Ophthalmic Hyperguide. Neuro-ophthalmology: Sixth Nerve Palsy

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Tutorial
Introduction
Anatomy
Clinical Evaluation
Differential Diagnosis
Evaluation
Non-isolated Sixth Nerve Palsy
Isolated Sixth Nerve Palsy
Traumatic Sixth Nerve Palsy
Vasculopathic Sixth Nerve Palsy
Demyelinating Sixth Nerve Palsy
Neoplastic
Inflammatory or Postinfectious
Prognosis
Treatment
Bibliography

Slides

Sixth Nerve Palsy

Andrew G. Lee, MD

Introduction

A sixth nerve palsy is a common cause for binocular horizontal diplopia in adults. A complete history and examination are necessary to differentiate the common and benign etiologies from the potentially dangerous neurologic causes (e.g., increased intracranial pressure, neoplasm) or the mimics of an abduction deficit (e.g., myasthenia gravis, thyroid eye disease, Duane's syndrome).

Anatomy

The sixth cranial nerve begins as a nucleus in the lower pons. The nucleus contains the motor neurons that innervate the ipsilateral lateral rectus muscle as well as supplying interneurons via the medial longitudinal fasciculus to the contralateral medial rectus muscle subnucleus of the third cranial nerve. The sixth nerve nucleus controls ipsilateral horizontal conjugate gaze.

The fascicle of the sixth nerve leaves the nucleus and travels within the substance of the pontine tegmentum, near the medial lemniscus, and the corticospinal tract. The nerve exits the pons ventrally, travels in the subarachnoid space within the prepontine cistern, rises vertically along the clivus bone over the petrous apex of the temporal bone, enters the substance of the cavernous sinus lateral to the internal carotid artery and medial to the ophthalmic division of the trigeminal nerve (V1), and passes into the orbit through the superior orbital fissure.

Therefore, a sixth nerve palsy may be divided anatomically into six locations:

Nucleus
Fascicle
Subarachnoid space and clivus
Petrous apex
Cavernous sinus
Superior orbital fissure and orbit

Topographical localization of a sixth nerve palsy using this anatomy is critical in the evaluation of patients.

Clinical Evaluation

Patients with a sixth nerve palsy typically complain about binocular horizontal diplopia. The diplopia is usually worse in the gaze direction of the paretic lateral rectus. Motility examination reveals an ipsilateral abduction deficit, a primary position esotropia, and a horizontally incomitant esotropia (i.e., worse in gaze toward the paretic muscle). A small vertical deviation (hypertropia typically more than 2 to 3 prism diopters) may be present in unilateral sixth nerve palsies due to a concomitant small hyperphoria. However, Wong and colleagues suggest that vertical deviations more than 5 prism diopters should implicate a concomitant skew deviation or an etiology other than an isolated sixth nerve palsy.

Table 1 lists the localizing nature of the clinical findings in patients with a non-isolated sixth nerve palsy. Table 2 lists potential etiologies for a sixth nerve palsy.

Table 1. Localizing Findings in a Sixth Nerve Palsy

Location	Clinical findings
Nuclear	Horizontal gaze palsy. May have seventh nerve dysfunction or other brainstem signs
Fascicle	Contralateral hemisensory or hemiparesis signs or symptoms; central Horner syndrome
Subarachnoid space	Other signs of increased intracranial pressure, other meningeal signs (e.g., headache, papilledema) or other cranial neuropathies
Petrous apex	Facial pain or dysfunction of the fifth, seventh, and eighth cranial nerves
Cavernous sinus	Sixth nerve palsy with any combination of third, fourth, and fifth cranial nerve dysfunction or a Horner syndrome
Orbit/superior orbital fissure	May have proptosis or other orbital signs or concomitant optic neuropathy

Table 2. Etiologies of a Sixth Nerve Palsy

Nuclear lesions	Congenital Demyelinating (i.e., multiple sclerosis) Ischemic or inflammatory (e.g., sarcoid) Neoplastic (e.g., glioma) Traumatic Vascular (e.g., vascular malformations) Metabolic processes (e.g., Wernicke disease)
Fascicular lesions	Demyelinating Ischemic or inflammatory Neoplastic Vascular (e.g., vascular malformations) Traumatic
Subarachnoid space lesions	Vascular (e.g., aneurysm or other vascular malformations) Infiltrative (e.g., carcinomatous meningitis) Post-procedures (e.g., cervical traction, lumbar puncture, myelography, radiculography, shunting for hydrocephalus, spinal or epidural anesthesia) Inflammatory lesions (e.g., vasculitis, sarcoidosis, systemic lupus erythematosus) Toxicity Infectious (e.g., Lyme disease, syphilis, tuberculosis, Cryptococcal, Cysticercosis, HIV-CMV encephalitis) Neoplastic Ophthalmoplegic migraine
Petrous apex lesions and clivus	Neoplastic (e.g., nasopharyngeal carcinoma, meningioma, chordoma, histiocytosis X, metastasis, myeloma) Infectious (e.g., complicated otitis media or mastoiditis) Thrombosis of inferior petrosal sinus Traumatic (e.g., surgical) Inflammatory lesions (e.g., sarcoid)
Cavernous sinus lesions	Thrombosis or fistula Neoplastic (e.g., nasopharyngeal cancer, pituitary adenoma, plasmacytoma, sixth nerve neuroma, skull base tumors, sphenoid sinus tumors, squamous cell cancer of the pterygopalatine fossa) Ischemic Inflammatory Infectious lesions Vascular (e.g., internal carotid artery aneurysms or dissection)
Orbital lesions	Neoplastic Inflammatory (e.g., orbital pseudotumor) Infectious (e.g., orbital abscess) Traumatic

Differential Diagnosis

The differential diagnosis of sixth nerve palsy includes any process that can produce an abduction deficit. Restrictive myopathy and orbitopathy (e.g., orbital wall fracture, orbital tumor, idiopathic myositis, thyroid eye disease) can produce an abduction deficit. Forced ductions may be positive in restrictive disorders. Myasthenia gravis may mimic any ophthalmoplegia including a sixth nerve palsy or horizontal gaze palsy. Spasm of the near reflex typically produces a variable abduction deficit and a variable esotropia associated with miotic pupils during the spasm phase. The Duane retraction syndrome may also be mistaken for a sixth nerve palsy. Lid fissure narrowing during adduction and widening in abduction in combination with a small or no primary position deviation and lack of diplopia suggest the diagnosis.

Evaluation

The main responsibilities of an ophthalmic clinician in evaluating a patient with a sixth nerve palsy are to:

Confirm the diagnosis clinically
Exclude mimics for a sixth nerve palsy
Test for bilateral sixth nerve dysfunction or other evidence for a non-isolated palsy
Ensure that the sixth nerve palsy is isolated
Perform appropriate laboratory and neuroimaging evaluation or refer for further evaluation

Non-isolated Sixth Nerve Palsy

Non-isolated palsies should be topographically localized based upon the accompanying neurologic signs or symptoms (Table 1). Bilateral sixth nerve palsies should not be considered isolated. The bilateral sixth nerve palsy always demands an assessment and may be a nonlocalizing sign of increased intracranial pressure or related to an underlying subarachnoid space, cavernous sinus, or clival lesion. As noted above, myasthenia gravis, thyroid eye disease, and spasm can mimic unilateral or bilateral sixth nerve palsy.

Isolated Sixth Nerve Palsy

The causes for an isolated sixth nerve palsy in an adult include:

Traumatic (including surgical trauma and post-lumbar puncture)
Vasculopathic (ischemic)
Demyelinating
Neoplastic
Infectious or inflammatory (often non-localizing sixth nerve palsy)

Each of these subcategories is discussed below.

Traumatic Sixth Nerve Palsy

Traumatic sixth nerve palsies that are old, static, or resolving do not require additional evaluation beyond that dictated by the initial injury or postsurgery event. Patients with minor trauma as the purported etiology of the palsy or who have progressive deficit should undergo additional evaluation, including neuroimaging for an occult skull base neoplasm or other etiology. Traumatic palsies often spontaneously improve over time.

Vasculopathic Sixth Nerve Palsy

An isolated and presumed vasculopathic-related (e.g., hypertension, diabetes) sixth nerve palsy may be observed for improvement from 4 weeks to 12 weeks. Vasculopathic risk factors should be sought in any patient older than 40 years of age presenting with a new sixth nerve palsy (e.g., hypertension, diabetes, smoking, cholesterol or atherosclerosis risk factors). Neuroimaging and further evaluation should be considered for patients with non-isolated, progressive, or unresolved sixth nerve palsy, even in a patient who is vasculopathic.

Demyelinating Sixth Nerve Palsy

Young patients with a new, isolated, non-traumatic sixth nerve palsy should undergo neuroimaging. Multiple sclerosis should be considered strongly in the differential diagnosis of a new isolated sixth nerve palsy in a young adult. Consideration for further evaluation, including lumbar puncture and laboratory testing, should be made depending upon the individual clinical features of the non-vasculopathic patient with a sixth nerve palsy.

Neoplastic

Neuroimaging (preferably cranial contrast magnetic resonance imaging [MRI]) should be performed in all chronic, non-resolving, progressive, or unexplained isolated, non-traumatic, non-vasculopathic sixth nerve palsies. Bendszus and colleagues performed a prospective study of MRI in 43 patients with acute unilateral sixth nerve palsies and 27 patients (63%) had an intracranial lesion. Ilhan and colleagues reported that 16 patients of 166 patients with nasopharyngeal carcinoma had a sixth nerve palsy and in 25% of cases of nasopharyngeal carcinoma it was the presenting sign.

Inflammatory or Postinfectious

Elderly patients who present with an isolated palsy and headache, scalp tenderness, jaw claudication, or visual loss should undergo an appropriate evaluation for temporal arteritis, including an erythrocyte sedimentation rate and, when clinically indicated, a temporal artery biopsy. Benign recurrent sixth nerve palsies may occur in children but should be considered a diagnosis of exclusion. Patients with progressive or non-isolated sixth nerve palsies and normal neuroimaging should be considered for a lumbar puncture for infectious and inflammatory etiologies.

Prognosis

Traumatic, demyelinating, post-infectious, and ischemic sixth nerve palsies often resolve spontaneously. Neoplastic or inflammatory lesions may improve depending on the completeness of therapy for the underlying etiology.

SLIDE 1

Treatment

SLIDE 2

Therapy should be directed at the underlying etiology of the sixth nerve palsy. Observation alone is appropriate for acute post-traumatic, demyelinating, post-infectious, and vasculopathic sixth nerve palsies. Patching of the involved eye in the short-term may alleviate diplopia symptoms. Prism therapy may be used for any residual primary position esotropia in patients with incompletely resolved diplopia. Botulinum toxin may also be used as a temporizing measure, but some patients require strabismus surgery for long-standing and stable deviations. (Slide 1, Slide 2, Slide 3)

SLIDE 3

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