-Gubler and Foville syndromes (06).

Paraneoplastic brainstem encephalitis associated with anti-Hu antibodies. 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 (189). Some patients undergoing cardiovascular bypass or aortic surgery with deep hypothermia emerge with horizontal and vertical supranuclear ophthalmoplegia that spares vestibulo-ocular movements. Recovery usually occurs slowly over weeks to months (26; 182). MRI in such cases often shows diffuse white matter lesions. The origin of this syndrome is unclear but may reflect diffuse damage to cerebral centers that initiate gaze.

Medication-induced brainstem syndromes. Medication-induced brainstem syndromes have been reported after administration of phenytoin (128), phenobarbital, primidone, carbamazepine, and amitriptyline. They are likely supranuclear disorders, possibly due to increased GABA inhibition in the vestibulocerebellum.

Myasthenia gravis. Myasthenia gravis can produce any ocular motor pattern and ptosis. It is usually bilateral but asymmetric. Variability and fatigability are key signs. 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 levator and extraocular muscles (168; 39; 111; 138). More than 50% of patients with ocular myasthenia gravis are seronegative for myasthenia gravis markers (34). In recent years, new video-based eye tracking has demonstrated a subclinical detection of myasthenia gravis (21). The single-fiber EMG test is highly sensitive. The pupils, optic nerves, and trigeminal nerve are not involved in myasthenia.

Botulism. Botulism is another neuromuscular junction disorder that may mimic multiple ocular motor palsies. Signs of cholinergic autonomic hypofunction, such as dilated unreactive pupils, urinary retention, and decreased bowel sounds, are important clues to diagnosis.

Diagnostic workup

MRI of the orbit and sella turcica, including cavernous sinus and MR angiography, are the diagnostic procedures of choice (28; 73; 114). MRI sequences should include axial and coronal sections of the orbit and cavernous sinus with fat suppression and gadolinium. Biopsies of imaged lesions may be required. Blood cultures or nasal biopsies are indicated if infection is suspected. MR and CT angiograms have a 95% specificity and 90% sensitivity for intracavernous aneurysms measuring 3 mm or greater in diameter (102; 132).

Investigation of carotid-cavernous fistulas depends on excluding orbital causes and visualizing abnormal flow patterns in the cavernous sinus (126; 150; 62; 66). MRI reveals shunted blood in the cavernous sinus and superior ophthalmic vein as well as increased volume of the cavernous sinus (91; 02). Digital subtraction angiography remains the gold standard for classifying and diagnosing carotid-cavernous fistulae (72; 175; 62).

In septic bacterial thrombosis, blood cultures are typically positive in 70% (156; 23). Complete blood count, ESR, C-reactive protein, ACE level, P-ANCA, C-ANCA, ANA, and protein electrophoresis can help in suspected temporal arteritis, sarcoidosis, Wegener granulomatosis, Churg-Strauss syndrome, systemic lupus erythematosus, rheumatoid arthritis, multiple myeloma, and lymphoma (90; 44).

For fungal cavernous sinus or orbital vein thrombosis, biopsy of the paranasal sinus, nasopharynx, or orbit is indicated (145; 81; 82; 69). Fine-needle aspiration with CT guidance has been employed safely and effectively for lesions of the anterior cavernous sinus (134). MR and CT venography demonstrate high sensitivity and specificity in detecting cavernous sinus thrombosis (44).

The diagnosis of Tolosa-Hunt syndrome relies on MRI and CT imaging. MRI can reveal signal changes and enlargement of the cavernous sinus, accompanied by convex bowing of its lateral wall (51; 139). CT imaging may show occlusion of the superior ophthalmic vein and intra-orbital changes that could indicate either contiguous orbital inflammation or secondary effects of vascular occlusion (50). Imaging also plays a crucial role in ruling out masses because Tolosa-Hunt syndrome accounts for only 3% of cavernous sinus syndromes and is, therefore, a diagnosis made by exclusion (158; 136; 85).

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Combined third, fourth, and sixth nerve palsies

Associated Disorders

Multiple ocular motor palsies

Differential Diagnosis

inflammation of extraocular muscles
chronic progressive external ophthalmoplegia
brainstem syndromes
paraneoplastic brainstem encephalitis associated with anti-Hu antibodies
medication-induced brainstem syndromes
- myasthenia gravis
- botulism

Also Relevant

Cerebellar astrocytoma
Diplopia
Ependymoma
Hereditary neuropathy with predisposition to pressure palsy
Isolated fourth nerve palsy
- Isolated sixth nerve palsy
- Multiple cranial neuropathies
- Neurosyphilis
- Third nerve palsy

Combined third, fourth, and sixth nerve palsies …

Combined third, fourth, and sixth nerve palsies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and management

Differential diagnosis

Diagnostic workup

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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to access the full version.

Questions or Comment?

Also in This Category

Transient global amnesia

Visual agnosias

Stereotactic radiosurgery

Neuroimaging of headache

Painful ophthalmoplegia

Retinal vascular disorders

Systemic small-vessel vasculitis

Placebo and nocebo effects in neurologic disorders

Combined third, fourth, and sixth nerve palsies

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and management

Differential diagnosis

Diagnostic workup

Media

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Transient global amnesia

Visual agnosias

Stereotactic radiosurgery

Neuroimaging of headache

Painful ophthalmoplegia

Retinal vascular disorders

Systemic small-vessel vasculitis

Placebo and nocebo effects in neurologic disorders

This is an article preview.
Start a Free Account
to access the full version.