Hemophilia and other coagulation disorders: neurologic aspects
Jun. 20, 2022
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An isolated sixth nerve palsy may be a harbinger of underlying intracranial disease. Due to its long subarachnoid course, it may be damaged by downward shift of the brainstem as often occurs in increased or decreased intracranial pressure (“false-localizing sixth nerve palsy”). Alternatively, the sixth nerve may be involved in isolation by a compressive lesion in the cavernous sinus or along the clivus (“true-localizing sixth nerve palsy”), and specific attention on neuroimaging should be paid to these areas, especially in chronic or progressive cases. The most common causes of a sixth nerve palsy in an adult include ischemia, head trauma, and compression by a mass lesion, but inflammation, primary demyelination, and intracranial hypotension may also produce a sixth nerve palsy.
• A deficit in abduction is not always due to a sixth nerve palsy; therefore, patients should be considered to have an “abduction deficit” rather than a “sixth nerve palsy” until a diagnosis is confirmed. Alternative causes of an abduction deficit are medial rectus muscle restriction (as in dysthyroid orbitopathy, myositis, orbital wall fracture), myasthenia gravis, Duane type I retraction syndrome, and convergence spasm.
• A minimal sixth nerve palsy can be present without causing a visible abduction deficit. Therefore, the evaluation of patients reporting diplopia may require testing of ocular alignment using prisms.
• Sixth nerve palsy may be caused by increased or decreased intracranial pressure (“false-localizing palsy”) or by lesions in the pons (nucleus and fascicle), subarachnoid space, clivus, cerebellopontine angle, cavernous sinus, superior orbital fissure, and orbit along the course of the nerve (“true-localizing palsy”).
• Chronic or slowly progressive sixth nerve palsies may reflect life-threatening intracranial disease.
The terms sixth nerve palsy, abducens nerve palsy, and lateral rectus palsy are essentially interchangeable.
Patients with sixth nerve palsies complain of binocular horizontal diplopia worse in the field of action of the paretic lateral rectus muscle. Examination often reveals an ipsilateral abduction deficit and a primary position esotropia that is worse in gaze toward the paretic muscle. A small hypertropia (less than 2 to 3 prism diopters) may be present in unilateral sixth nerve palsies, its mechanism being unresolved. However, a hypertropia greater than 5 prism diopters indicates a concurrent skew deviation, coexisting third or fourth nerve palsy, or ocular myasthenia gravis.
Microvascular infarction of the sixth nerve is the most common cause in patients older than 50 years of age. Periorbital pain is present in 54% of patients (115).
Lesions of the sixth nerve nucleus cause an ipsilateral gaze palsy (neither eye can move fully ipsilateral to the lesion) rather than an isolated abduction deficit because of damage to the interneurons of the medial longitudinal fasciculus (MLF). Oculocephalic maneuvers and caloric testing will not overcome a gaze palsy caused by a nuclear sixth nerve lesion. Damage to the paramedian pontine reticular formation (PPRF) will cause a supranuclear ipsilateral gaze palsy, that is, one that can be overcome by oculocephalic maneuvers and caloric testing. An ipsilateral facial palsy is often present due to the close proximity of the facial nerve fascicles to the sixth nerve nucleus in the pons. Nuclear lesions are often also associated with ataxia. Fascicular lesions are often associated with ataxia, contralateral hemiparesis, or contralateral hemisensory loss. Subarachnoid space lesions result in unilateral or bilateral sixth nerve palsies. Petrous apex lesions may cause facial pain and damage to the fifth, sixth, seventh, and eighth cranial nerves. Gradenigo syndrome includes the triad: periocular pain, otitis media, and ipsilateral sixth nerve palsy; it may be treated surgically or with myringotomy and broad-spectrum antibiotics (08). Mastoid or middle ear infection may also lead to ipsilateral transverse sinus thrombosis, especially in children, causing increased intracranial pressure (“otitic hydrocephalus”). Manifestations of mastoiditis with transverse sinus thrombosis include sixth nerve palsy (-ies), papilledema, headache, pulsatile tinnitus, fever, ipsilateral hearing loss, and ear pain (03). Clivus lesions, including chordomas, chondrosarcomas, and metastases, produce unilateral or bilateral sixth nerve palsies and may be associated with lower cranial neuropathies (50). A literature review reported 58 patients with metastatic lesions to the clivus bone causing sixth nerve palsy between 2001 and 2021 (39). The most common primary tumor was prostate (22%), followed by gastrointestinal tract (15%), lung (13%), and kidney (11%). In 43%, the sixth nerve palsy led to the diagnosis of metastatic disease. Cavernous sinus lesions often damage cranial nerves 3, 4, 6, the first and second divisions of 5, and the postganglionic oculosympathetic fibers (causing ipsilateral Horner syndrome). Lesions of the orbit are associated with proptosis, eyelid swelling, conjunctival hyperemia, and impaired eye movements in various directions as well as periocular pain (07). Sixth nerve palsy is a common complication of endovascular treatment of carotid-cavernous sinus fistulas, reported in 16% of 101 embolization procedures involving the inferior petrosal sinus (88).
Neuromyotonia of the sixth nerve presents with limited abduction and transient delayed adduction due to sustained contraction of the lateral rectus muscle during adduction. A slowly growing compressive lesion or previous external therapeutic radiation of the middle fossa is almost always the cause (90).
Any cause of increased or decreased intracranial pressure may result in a unilateral or bilateral sixth nerve palsy. The mechanism is believed to be downward displacement of the brain with tugging on the sixth nerve at its anchor point at the petroclival junction (Dorello canal) (51; 103). High-resolution 3D MRI using constructive interference in steady state (CISS) technique has detected a dilated Dorello canal in patients with sixth nerve palsies due to idiopathic intracranial hypertension (49).
A study of 59 patients with presumed vasculopathic sixth nerve palsy disclosed that 51 (86%) recovered completely within six months (94). In traumatic sixth nerve palsy, injection of botulinum toxin into the medial rectus was initially favored as a means of improving recovery. However, in a prospective observational series of 84 patients with acute traumatic sixth nerve palsies, botulinum toxin injections into the medial rectus muscle had no effect on recovery of sixth nerve function (33).
A 60-year-old man with hypertension and diabetes presented with acute, painless, binocular horizontal diplopia that was worse in right gaze. The patient was maintaining a face turn to the right to avoid diplopia. Testing of ocular movements revealed a moderate abduction deficit of the right eye. On examination of ocular alignment, there was an esotropia (uncrossed diplopia) of 25 prism diopters in primary position, increasing in right gaze to 40 prism diopters. The remainder of the ophthalmological and neurologic examinations was normal. The patient was diagnosed with an isolated, presumed vasculopathic right sixth nerve palsy. No studies were ordered. The patient experienced complete resolution of the sixth nerve palsy within six weeks.
The etiologies of a sixth nerve palsy are listed in Table 1 (12; 05; 59; 93; 02; 24; 36; 38; 53; 54; 63; 72; 104; 76; 68; 91; 98).
• Congenital aplasia (Duane, Mobius syndrome) (87), demyelinating (109), ischemic, neoplastic, traumatic, metabolic (Wernicke disease) processes.
• Demyelination (104; 119), infarction, neoplasm, hemorrhage (61), or trauma (surgical or nonsurgical) (78).
Subarachnoid space meningeal lesions
• Aneurysm, including subarachnoid hemorrhage (69) or other vascular (eg, basilar or carotid artery) abnormalities such as dolichoectasia and root exit zone vascular compression (95; 107); following microvascular decompression of seventh nerve causing hemifacial spasm (30); ischemia from diabetes (26); carcinomatous meningitis; primary diffuse leptomeningeal gliomatosis (73); damage following surgical and other procedures, such as radical neck dissection (114), cervical traction, lumbar puncture, myelography, postvaccination, radiculography, arachnoid cyst (38), shunting for hydrocephalus, spinal or epidural anesthesia (47), spontaneous CSF leak (84), or postsurgical pneumocephalus (102); inflammatory lesions such as vasculitis (17), sarcoidosis, Lewis-Sumner syndrome (demyelinating mononeuritis multiplex) (57), or systemic lupus erythematosus; toxicity; infectious diseases such as Lyme disease, syphilis, tuberculosis (10), malaria (16), leprosy (110), cryptococcus (52), scrub typhus (56), hepatitis A (105), and other meningitides or pachymeningitis (41), cysticercosis, HIV or CMV encephalitis, herpes zoster virus, or West Nile virus; and neoplastic tumors such as abducens nerve schwannoma (37; 18; 81; 31), cerebellopontine angle tumor, clivus chordoma, metastasis or other tumor, leukemia, and infiltrative, metastatic, trigeminal nerve tumor. Increased or decreased intracranial pressure (106; 51). Ophthalmoplegic migraine is a rare cause (62; 112; 55; 64).
Skull base, petrous apex lesions and clivus
• Neoplasm (nasopharyngeal carcinoma, meningioma, chordoma, metastasis) (77; 48), myeloma (71; 100), infection (eg, complicated otitis media or mastoiditis), leprosy, Paget disease (79) thrombosis of inferior petrosal sinus, trauma (eg, basilar skull fracture, clival epidural hematoma) (43; 23), or inflammatory lesions (histiocytosis X). Hypophosphatasia syndrome causing dural calcification near the Dorello canal (46). CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M-protein agglutination, and disialosyl antibodies) (29), vertebral artery unruptured saccular aneurysms (113).
Cavernous sinus lesions
• Cavernous sinus thrombosis (spontaneous or iatrogenic after embolization treatments); dural (85) or cavernous sinus fistula; neoplasm such as nasopharyngeal cancer, adenoid cystic carcinoma with perineural spread (01), delayed reaction to local radiation (111), pituitary adenoma, Rathke cleft cyst (25), lymphocytic hypophysitis (40; 89) or pituitary apoplexy (66), plasmacytoma, sixth nerve neuroma, skull base tumors, sphenoid sinus tumors (42), squamous cell cancer of the pterygopalatine fossa; ischemic lesions, inflammatory or infectious lesions such as septic thrombosis, herpes zoster (99), internal carotid artery aneurysms (21), dolichoectasia, or dissection.
Sphenoid sinus-orbital lesions
• Neoplastic, inflammatory, infectious (bacterial or fungal) (58; 27), or traumatic lesions. After intravitreal injection (80) or botulinum toxin injection (09).
• Capecitabine, intravitreal bevacizumab, and systemic lupus erythematosus (13).
The sixth nerve originates in a lower pontine nucleus. This nucleus contains motor neurons for the lateral rectus muscle and interneurons traveling via the medial longitudinal fasciculus (MLF) to the contralateral third nerve medial rectus subnucleus. Thus, the nucleus contains all of the neurons responsible for ipsilateral horizontal conjugate gaze. The sixth nerve fascicles leave the sixth nerve nucleus and travel within the substance of the pontine tegmentum, adjacent to the medial lemniscus, and adjacent to the corticospinal tract. The sixth nerve leaves the brainstem and enters the subarachnoid space (prepontine cistern), and it courses nearly vertically along the clivus bone, traveling over the petrous apex of the temporal bone where it is tethered at the petroclinoid ligament in the Dorello canal. A study of 12 cadavers found that the sixth nerve was fixed to the Dorello canal in all cases, putting the sixth nerve at risk of traction even from minor head injury (108). The nerve enters the substance of the cavernous sinus lateral to the internal carotid artery and medial to the ophthalmic division of the trigeminal nerve. It enters the orbit through the superior orbital fissure to innervate the lateral rectus muscle.
Isolated sixth nerve palsy has no gender, age, or racial predilection. It is the most common ocular motor cranial neuropathy in isolation at 11 per 100,000 (83). Trauma is a common cause in all age groups. Children or young adults should be suspected of harboring an intracranial lesion, including brainstem glioma or demyelinating disease. In a review of 16 children younger than 18 years of age (mean=4.5 years) with unilateral isolated sixth nerve palsy, five were due to tumor, four were idiopathic and recurrent, three were postvaccination or post-viral, one was traumatic, one was associated with Chiari malformation, one was congenital, and one was idiopathic and nonrecurrent (15). Children are subject to a persistently isolated but recurrent sixth nerve palsy that may show enhancement of the subarachnoid portion of the nerve (60; 75). A review of the reported cases of recurrent sixth nerve palsy in children described 41 cases, concluding that female gender, left eye involvement, younger age, and recent vaccination were associated with recurrence and that a recurrence was less likely if it did not occur within one year of the initial event (117).
Older patients are more likely to have a vasculopathic ischemic palsy associated with standard risk factors for small-vessel arteriosclerosis, namely diabetes, hypertension, dyslipidemia, cardiovascular and cerebrovascular disease, and smoking (82).
A study of 466 patients in Korea with isolated third, fourth, or sixth nerve palsies followed for 5 years, along with 2281 control subjects matched for age and vascular risk factors, noted a markedly increased risk of stroke in the patients with microvascular cranial nerve palsies. Within 5 years, stroke occurred in 19% of patients with previous sixth nerve palsy but in only 7.5% of control subjects.
There is no preventive measure for sixth nerve palsy.
The differential diagnosis of sixth nerve palsy includes restrictive orbitopathies (medial orbital wall fracture, orbital tumor, idiopathic myositis, thyroid eye disease, IgG4 disease), myasthenia gravis, and spasm of the near reflex. These entities can usually be distinguished on clinical grounds alone. Patients with restrictive orbital disease usually demonstrate proptosis, chemosis, conjunctival injection, pain with attempted abduction, and positive forced ductions. Myasthenia gravis may mimic any painless, pupil-sparing ophthalmoplegia; other signs of myasthenia such as ptosis, variability, and fatigue are often present. Spasm of the near reflex is associated with a variable esotropia, intermittent pupil constriction, blurred vision (owing to inappropriate accommodation), and a feeling of eye strain. The abduction deficit resolves when the contralateral eye is occluded due to a break in binocular fusion. Correct identification of patients with convergence spasm (often volitional) will avoid extensive, time-consuming, invasive, and potentially harmful procedures.
Sixth nerve palsies may be divided into those that are “isolated” (not accompanied by other pertinent findings) and those that are “non-isolated” (accompanied by other findings). Bilateral sixth nerve palsies are considered “non-isolated;” they may reflect increased or decreased intracranial pressure or be caused by meningeal or clival lesions in the path of the sixth cranial nerves. Bilateral sixth nerve palsies have also been reported after MDMA (“ecstasy”) abuse (97), in association with anti-GQ1b (96) and anti-GM2 antibody positivity (101), and, rarely, with extra-axial ischemia (04).
Isolated sixth nerve palsies may be traumatic (including surgical), vasculopathic, and idiopathic in origin (44). Sixth nerve palsies in the setting of head trauma should be evaluated as indicated by the trauma-associated neurologic signs and symptoms. Patients with traumatic sixth nerve palsy(-ies) should be evaluated for signs of increased intracranial pressure (traumatic cerebral hemorrhage) and decreased intracranial pressure (traumatic CSF leak). Severe occipitocervical trauma may cause sixth nerve palsies, clival epidural hematoma, and C1-2 instability (23). Sixth nerve palsy may appear as long as three weeks after head trauma due to delayed development of a subdural hematoma (92).
An isolated sixth nerve palsy in patients with ample arteriosclerotic risk factors may be presumed to have an ischemic cause and should be observed without neuroimaging for improvement over four to 12 weeks. If no improvement has occurred by 12 weeks, or if new findings appear, MRI should be considered. The notion of withholding brain imaging in this setting is controversial; some authorities recommending immediate brain imaging in all new cases of isolated sixth nerve palsy. One group found MRI abnormalities in 27 of 43 patients presenting with an isolated sixth nerve palsy at a tertiary care center. Those with MRI abnormalities were younger (mean age= 43 years) than those with normal imaging (mean age= 56 years); no further information was given about the patients with abnormal imaging (06). Another publication reported 66 patients who were older than 50 years of age with third, fourth, or sixth cranial mononeuropathies and found nine with MRI abnormalities, two of whom had isolated sixth nerve palsies (one pituitary apoplexy, one brainstem stroke) (11). In contrast, a prospective study of 52 patients who were older than 50 years age who presented with an acute isolated third, fourth, or sixth nerve palsy and underwent high quality MRI found only one patient out of 93 with a pertinent MRI abnormality—a pontine hemorrhage that resolved spontaneously (70).
Improper imaging or misinterpretation of imaging occurred in 38% of patients at an academic neuro-ophthalmology center who had undergone initial evaluations at outside nonacademic centers (67).
Because sixth nerve palsy in the elderly may occasionally be caused by giant cell arteritis, other manifestations of this condition (headache, scalp tenderness, jaw claudication, fever, malaise, weight loss, anorexia, polymyalgia rheumatica, visual loss) should be sought. Even if these manifestations are not found, such patients should undergo testing of erythrocyte sedimentation rate (ESR) and noncardiac C-reactive protein (CRP) and, when clinically indicated, a temporal artery biopsy greater than 2 cm long. A 74-year-old Caucasian female presented with an isolated, left sixth nerve palsy and arrythmia, with no other stigmata of giant cell arteritis (65). Her ESR was 82 (nl < 42) and CRP was 12 (nl < 10). Within 2 days of starting oral prednisone 60 mg/d, the diplopia resolved. Hypokinesis of the left heart ventricle was noted, with negative cardiac enzymes, which also resolved within days after starting steroids. A temporal artery biopsy was consistent with giant cell arteritis. Patients with progression or lack of improvement by 12 weeks should undergo neuroimaging because such patients may harbor an occult skull base lesion (22). Attention on imaging should also be directed toward signs of intracranial hypotension (103). Testing for clinical manifestations of myasthenia gravis should also be sought. Even if not evident, patients should undergo ancillary testing in the appropriate setting. The fundus should be particularly examined to rule out papilledema, as sixth nerve palsy may be a sign of increased intracranial pressure.
COVID-19 infection has rarely been associated with sixth nerve palsy. A healthy 47-year-old male presented with a 1-day history of horizontal binocular diplopia to the right with fever (max 38.7° C), myalgias, headache, and a positive SARS-CoV-2 nasopharyngeal swab (86). MRI demonstrated diffuse confluent bilateral white matter abnormalities in perirolandic subcortical regions, centrum semiovale, corona radiata, and pons. CSF was unremarkable, including the opening pressure (16 cm H2O), SARS-CoV-2 PCR, IgG index, cell count, protein, and glucose. The sixth nerve palsy resolved within several days of receiving high-dose intravenous steroids. Follow-up MRI 3 months later was unremarkable, showing complete resolution of the prior lesions.
There is a reported case of a third and sixth nerve palsy attributed to SARS-CoV-2 infection (14) and a reported case of a left sixth nerve palsy attributed to SARS-CoV-2 (20). There is one case of Miller Fisher syndrome causing multiple cranial neuropathies, including a sixth nerve palsy, attributed to SARS-CoV-2 (28).
Therapy should be directed at the underlying etiology of the sixth nerve palsy and at palliating the diplopia. All patients with non-isolated sixth nerve palsy should undergo a thorough workup that may include brain imaging (MRI more sensitive than CT), laboratory tests, and lumbar puncture, as appropriate. Patients with isolated sixth nerve palsy should be divided into two groups: those that are considered very likely to have a vasculopathic ischemic cause (group 1) and all others (group 2). Group 1 patients may be observed for improvement (see controversy, above). Group 2 patients require a thorough diagnostic workup akin to that for non-isolated palsies.
To alleviate diplopia, one can recommend occlusion of one eye, a skin patch, or spectacle occlude (opaque Scotch tape). Alternating the skin patch between each eye is reasonable to avoid maceration of the skin but is not necessary as a means of preventing amblyopia in teenagers or adults because they are too old to develop amblyopia. If the misalignment is not severe, press-on (Fresnel) prisms may provide a reasonable zone of single binocular vision as a temporizing measure. If the sixth nerve palsy persists in a stable form for more than 6 to 12 months, and if diplopia is not satisfactorily relieved by prisms, the patient does not wear glasses, or does not tolerate long-term prism glasses, then surgical realignment of the eyes may be indicated (Holmes and Leske 2002; 74; 118). Long-term alleviation of diplopia was reported in 11 of 20 patients with complete unilateral sixth nerve palsy after vertical rectus muscle transposition surgery (35).
Botulinum toxin injections to the corresponding medial rectus muscle did not seem to alter the long-term outcome of acute traumatic sixth nerve palsy recovery (34; 19; 32) or related brain tumors (45).
Microvascular decompression resolved a sixth nerve in a 46-year-old male who had neurovascular compression of the sixth nerve by the vertebral artery noted on MRI (116).
Sixth nerve palsies arising or worsening during pregnancy may be caused by the following conditions: (1) meningiomas with estrogen surface receptors whose growth accelerates in pregnancy; (2) pituitary adenomas that grow under hormonal influence and even lead to pituitary gland hemorrhage (pituitary apoplexy); (3) idiopathic intracranial hypertension, which may also be stimulated by weight gain or hormonal influence.
Unilateral or bilateral sixth nerve palsy may result from intracranial hypotension from epidural anesthesia or blocks, complicated by a CSF leak (103).
David M Katz MD
Dr. Katz of Georgetown University Hospital and Howard University Hospital has no relevant financial relationships to disclose.See Profile
Jonathan D Trobe MD
Dr. Trobe of the University of Michigan has no relevant financial relationships to disclose.See Profile
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