Third Nerve Palsy (Oculomotor Nerve Palsy) Differential Diagnoses

Symptom

Clinical Relevance

Nature of Diplopia (Binocular versus Monocular; Horizontal versus Vertical or Oblique)

Binocular diplopia reflects ocular misalignment whereas monocular diplopia implicates an anterior segment issue, or retinal abnormality.  Ask the patient to alternately occlude each eye to localize the nature of the diplopia.

Directionality

Third cranial nerve palsies can cause variable patterns of diplopia, and manifestations of horizontal and vertical misalignment will reflect to what extent elevation, adduction, and depression of the eye are impaired. Diplopia is typically worse in the gaze direction of weakest muscle action.

Intermittent or Constant

Intermittent diplopia may be gaze directional or reflect a breakdown of binocular fusional control. In the case of a neuromuscular junction mimicking a third cranial nerve palsy, the diplopia may be truly intermittent.

Associated Symptoms (Pain and Other Systemic Complaints)

Inflammatory and compressive causes of third cranial nerve palsy may be associated with pain, whereas microvascular ischemic lesions are less commonly painful.  Patients older than 50 years may experience third cranial nerve palsies secondary to giant cell arteritis (GCA); therefore, asking about transient vision loss, headache, scalp pain, weight loss, muscle aches, and jaw claudication are important facets of the history to explore so as not to miss this vision-threatening/life threatening diagnosis.

Onset

Abrupt onset cranial third nerve palsies suggest a vascular etiology (pituitary apoplexy, subarachnoid hemorrhage) whereas compressive lesions may cause more insidious onset of deficits.

Progression and Course

Progressive worsening of third cranial nerve palsies may be seen with compressive lesions. Progressive improvement over weeks to months after acute onset symptomatology (diplopia) may implicate an ischemic cranial nerve palsy.

Fatigue/Variability

Prominent fatigue and variability with respect to ptosis and diplopia often implicate a neuromuscular junction abnormality in lieu of a third cranial nerve palsy.

Other Neurological Manifestations

Localizing brainstem findings such as a third cranial nerve palsy and contralateral weakness (Weber syndrome) can help localize a midbrain lesion such as stroke, whereas multiple cranial nerve palsies that are slowly progressive can implicate a chronic compressive lesion (aneurysm, meningioma) of the cavernous sinus. Multiple cranial nerve palsies with vision loss in the ipsilateral eye can implicate a lesion of the orbital apex.

Co-morbidities

Underlying diagnoses such as diabetes, pituitary macroadenomas, and multiple sclerosis can help localize the cause of third nerve palsies, when known. Systemic conditions such as Grave’s Disease can cause a restrictive orbitopathy which may mimic manifestations of a third cranial nerve palsy.

Medications

Some medications such as immune check point inhibitors (inflammatory), vaccinations (inflammatory), tumor necrosis factor alpha inhibitors (demyelinating), and bisphosphonates (inflammatory) may cause manifestations of third nerve palsies or, in the case of restrictive orbital lesions, mimic third nerve palsies.

Prior Strabismus

Patients with a prior history of strabismus with or without surgery might be interpreted to have an acquired third nerve palsy if they are symptomatic for loss of fusional control.

Recurrence

Patients with a history of  what was previously called "ophthalmoplegic migraine" may experience recurrent painful stereotyped third cranial nerve palsies over time.

Examination Finding

Clinical Relevance

Afferent Examination

Visual Acuity

Evidence of vision loss with a third cranial nerve palsy may implicate a common underlying mechanism such as papilledema, or localize lesions in the sellar region (pituitary apoplexy) or orbital apex.

Pupils (Efferent and Afferent Functions)

Evidence of anisocoria, with a mydriatic pupil or tonic pupil with light near dissociation ipsilateral to the third cranial nerve palsy will help localize the lesion; the presence of a concomitant ipsilateral relative afferent pupil defect may implicate a lesion of the orbital apex.

Color Vision 

Color vision loss disproportionate to high contrast visual acuity deficits may implicate a third cranial nerve palsy and ipsilateral optic neuropathy.

Fundus Examination

Evidence of optic atrophy (compressive lesion) or optic disc edema (anterior ischemic optic neuropathy or papilledema) may help localize the lesion or mechanism causing the third cranial nerve palsy.

Perimetry

The presence of focal visual deficits ipsilateral to the third cranial nerve palsy might suggest an orbital apex syndrome, whereas enlarged blind spots might implicate raised intracranial pressure with papilledema. A bitemporal defect suggests a lesion of the sellar region (pituitary tumor) with cavernous sinus involvement.

Efferent Examination

Inspection

Evidence of ptosis suggests a third cranial nerve palsy. Orbital signs such as proptosis and arterialized conjunctival vessels, might suggest an orbital process mimicking a third nerve palsy due to muscle restriction, including Grave’s Disease, orbital inflammation, orbital infiltration, or a carotid cavernous sinus fistula (CCF).

Ocular Motility

An isolated third cranial nerve palsy may cause variable ipsilateral involvement of the superior, inferior, and medial recti muscles and/or inferior oblique muscle. Multiple cranial nerve palsies might indicate lesions of the brainstem, cavernous sinus, skull base, or a more generalized peripheral nerve process such as Miller Fisher Syndrome. 

Aberrant Regeneration

Signs of aberrant regeneration involving the lid, pupil, and muscles innervated by the third cranial nerve can be seen with chronic compressive lesions in the cavernous sinus, and in the setting of what has previously been called “ophthalmoplegic migraine”.

Lid Function

Ipsilateral ptosis is localizing for a third cranial nerve palsy. Weakness of eye closure can be seen with myasthenia gravis and in patients with multiple cranial neuropathies (ie, Miller Fisher Syndrome) 

Fatigue Testing

Evidence of fatigability and variability (and Cogan’s lid twitch sign) on the examination suggests a neuromuscular junction abnormality.

Ice Test

After ice application, improvement of ptosis suggests a disorder of the neuromuscular junction as a possible mimic of a third cranial nerve palsy

Other

Blood Pressure

Systemic hypertension may implicate vascular risk factors linked to microvascular ischemic third cranial nerve palsy.

Syndrome

Cranial Nerve Involved

Clinical Pearl

Cavernous Sinus Syndrome

CNIII, CNIV, CNV1, CNV1, CNV2 (posterior), sympathetic innervation

CNII spared

Orbital Apex Syndrome

CNII, CNIII, CNIV, CNV1, CNV2, CNVI

Superior Orbital Fissure Syndrome

CNIII, CNIV, CNV1, CNVI

CNII spared, CNV2 spared

Investigation

Rationale

Serological Testing

Cell count with differential, hemoglobin AIC, serum sedimentation rate, c-reactive protein, free T3, free T4, TSH, prolactin, FSH, LH, free testosterone, lipid profile, IGF-1, morning cortisol, anti-acetylcholine receptor antibodies, anti-MuSK antibodies, serum lactate, connective tissue screen, genetic testing for mitochondrial disorders and oculopharyngeal muscular dystrophy.

Serological tests are indicated for suspected cases of diabetic microvascular ischemic cranial nerve palsy, pituitary macroadenomas, giant cell arteritis, myasthenia mimics, and thyroid related eye disease. Chronic progressive external ophthalmoplegia and oculopharyngeal muscular dystrophy can be evaluated with specific genetic testing.

Cerebrospinal Fluid Analysis

CSF cell count with differential, glucose, protein, cytopathology, gram stain, viral cultures, fungal cultures, and opening pressure as indicated

CSF analysis can help determine infectious (meningitis), inflammatory (cyto-albuminemic dissociation), malignant, and raised intracranial pressure mechanisms of third cranial nerve palsies.

Imaging

CT head, cranial and orbital MRI with gadolinium and gadolinium enhanced views, cranial MRI or CT angiography/venography, catheter angiography, CT scan of the chest, whole body PET imaging, orbital ultrasound

CT imaging is needed acutely in the setting of ICH or hydrocephalus with raised intracranial pressure. CT or MRI with detailed vascular imaging can be used to localize lesions along the fascicle, in the cavernous sinus, in the region of the superior orbital fissure and orbital apices, and orbit. Orbital ultrasound can detect arterialized flow through the superior ophthalmic vein, and help localize cases of CCFs. CT imaging of the chest is needed to check for hilar lymphadenopathy in the case of sarcoid, and thymic hyperplasia/thymoma in suspected MG. Whole body PET CT is useful in detecting inflammatory conditions such as sarcoid and systemic diseases/neoplasms.

Electrophysiology

Nerve conduction studies (NCS), electromyography (EMG), repetitive nerve stimulation (RNS) studies and single fiber EMG.

EMG/NCS/SF-EMG and RNS studies can be used to identify cases of neuromuscular junction abnormalities (myasthenia gravis) versus mitochondrial disorders and OPMD.

Tissue Analysis

Temporal artery biopsy, muscle biopsy, lesion biopsy (pituitary tumors, lesions of the parasellar space and cavernous sinus)

TAB is needed to confirm a diagnosis of GCA, whereas characteristic findings on muscle biopsy will characterize underlying myopathies.