Sixth cranial nerve (abducens nerve) palsy

INTRODUCTION — Sixth cranial nerve palsy refers to dysfunction of the sixth cranial nerve (abducens nerve). This is also known as lateral rectus palsy and abducens nerve palsy. It is the most common ocular cranial nerve palsy to occur in isolation [1].

A sixth cranial nerve palsy most commonly arises from an acquired lesion occurring anywhere along its path between the sixth nucleus in the dorsal pons and the lateral rectus muscle within the orbit.

The clinical manifestations, evaluation, and diagnosis of sixth nerve palsy are reviewed here. The evaluation of diplopia and palsies of the third and fourth cranial nerves are discussed separately. (See "Overview of diplopia" and "Third cranial nerve (oculomotor nerve) palsy in children" and "Fourth cranial nerve (trochlear nerve) palsy" and "Third cranial nerve (oculomotor nerve) palsy in adults".)

ANATOMY — The sixth cranial nerve (abducens) innervates only the ipsilateral lateral rectus, which abducts the eye.

Each sixth nerve nucleus in the dorsal pons contains all of the neurons responsible for ipsilateral horizontal gaze [1]. These include the motor neurons for the ipsilateral lateral rectus muscle and the interneurons to the contralateral third nerve medial rectus muscle subnucleus in the midbrain. The interneurons travel through the medial longitudinal fasciculus to the contralateral third nerve subnucleus (figure 1).

The nucleus is located in the pons near midline, ventral to the floor of the fourth ventricle, and at the level of the facial colliculus. The sixth nerve fascicle leaves the nucleus, courses anteroinferiorly through the pontine tegmentum, adjacent to the medial lemniscus and adjacent to the corticospinal tract. It exits the ventral pons at the pontomedullary junction and enters the subarachnoid space in the prepontine cistern, where it follows a long (1.9 cm) anterolateral-superior course along the clivus over the apex of the petrous temporal bone. It pierces the dura at Dorello's canal, posterior to the sphenoid sinus between the petrous bone, where it is tethered by the petrosphenoidal ligament. Here, the nerve is most susceptible to changes in intracranial cerebrospinal fluid pressure. The nerve then courses through the cavernous sinus, where it lies lateral to the cavernous carotid artery and medial to the ophthalmic division of the trigeminal nerve (V1). Sympathetic fibers travel with the sixth nerve in the cavernous sinus before continuing anteriorly with the superior division of the fifth (trigeminal) nerve (V1).

The sixth nerve enters the orbit via the superior orbital fissure through the annulus of Zinn to innervate the lateral rectus muscle (table 1) [1].

Rare anatomic variations have been described, for example, nerve roots that originate from the brainstem and insert into the lateral rectus at different spots [2]; division of nerve into two fascicles by the anterior cerebellar artery has also been reported.

ETIOLOGIES — Sixth nerve palsy may be due to a number of causes, depending on the location along the path of the nerve (table 2) [3-9]. Neoplasia, vascular disease, and trauma are among the most common causes.

Tumors can compress the sixth nerve anywhere along its path. Elevated intracranial pressure (ICP) produces a sixth nerve palsy by causing pressure or traction of the nerve at the skull base. Inflammatory and infectious (eg, meningitis) disorders tend to affect the sixth nerve in the subarachnoid space or in the petrous apex. Traumatic sixth nerve palsies often are associated with fractures of the base of the skull. Hemorrhagic and ischemic vascular disease can affect the pons; microvascular ischemic disease related to hypertension and/or diabetes is a commonly identified cause of sixth nerve palsy in older adults.

In children, the most common causes of sixth nerve palsy are tumors, trauma, increased ICP, and congenital lesions. In one study of 75 children (average age eight years) with sixth cranial nerve palsy, neoplasms or their neurosurgical removal were the most common cause, accounting for 34 cases (45 percent) [10]. The most common tumors were posterior fossa medulloblastoma and brainstem glioma. Other causes included elevated ICP (of any cause, including idiopathic intracranial hypertension; 15 percent), trauma (12 percent), congenital causes (11 percent), inflammation (7 percent), miscellaneous (5 percent), and idiopathic cases (5 percent).

In adults, the most common causes of sixth nerve palsy include vascular disease, inflammation, trauma, tumors, and idiopathic cases. In a retrospective chart review of 104 patients with isolated sixth cranial nerve palsy, nine cases were associated with trauma [11]. Of the remaining 95, 52 were attributed to vasculopathic risk factors (eg, hypertension, diabetes), and six cases were presumed congenital. Demyelinating disease, such as multiple sclerosis, can initially present with sixth nerve palsy in isolation or along with other neurologic symptoms [12]. Recurrent painful ophthalmoplegic neuropathy, previously known as ophthalmoplegic migraine, more commonly presents as a third cranial nerve palsy but has been reported to cause a sixth nerve palsy along with ipsilateral headache [13].

Sixth nerve palsies are often classified as isolated (ie, no associated neurologic deficits) or nonisolated (ie, with associated neurologic deficits). While a specific cluster of accompanying neurologic deficits may vary according to the location of the lesion, isolated sixth nerve palsies may occur with lesions in any location. Isolated sixth nerve palsies in patients may be congenital, traumatic, postviral (including severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]), microvascular, or idiopathic [10,14-22]. Malignancy occasionally can present with an isolated sixth nerve palsy [23]. Some reports have documented sixth nerve palsy following SARS-CoV-2 immunizations; however, additional studies are needed to further establish a potential correlation [24,25]. Giant cell arteritis (GCA) and granulomatosis with polyangiitis are also reported causes [26-31].

Bilateral sixth nerve palsies have a different distribution of etiologies. Increased ICP, trauma, and disorders affecting the cerebrospinal fluid (eg, Guillain-Barré syndrome) are among the more likely etiologies, although microvascular disease and many other causes have been found as well [16,32-34]. GCA may be an underappreciated cause of both bilateral and unilateral sixth nerve palsy [27,35,36].

CLINICAL MANIFESTATIONS

Sixth nerve palsy — Patients with sixth nerve palsies typically complain of horizontal diplopia. The diplopia is binocular (ie, it requires both eyes to be open) and worsens with horizontal gaze toward the paretic (weak) lateral rectus muscle. More mildly affected individuals may complain of blurred vision, difficulty focusing, and dizziness rather than overt diplopia.

Eye pain is not infrequent with a sixth nerve palsy, particularly in patients with microvascular cranial neuropathies. In one series, more than half of patients with microvascular sixth nerve palsy had eye pain, which preceded the onset of diplopia in one-third of patients [1,37].

Early in the course, strabismus (lack of eye alignment) may be present only in the gaze toward the paralyzed side, but with time, the strabismus (ie, esotropia or inward deviation) may also be present when gazing straight ahead (in primary position). The deviation worsens in gaze toward the paretic muscle (lateral incomitance), and the eye fails to completely abduct. The degree of esotropia and abduction deficit are markers of severity of the paresis or palsy.

Often, patients turn their head toward the paralyzed side to avoid the gaze toward the symptomatic lateral rectus muscle. Other patients may close one eye to avoid diplopia.

Accompanying manifestations — Accompanying clinical manifestations identify the palsy as a nonisolated palsy. Specific neurologic deficits associate with the location of the lesion along the course of the nerve (table 2):

●An ipsilateral horizontal gaze palsy (failure of both eyes to deviate in one direction) rather than an isolated abduction deficit occurs with lesions involving the abducens nucleus in the pons because of involvement of the interneurons of the medial longitudinal fasciculus. These interneurons control contralateral medial rectus function (adduction) during attempted ipsilateral horizontal gaze (figure 1). (See 'Anatomy' above.)

An ipsilateral facial nerve palsy usually also occurs with a pontine lesion because of the close proximity of the facial and abducens nuclei.

Other brainstem signs (eg, hemiparesis, hemisensory loss, central Horner syndrome) may accompany a sixth nerve nucleus lesion with more extensive brainstem pathologies.

●Bilateral sixth nerve palsies suggest a lesion in the subarachnoid space (eg, meningitis). A sixth nerve palsy can occur in these patients as a nonlocalizing sign of increased intracranial pressure (ICP), due to traction of the sixth nerve. The sixth nerve is particularly susceptible to this phenomenon because of its long course within the subarachnoid space.

Other symptoms (eg, headache, nausea, vomiting) and signs (eg, papilledema (picture 1)) of increased ICP may be present when this is the underlying cause. (See "Evaluation and management of elevated intracranial pressure in adults", section on 'Clinical manifestations' and "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis" and "Idiopathic intracranial hypertension (pseudotumor cerebri): Clinical features and diagnosis", section on 'Clinical presentation'.)

●Facial pain and involvement of the fifth, seventh, and eighth cranial nerves in addition to the sixth nerve suggest a lesion of the petrous apex; this is sometimes referred to as Gradenigo syndrome.

●Impaired function of the third, fourth, and fifth (subdivisions one and two) cranial nerves and/or an ipsilateral Horner syndrome occur with cavernous sinus lesions or pathologies involving the superior orbital fissure. (See "Septic dural sinus thrombosis", section on 'Septic cavernous sinus thrombosis'.)

●Orbital signs such as proptosis or chemosis (conjunctival swelling) and/or a compressive optic neuropathy (with or without optic disc edema) can occur with lesions of the orbit.

●A small-angle hypertropia has been observed in isolated sixth nerve palsies and does not typically indicate skew deviation or involvement of other cranial nerves [38-40].

DIFFERENTIAL DIAGNOSIS — Not all isolated abduction deficits are related to a sixth cranial nerve palsy. The differential diagnosis of sixth nerve palsy includes:

●Restrictive orbitopathy – Thyroid eye disease often mimics a sixth nerve palsy when the medial rectus muscle is involved, thus restricting abduction of the eye. Orbital floor fracture, orbital tumor, or orbital pseudotumor are other causes of restrictive orbitopathy. Patients with restrictive orbital disease usually demonstrate proptosis, chemosis (conjunctival edema), and conjunctival injection. Magnetic resonance imaging (MRI) of the orbit can reveal the underlying entity. Alternatively, forced duction testing demonstrating restrictive findings on passive movement of the globe using ophthalmic forceps can identify a restrictive process. (See "Orbital fractures" and "Clinical features and diagnosis of thyroid eye disease".)

●Orbital myositis – Orbital myositis can mimic sixth nerve palsy presenting with pain and diplopia with either restriction or paresis of abduction. MRI will typically reveal the muscle involvement. (See "Overview of diplopia", section on 'Orbital myositis'.)

●Myasthenia gravis – Myasthenia gravis should be considered in any painless, pupil-sparing ophthalmoplegia, including sixth nerve palsy [23,41,42]. Additional signs and symptoms of myasthenia gravis, such as ptosis, variability, and fatigue, usually are present. (See "Ocular myasthenia gravis", section on 'Clinical features'.)

●Supranuclear disorders of gaze – Paralysis of ocular movements also occurs with supranuclear paralyses. In contrast with patients with sixth nerve palsy, patients who have supranuclear disorders of gaze may not have diplopia because the eyes remain parallel. (See "Ocular gaze disorders".)

●Childhood esotropia – Childhood esotropia includes congenital and acquired conditions. The most common of these include accommodative esotropia, idiopathic infantile esotropias, and Duane syndrome. Despite the esotropia, patients typically do not have diplopia, a feature that distinguishes these from an acquired sixth nerve palsy. (See "Causes of horizontal strabismus in children", section on 'Esodeviations'.)

●Spasm of the near reflex – Spasm of the near reflex (eg, convergence spasm) is associated with a variable esotropia (turning in of the eyes) and abduction deficit with miosis (constriction) of the pupil. The finding of intense miosis on attempted lateral gaze is an important clue to making the correct diagnosis [43-46]. Spasm of the near reflex usually is a nonphysiologic finding but rarely may be caused by an intracranial process.

●Sagging eye syndrome – Sagging eye syndrome can cause horizontal diplopia in older patients. Involutional change in the extraocular muscles and orbital connective tissues leads to inferior displacement of the lateral rectus leading to a mechanical (as opposed to neurologic) strabismus [47,48]. On examination, esotropia may be accompanied by limited supraduction, involutional blepharoptosis and floppy lower lids, along with retraction of the upper eyelid into the superior orbit with deepening of the superior sulcus and high upper eyelid crease. Horizontal ductions are typically full, and abducting saccade velocities are normal compared with slow abducting velocity observed with a sixth nerve palsy. MRI (not required but helpful for diagnosis) can reveal thinning, elongation, or rupture of the lateral rectus-superior rectus band.

EVALUATION

History and examination — The evaluation of patients with sixth nerve palsy depends upon whether the palsy is isolated or accompanied by other neurologic abnormalities [14,41,49]. The initial history and physical examination should focus on this distinction and should include the following components:

●Is the palsy isolated neurologically or are there other neurologic signs or symptoms?

●Does the patient have a history of trauma or systemic illness?

In patients with other neurologic abnormalities:

●Are symptoms and signs of increased intracranial pressure (ICP; eg, headache, nausea, vomiting, papilledema, involvement of other cranial nerves) present?

●Is the neurologic examination normal?

●Does the patient have focal hemispheric signs (eg, aphasia and hemianopsia)?

●Does the patient have posterior fossa signs (eg, nystagmus, ataxia, and facial palsy)?

The presence of neurologic findings (table 2) helps narrow the location of the lesion, and the differential diagnosis and can help direct neuroimaging.

Neuroimaging

Indications — Neuroimaging is always indicated whenever a sixth nerve palsy is accompanied by other neurologic findings. Neuroimaging should also be performed in most children and adults with an isolated sixth nerve palsy. Isolated sixth nerve palsies in patients may be congenital, traumatic, postviral, and idiopathic [10,14,15]. Malignancy occasionally can present with an isolated sixth nerve palsy [23]. The imaging should be performed urgently when focal signs or papilledema are present.

In older patients with vascular risk factors and an isolated sixth cranial nerve palsy, a microvascular (ischemic) mononeuropathy is the most likely etiology; thus, neuroimaging is not always required and may be delayed. Because a majority of patients with microvascular sixth nerve palsies improve spontaneously after a few weeks or months, neuroimaging should be obtained if there is no improvement after three months, if there is fluctuation over a six-month period, or if there is recurrence [50]. In two series, 15 to 20 percent of such patients were found to have neoplasm, brainstem infarction, demyelinating disease, pituitary apoplexy, or meningioma [27,51]. Many of these diagnoses affected the early management and long-term prognosis, emphasizing the need to be thorough when evaluating patients with an isolated sixth nerve palsy.

Preferred modality — MRI of the brain and orbits with gadolinium is the preferred modality because of superior capability of imaging of the posterior fossa [52]. Contrast-enhanced computed tomography (CT) is an alternative when MRI cannot be performed. The sensitivity of the study can be improved by consultation with a neuroradiologist to determine the optimal protocol. Ideally, high-resolution three-dimensional (3D) protocols are used, which include isotropic submillimeter slices obtained with sequences such as T1-weighted, ultrafast spoiled gradient echo pre- and postcontrast (3D fSPGR, 3D TFE, or MPRAGE); T2-weighted balanced steady-state gradient echo sequences (FIESTA-C or CISS); or T2-weighted turbo spin echo (SPACE, CUBE, or VISTA). These protocols should image the entire course of the abducens nerve from its pontomedullary origin to the superior orbital fissure. In addition to the above, the yield of the study can be improved by diffusion-weighted imaging and fat suppression, as well as thin coronal and axial cuts through the anatomic area of highest interest (eg, orbits) based on the clinical findings (table 2). (See 'Clinical manifestations' above.)

Neuroimaging is useful to identify a secondary cause of increased ICP and may also identify findings suggestive of idiopathic intracranial hypertension (eg, empty sella, flattened posterior globes, dilated perioptic nerve sheath's space, and focal bilateral stenosis at the junction of the transverse and sigmoid dural venous sinuses); MRI is also sensitive for vascular and demyelinating lesions in the brainstem. Contrast-enhanced MRI may also help to evaluate neoplastic lesions in any location as well as other pathologies in the subarachnoid space such as meningeal or parameningeal infections (viral, bacterial, fungal), inflammation (sarcoidosis), demyelination (multiple sclerosis) [53], or infiltration (lymphoma, leukemia, carcinoma) [11]. It can also assist in evaluating petrous apex inflammations or extradural abscesses to rule out Gradenigo syndrome. The cavernous sinus should be thoroughly assessed to rule out nasopharyngeal carcinoma; carotid-cavernous fistula; intracavernous internal carotid artery aneurysm; Tolosa-Hunt syndrome; meningioma involving the medial aspect of the sphenoid ridge, anterior clinoid process, or tuberculum sellae; and other tumors or neoplastic processes including metastasis, neurofibroma, craniopharyngioma, multiple myeloma, and lymphoma [54].

Other testing — If imaging is unrevealing, other etiologies should be considered and ruled out. Exceptions may include patients with a corresponding history of trauma or older patients with microvascular risk factors and an isolated sixth nerve palsy. In most other patients this requires a lumbar puncture with measuring of opening pressure and analysis of cerebrospinal fluid in order to assess for meningeal processes and idiopathic intracranial hypertension [50].

Older patients (>60 years) should also have a sedimentation rate and C-reactive protein to evaluate for potential giant cell arteritis (GCA), which can cause unilateral as well as bilateral sixth nerve palsy. Some patients with GCA will have other symptoms of polymyalgia rheumatica; others may have isolated sixth nerve palsy [27,35,36]. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis".)

Antineutrophil cytoplasmic antibodies (ANCA) testing could be considered if there is suspicion for granulomatosis with polyangiitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

In one series of 19 patients with isolated sixth nerve palsy with normal neuroimaging, 6 were found to be related to infectious etiology, 2 were associated with idiopathic intracranial hypertension, and 11 remained indeterminate [11].

In a subset of patients, no cause for a sixth nerve palsy is found. In older patients, a presumptive diagnosis of microvascular disease is made, particularly if hypertension and/or diabetes is present. Such patients should be followed with repeat evaluation for worsening or new symptoms.

TREATMENT AND PROGNOSIS — Patients with infectious, inflammatory, or neoplastic lesions should receive appropriate therapy for the underlying condition. In patients with suspected giant cell arteritis (GCA), prompt initiation of steroid therapy is recommended. Such treatments may alleviate diplopia. (See "Treatment of giant cell arteritis".)

Spontaneous recovery is common in patients with unilateral, isolated, nontraumatic sixth nerve palsy [1,55,56].

Traumatic sixth nerve palsy may also resolve spontaneously [1]. Spontaneous recovery occurs more commonly in unilateral than in bilateral cases [15,57,58]. Thus, patients with traumatic sixth nerve palsy usually are observed for several months before treatment is considered. Inability to abduct past midline (complete palsy) and bilateral involvement at the time of presentation are associated with failure to recover by six months after injury, with or without therapy (prism, patch, or botulinum) [59]. Palsies that do not resolve tend to become comitant deviations. Comitant deviations are those in which the distance between the double images is equal in the various gaze directions and symptoms are affected only slightly by the direction of gaze.

Symptomatic patients with isolated congenital or acquired palsies should be considered for treatment. The goal is to maximize visual function, including alignment. Treatment modalities may include alternate patching, prism therapy, strabismus surgery, and/or botulinum toxin.

●Patching – Patching of one eye alleviates binocular diplopia in individuals with sixth nerve palsy. Patching is useful in patients who are being observed or who defer treatment with prisms or surgery. Patching in children younger than nine years of age should be employed with caution and with the assistance of an ophthalmology consultant because complete full-time occlusion of a single eye can lead to the development of iatrogenic (occlusion) amblyopia. (See "Amblyopia in children: Classification, screening, and evaluation", section on 'Definition'.)

●Prism therapy – Prism therapy may be employed for small, comitant, long-standing deviations. A temporary press-on (Fresnel) prism of sufficient power to align the eyes is placed on the spectacle lens. Permanent prisms can be ground into the spectacle lens if the patient is happy with the result and the deviation fails to improve spontaneously.

●Strabismus surgery – Strabismus surgery may be helpful in patients who fail prism therapy. In one study of 64 children seven years of age or younger with sixth nerve palsy of varying etiologies, approximately one-quarter underwent strabismus surgery; residual strabismus was present in 66 percent [60].

A retrospective study of 81 patients 20 to 86 years of age with isolated chronic acquired sixth cranial nerve palsy who underwent strabismus surgery concluded that patients with neoplastic and traumatic etiology were more likely to require more than one operation when compared with microvascular, idiopathic, or central nervous system etiologies [61].

●Botulinum toxin – Botulinum toxin, a neurotoxin that causes temporary muscle paralysis, can be used in patients with acute unilateral sixth nerve palsy. It is injected into the ipsilateral medial rectus muscle (the antagonist of the lateral rectus) to prevent secondary contracture and to reduce the nasal deviation. In a randomized trial in adults with acute unilateral sixth nerve palsy of various etiologies, recovery rates were similar between the treatment and control groups (19 out of 22 [86 percent] versus 20 out of 25 [80 percent], respectively) [62]. Randomized controlled trials have not been performed in children [63].

Botulinum toxin has been useful in the management of chronic sixth nerve palsy in some patients in uncontrolled studies [64,65]. It appears to work best when used in conjunction with strabismus surgery.

SUMMARY AND RECOMMENDATIONS

●Causes – Causes of sixth nerve (abducens) palsy include a variety of processes that can affect the nerve anywhere between the sixth nerve nucleus in the pons, or its course through the subarachnoid space along the petrous apex, or in the cavernous sinus and orbit (table 2).

The most common causes in children are tumors, trauma, increased intracranial pressure (ICP), and congenital causes. In adults, these are vascular disease, inflammation, trauma, and tumors. (See 'Etiologies' above.)

●Clinical features – Patients with sixth nerve palsies complain of binocular horizontal diplopia that worsens with gaze toward the paretic lateral rectus muscle. (See 'Clinical manifestations' above.)

Examination reveals a primary position esotropia worse in gaze toward the paretic muscle (lateral incomitance) and an ipsilateral abduction deficit. Other manifestations depend upon the location of the lesion along the course of the nerve (table 2). (See 'Clinical manifestations' above.)

●Differential diagnosis – The differential diagnosis includes restrictive orbitopathies, thyroid eye disease, myasthenia gravis, supranuclear disorders of gaze, childhood esotropia, Duane syndrome type 1, and spasm of the near reflex. (See 'Differential diagnosis' above.)

●Evaluation – The evaluation of patients with sixth nerve palsy depends upon whether the palsy is isolated or accompanied by other neurologic abnormalities (table 2). (See 'History and examination' above.)

●Neuroimaging evaluation – Neuroimaging is indicated in most patients. Imaging should be performed urgently when focal signs or papilledema are present. In older adults with vascular risk factors, neuroimaging may not be necessary or may be delayed for isolated sixth nerve deficits but should be performed if the sixth nerve palsy does not improve over three months or if the patient develops other clinical findings. (See 'Neuroimaging' above.)

The preferred neuroimaging study is MRI without and with contrast. Special sequences and fine cuts through a targeted anatomic area as suggested by the patient's clinical syndrome (table 2) can also improve the sensitivity of the examination. (See 'Preferred modality' above.)

●Management and prognosis – Most isolated sixth nerve palsies will recover spontaneously. Treatment modalities for those with persistent disability may include patching, prism therapy, strabismus surgery, and/or botulinum toxin. The goal is to maximize visual function, including alignment. (See 'Treatment and prognosis' above.)