Anatomical correlations

The nucleus of the 3rd CN is actually a nuclear complex that contains subnuclei for the four extraocular muscles it supplies(superior, inferior, medial recti, and inferior oblique), a single subnucleus (central caudal nucleus) for the levator palpebrae muscles, and paired subnuclei (Edinger-Westphal nuclei) for the pupillary constrictor muscles.
Since the single central caudal nucleus controls both levator palpebrae superioris muscles, and the superior rectus fascicles decussate just after emerging from their subnuclei, lesions of the CN III nuclear complex either affect or spare both upper eyelids and may affect the contralateral superior rectus muscle.
Injury to the 3rd CN nuclear complex may occur secondary to ischaemia of a small, paramedian-penetrating blood vessel, causing unilateral damage to a single nuclear complex. Such lesions are often asymmetric and may affect the 3rd CN fascicle on one side in addition to the nucleus.

Brainstem Syndromes

Intra-axial (fascicular) ocular motor CN palsies are due to lesions of the nerve distal to its nucleus but within the brainstem. In the midbrain, intra-axial lesions can damage either the  3rd CN or 4th CN.
Intra-axial involvement of the 3rd CN fascicle can produce specific syndromes, each of which includes an ipsilateral 3rd CN palsy: 
1. Damage to the ventral midbrain and the cerebral peduncle can cause a contralateral hemiparesis (Weber syndrome).
2. Involvement of the red nucleus and substantia nigra may produce contralateral ataxia or tremor (Benedikt syndrome).
3. Damage to the dorsal midbrain may involve the superior cerebellar peduncle and produce contralateral ataxia (Claude syndrome).
4. Dorsal lesion with a slightly different configuration can produce the same type of ataxia plus a 3rd CN nuclear lesion and features of supranuclear eye movement dysfunction (Nothnagel syndrome)

Causes

• Most isolated unilateral 3rd CN palsies result from (presumed) microvascular injury in the subarachnoid space or cavernous sinus.
• An isolated mononeuropathy of the 3rd CN warrants special attention because of the nerve’s close anatomical proximity to the cerebral vasculature (especially the posterior communicating artery) and the potential for aneurysmal compression.
• Myasthenia gravis may mimic any pattern of painless, pupil-sparing extraocular muscle dysfunction and should be included in the diʃerential diagnosis of such cases.
• Less common causes include aneurysmal compression, tumor, inÉ»ammation (eg, sarcoidosis), vasculitis, infection (eg, meningitis), inɹltration (eg, lymphoma, carcinoma), and trauma.

Pupil-involving third cranial nerve palsy

Due to loss of parasympathetic input this produces a mid-dilated pupil that responds poorly to light. Patients may present with variable dysfunction of the levator palpebrae or extraocular muscles. Aneurysms that arise at the junction of the posterior communicating artery (PCoA) and internal carotid artery are juxtaposed to the 3rd CN and are, therefore, in a position to produce a 3rd CN palsy as the initial manifestation of aneurysmal expansion or rupture. Pupillary involvement occurs because the pupillomotor ɹbers reside superɹcially in the medial aspect of the nerve adjacent to the PCoA. Emergent cerebrovascular imaging (eg, catheter angiography, magnetic resonance angiography (MRA), or computed tomography angiography (CTA), depending on the clinical scenario and neuroradiologic consultation) should be undertaken, and can detect almost all aneurysms. Modern CTA and MRA techniques can reliably detect aneurysms as small as 3 mm in diameter. Of these 2 methods, CTA is faster, provides images with slightly greater resolution, and may show evidence of a subarachnoid hemorrhage. 
When neuroimaging appears normal, lumbar puncture may yield evidence of a subarachnoid hemorrhage (xanthochromia of the spinal É»uid) or detect an inÉ»ammatory or neoplastic cause. 

Efferent pupillary dysfunction

In this case, the pupil is dilated and responds poorly to light, but exhibits normal eyelid and extraocular muscle function. This is not a form of 3rd CN palsy but rather represents a pupil that is either tonic (Adie), pharmacologically dilated, or mechanically damaged. Before concluding that the problem is limited to the pupil, the clinician must exclude a subtle CN 3palsy. Tentorial herniation is an unusual explanation for an isolated, fixed, and dilated pupil in the absence of altered mental status or other neurologic abnormalities.

Pupil-sparing third cranial nerve palsy

This term should be reserved for cases in which pupillary function is normal (ie, equal pupil size and reactivity), but there is total loss of eyelid and ocular motor functions of the 3rd CN. These are the typical ɹndings for ischemic cranial neuropathy, which usually fully resolves within 6 months. A pupil-sparing complete 3rd CN palsy is almost always benign and secondary to microvascular disease (diabetes mellitus, hypertension, or hyperlipidemia). An acute, isolated, pupil-sparing (but otherwise complete) 3rd CN palsy in a patient over 50 years of age with known vascular risk factors and without history of cancer does not necessarily require neuroimaging. However, a general medical evaluation is indicated to assess the patient’s serum glucose levels, systemic blood pressure, and serum lipid levels. In older adults, screening for vasculitis (eg, temporal arteritis) using ESR and C-reactive protein. If progression occurs, other cranial neuropathies develop, or the expected improvement does not ensue within 3 months, then neuroimaging should be undertaken to search for a mass or inɹltrative lesion at the base of the skull or within the cavernous sinus. Occasionally, neuroimaging studies need to be repeated to discover a mass, especially if it is within the cavernous sinus. Lumbar puncture may be needed to detect carcinomatous meningitis, inÉ»ammation, or infection.

Partial Pupil-sparing third cranial nerve palsy

In contrast, if the pupil reacts normally, with incomplete impairment of levator palpebrae and extraocular muscle function, the pupil-sparing CN III palsy is partial. Although the pupil is normal, this does not have the same benign implication as in pupil-sparing but otherwise complete oculomotor paresis. This distinction is crucial because some partial CN III palsies with normal pupillary function are due to compressive lesions, including aneurysm, and may later progress to involve the pupil. An MRA or CTA is therefore indicated to exclude an aneurysm. If the MRA/CTA is negative and the CN III palsy has progressed on follow-up, MRI of the brain and orbits with gadolinium should be obtained.

Divisional third cranial nerve palsy

CN III branches into superior and inferior divisions within the cavernous sinus and superior orbital fissure. Isolated involvement of either division usually indicates a lesion of the anterior cavernous sinus or posterior orbit. The initial diagnostic study of choice is cranial and orbital MRI with contrast and fat suppression in addition to an MRA. If neuroimaging results are normal, then evaluation of risk factors for stroke is appropriate. In rare cases, a divisional 3rd CN palsy may be secondary to brainstem disease, usually from small-vessel stroke (lacunae) or demyelination. Aneurysms are a much less common but potentially lethal cause of divisional CN III palsy. Rare additional causes include tumors, inflammation (eg, sarcoidosis, vasculitis), infection (eg, meningitis), infilltration (eg, carcinomatous meningitis or lymphoma), and trauma.

Aberrant regeneration

When a third nerve palsy is suspected, evidence of aberrant regeneration (or anomalous axon innervation) should be looked for. To assess for this, watch carefully for elevation of the lid or constriction of the pupil during adduction or depression of the eye. If aberrant regeneration occurs following an acute third nerve palsy, a compressive posterior communicating artery aneurysm or traumatic etiology is strongly suggested.

If aberrant regeneration occurs spontaneously without a preexisting third nerve palsy, a cavernous sinus meningioma or internal carotid artery aneurysm is suggested.

Aberrant regeneration of CN3 (right).
A, In primary gaze, there is mild ptosis, pupillary mydriasis, and exotropia, all on the right. B, With attempted downward gaze, the right eyelid retracts as ɹbers of the right CN 3 supplying the inferior rectus now also innervate the levator muscle

Aberrant regeneration of CN3 (left).
(A) Left mydriasis, exotropia, and right hypertropia in primary position. (B) Reduced left adduction with synkinetic left pupillary constriction and left lid elevation. (C) Complete left gaze (not fully shown in this photograph). (D) Reduced left elevation. (E) Reduced left depression with abnormal lid elevation due to synkinesis.