Aberrant Regeneration of Cranial Nerve III

Left adduction deficit in aberrant regeneration of CN III.

Left pseudo-Von Graefe's sign in aberrant regeneration of CN III.

Signs and symptoms: If patients have had a previous CN III palsy, they are likely to undergo secondary aberrant regeneration. In the absence of previous CN III palsy, this is termed primary aberrant regeneration.

Patients will have characteristic eyelid positioning and action as well as ocular motility deficits. In secondary aberrant regeneration, there may be residual adduction, elevation and depression deficits, as well as some degree of ptosis. The ptosis and ophthalmoplegia will be much less pronounced than during the clinical phase of the CN III palsy.

The patient's upper eyelid will lower on abduction and elevate on adduction. The eyelid will elevate when the patient looks down--pseudo-Von Graefe's sign. The motor root of the pupil will be active as the patient looks about. The pupil will constrict with attempted adduction.

Pathophysiology: CN III is the only cranial nerve with a subnuclear complex that arises in the dorsal mesencephalon at the level of the superior colliculus. Fascicles pass through the parenchyma of the midbrain via the red nucleus and corticospinal tract. They exit the mesencephalon and emerge into the subarachnoid space between the cerebral peduncles.

CN III enters the lateral wall of the cavernous sinus, bifurcating into superior and inferior divisions before exiting. Finally, it enters the superior orbital fissure, where it divides to innervate the muscles. Nerve fibers of CN III innervate the medial rectus, inferior rectus, inferior oblique, superior rectus, levator palpebrae superioris of the eyelid and the iris sphincter.

Aberrant regeneration occurs when damage to the CN III results in a resprouting and miscommunication of nerve to muscles. Fibers meant for certain muscles innervate the wrong muscles. The inferior rectus and medial rectus both communicate with the levator. As the medial rectus receives stimulation to contract and adduct the eye, it also stimulates the levator. Upon adduction, there will also be lid elevation and widening of the palpebral fissure. With attempted abduction, the medial rectus and the levator will be inhibited. The lid assumes a ptotic state when the eye abducts.

The inferior rectus shares fibers with the levator. When the patient looks down, the eyelid will retract, increasing the interpalpebral fissure. The medial rectus shares communication with the pupil. When the patient adducts, the pupil constricts.

There are two types of CN III aberrant regeneration: primary and secondary. The secondary form commonly occurs after CN III palsy, resulting from direct damage to CN III. Aneurysm, trauma and compression by tumor are typical causes. Inflammatory causes of CN III palsy may result in aberrant regeneration. Aberrant regeneration does not occur after CN III palsy from ischemic infarct.

Primary aberrant regeneration occurs independently of antecedent CN III palsy. A slow-growing mass, such as an aneurysm or meningioma within the cavernous sinus, causes this variant. The mass theoretically exerts subclinical compression on CN III, damaging the nerve fibers with a simultaneous regeneration and aberrant resprouting of fibers to incorrect muscles. The patient may not complain of diplopia or ptosis, or even be aware of the changes occurring.

Management: Secondary aberrant regeneration requires no management beyond recognition, unless it follows a presumed ischemic vascular CN III palsy. In such a case, look for another potential etiology.

With primary aberrant regeneration of CN III, look for signs of a meningioma or internal carotid artery aneurysm within the ipsilateral cavernous sinus. Obtain neuroradiological imaging--preferably MRI with contrast--of the chiasm, cavernous sinuses and parasellar areas. Neurosurgical consultation will be necessary if imaging reveals a mass lesion within the cavernous sinus.

Clinical Pearls:

• Primary aberrant regeneration of CN III represents a meningioma or internal carotid artery aneurysm within the cavernous sinus.
• The most clinically identifiable sign in CN III aberrant regeneration is lid elevation and retraction in downgaze.
• Secondary aberrant regeneration occurs after nearly every CN III palsy unless ischemic vascular infarct caused the palsy.