IV. Neuropathies and Nuclear Palsies

i. III nerve palsy


contributed by Jason Barton, University of British Columbia, June 2008

Symptoms and signs

Paresis of the III nerve leads to complaints of diplopia, ptosis and blurred near vision. Diplopia is usually oblique in primary position, but varies with the degree of weakness in various muscles. The patient may not complain of double vision if the ptosis obscures the vision of the paretic eye. Usually the paresis is persistent. Intermittent III nerve palsies are uncommon. Short-term fluctuations may indicate a compressive cause. They have been reported with fluctuations of intracranial pressure in AIDS-related cryptococcal meningitis (1), and uncal compression from a temporoparietal glioblastoma has caused adduction paresis and mydriasis that was precipitated by the Valsalva maneuver or changes in head position (2).

With a complete III nerve palsy, the eye in primary position is depressed and abducted – “down and out“. It cannot elevate or adduct but has full abduction and some residual depression. Depression is accompanied by intorsion, maximally when the eye is abducted, and is due to the action of the superior oblique. This evidence of superior oblique function should be sought, as the differential diagnosis of III nerve palsy differs considerably from that of combined III and IV nerve palsies. Despite loss of inferior oblique function, pathologic intorsion of the eye is seldom seen, but measures of the patient?s sense of the vertical often reveals monocular tilts, though not always in the expected direction or in the paretic eye (3). Ptosis is severe, accommodation impaired, and the pupil is large and does not constrict to light or vergence efforts.
See video: III palsy with preserved IV nerve functionSee video: combined III and IV palsy ).

Incomplete palsies are more common than complete palsies. If so, the examination should seek to determine whether the partial involvement conforms to a superior or inferior divisional palsy. Once attributed to cavernous sinus pathology, divisional palsies may occur from a lesion anywhere along the course of the III nerve or fascicle.

The most frequently identified causes of III nerve palsies are ischemia and aneurysms. Tumors and trauma account for another 10% each, and a cause is not found in 20%. Differentiating benign ischemic palsies from those due to potentially fatal aneurysms is a challenge, especially since both can present with painful diplopia, and delay in diagnosis increases mortality (4). Two clinical signs help differentiate aneurysmal and neoplastic palsies from the more benign ischemic palsy: pupillary involvement and oculomotor synkinesis.

The pupil rule

The pupil is spared in 75% of ischemic III nerve palsies, but involved in over 90% of aneurysmal palsies (5, 6 , 7, 8). Furthermore, pupil-sparing in aneurysmal palsies almost never occurs with complete dysfunction of all other III nerve muscles (9-11). Hence the correct ‘pupil rule’ is that complete pupil-sparing with otherwise complete and isolated palsy of the III nerve is never due to an aneurysm (12, 13). Though a small degree (less than 1mm) of anisocoria is present in a third of microvascular III nerve palsies (14), relative pupil sparing in an otherwise complete III nerve palsy, and complete pupil sparing with incomplete palsy of extra-ocular muscles and the levator do not reliably exclude an aneurysm or other mass lesion (15) (16). Also, the presence of pain and the degree of associated external ophthalmoplegia do not distinguish microvascular from compression causes of relative pupil-sparing III nerve palsies (16). The presence of other cranial nerve palsies or neurologic signs should prompt investigation for a mass lesion. Also, caution is required to ensure that a coexistent Horner’s syndrome (17) or aberrant regeneration of the pupil are not mimicking pupil sparing (13), as these may indicate a mass. Given these caveats, correct use of the pupil rule is not likely to miss an aneurysmal III nerve palsy (18).

[Above] III nerve, microvascular complete extraocular palsy with pupil-sparing.Photos illustrate primary and secondary gaze positions, as well as the complete ptosis (left).
This 66 year old man had diabetes and his painful right III palsy recovered after 12 weeks.


The reason for frequent and early pupillary involvement in aneurysmal palsies relates to III nerve topography. Pupillomotor fibers run in its dorsomedial periphery (19). Presumably, such fibers are often spared by ischemia because the nerve’s periphery has better vascular supply than its center, since the nutrient vessels run centripetally (20). On the other hand, the most frequent aneurysm affecting the III nerve occurs at the junction of the internal carotid and posterior communicating artery. These aneurysms compress the dorsomedial surface of the nerve, where the pupillomotor fibers lie (12). The less frequent basilar artery aneurysm may approach the nerve differently, however, and there is one case of such an aneurysm causing a pupil-sparing complete III nerve palsy (21).

III nerve: aneurysm of the posterior communicating artery, angiogram. Lateral view of cerebral angiogram showing IC-PCA aneurysm (arrow) at the junction of the internal carotid and posterior communicating arteries, from a patient with pupil-involving partial III nerve palsy.

The management of acute partial pupil-sparing or partial III nerve palsies is controversial. Some suggest that the incidence of aneurysms in this group is low enough that imaging is not necessary (22) but others advocate angiography for all (23). Since a pupil-sparing partial III palsy from an aneurysm usually develops pupillary involvement within a few days (9), others suggest a period of observation (24). In any case, improved detection of aneurysms by MR angiography or high resolution CT (25) has reduced the requirement for conventional angiography and its attendant risks. Whether these are sufficient to eliminate the need for conventional angiography entirely (26) is not yet clear. MRA may still miss 1.5% of aneurysms causing III palsy, and some suggest that conventional angiography should still be done when an aneurysm is highly suspect, unless there are factors indicating an increased risk of angiographic complications (27). Current algorithms advocate that MR or CT angiography is a reasonable first step for imaging patients with III nerve palsies, but that conventional angiography be done after a negative result if the pupil is completely involved, be considered with relative pupil sparing, and is unnecessary if the pupil rule is obeyed (28).

Oculomotor synkinesis

Some III nerve palsies also have anomalous co-contraction of muscles. The most common sign is lid elevation on adduction, though lid elevation with attempted depression is also frequent (29). Pupillary constriction on attempted adduction or depression also occurs, often with poor light reaction (29). Careful examination may reveal normal constriction of some sectors of the iris to light and synkinetic constriction of other sectors with eye movement (30). Synkinesis between extra-ocular muscles causes adduction or globe retraction with attempted vertical gaze. Any of these signs in an adult implies III nerve compression by an aneurysm or tumor until proven otherwise, since microvascular or idiopathic lesions are rarely if ever responsible. Oculomotor synkinsesis also occurs after trauma, including neurosurgical procedures, and migraine. It is not so ominous in children, as it occurs frequently withcongenital palsies. Rarely it has occurred following a midbrain ischemic lesion (31). When the initial lesion can be dated, synkinesis requires at least six weeks to develop (29).

Occasionally synkinetic signs occur in patients without a preceding acute III nerve palsy, when it is known asprimary aberrant regeneration (32). These patients do have signs of partial III palsy at the time when synkinetic signs are found, and often have a history of slowly progressive diplopia or ptosis (32). Primary aberrant regeneration indicates an intracavernous mass lesion, most often a meningioma or giant aneurysm (32, 33).

The origin of synkinetic signs is debated. Most commonly synkinesis is attributed to aberrant regeneration. The original neural insult is followed by randomly directed regeneration of partially damaged neurons, with some axons eventually misdirected to wrong muscles, causing abnormal synkinetic movements. Such movements would then be permanent, which is often the case. However, transient synkinetic movements have also been observed with treated lymphoma and migraine (33, 34). In such cases the explanation may be ephaptic transmission rather than misdirection (33).


III nerve, oculomotor synkinesis (aberrant regeneration). 54 year old woman with paresis of elevation, abduction and depression of the right eye, and partial ptosis in primary. Note the increase in the palpebral fissure in down and left gaze, compared with primary and right gaze. These indicate aberrant re-innervation of the levator by fibers originally directed to the medial and inferior recti. Coronal MRI shows a cavernous sinus meningioma.

Synkinetic signs between different cranial nerves can also occur. Lid elevations with abduction in eyes with congenital and traumatic III nerve palsies have been attributed to aberrant innervation from VI to III nerve structures (35, 36). A contralateral post-traumatic oculomotor synkinesis has been proposed for elevation of the contralateral normal lid with depression of a paretic eye (37). Synkinesis between cranial nerves most likely originates from aberrant regeneration rather than ephaptic transmission (37).

III nerve syndromes
Brainstem lesions

Nuclear lesions are rare, but can be diagnosed often by signs reflecting the anatomy of the III nuclear complex (Table 5). Some patterns of ocular motor weakness occur only with nuclear damage and not with fascicular or neuropathic lesions: for example, a unilateral III nerve palsy with bilateral superior rectus weakness (38, 39) orbilateral ptosis (40-42), or nearly isolated bilateral ptosis (43-45). Other patterns of weakness cannot occur with nuclear lesions, such as III nerve palsy with unilateral ptosis or unilateral mydriasis. Many patients with III nuclear lesions also have supranuclear palsies of vertical eye movements, especially of saccades, because of the proximity of the inC and riMLF (46, 47). The plus-minus lid syndrome (48, 49) is a rare combination of a III nuclear palsy with unilateral ptosis and contralateral lid elevation. This may reflect a lesion sparing the central caudal nucleus but affecting axons from it to the ipsilateral eye and supranuclear inhibitory projections to it. Somnolence from involvement of the adjacent reticular formation is frequent with nuclear III palsies (41, 46).

Table: Nuclear versus Non-nuclear Syndromes of Cranial Nerve III

Unilateral CN III palsy with: Contralateral superior rectus palsy
Bilateral ptosis
Bilateral CN III palsy without ptosis
Bilateral isolated palsy of: levator palpebrae superioris
pupillary sphincter
superior rectus
Unilateral isolated palsy of: medial rectus
inferior rectus
inferior oblique
Unilateral mydriasis
Unilateral ptosis
Unilateral isolated superior rectus palsy
Unilateral complete CN III palsy sparing contralateral superior rectus

Fascicular lesions cause partial or complete unilateral palsies, with ocular signs indistinguishable from peripheral palsies. MRI has revealed ipsilateral fascicular lesions with isolated palsies of the medial and inferior recti (50, 51), with contralateral lesions with isolated palsies of the superior rectus (52). Disruption of the fascicle can even evident with diffusion-tensor tractography in some cases (53). Usually, though, there are other signs of midbrain damage. Disrupted dentato-rubro-thalamic axons in the brachium conjunctivum cause ipsilateral limb ataxia, and damage to the red nucleus causes contralateral resting hemitremor, hemichorea, or hemiballismus. If the lesion affects the cerebral peduncle there is contralateral paresis of the limbs and/or face – Weber’s syndrome (54). More rostral spread may affect prenuclear structures for vertical gaze. Combinations of these signs occur frequently, and bear eponymous names of historical interest (55).

Partial fascicular palsies may mimic superior and inferior divisional palsies (56, 57) (58), monocular elevation paresis (59, 60) or cause isolated paresis of the pupil (61) or inferior oblique (62). Analyzing these cases suggests a topographic fascicular organization with the pupil, inferior rectus, medial rectus, lid, superior rectus and inferior oblique proceeding from superomedial to inferolateral (62-65). If so, the fascicular palsies may be pseudo-divisional palsies, distinguished from true divisional palsies at the cavernous sinus by the involvement of the inferior oblique together with the superior rectus and levator (62), or sparing of the inferior oblique with palsy of other inferior division muscles. This hypothesis requires confirmation with observations on elevation in adduction and extorsional motion in attempted upgaze. Otherwise, most of these partial palsies are accompanied by other midbrain signs that do not occur with cavernous sinus pathology.

Causes of midbrain III syndromes reflect the general distribution of intrinsic brainstem lesions. They are most commonly vascular ‘top of the basilar’ syndromes (66). Occasionally they occur with intrinsic primary or secondary tumors or infections, such as AIDS or tuberculosis. Fascicular III palsies can also occur with demyelination and brainstem hemorrhages, including the Duret’s hemorrhages of uncal herniation.

Peripheral nerve lesions

Lesions of the subarachnoid portion of the nerve most often cause an isolated unilateral III palsy with few localizing clues. Occasionally an extra-axial mass affecting the III nerve within the interpeduncular fossa may be associated with contralateral hemiparesis, mimicking Weber’s fascicular syndrome. Meningismus may occur, depending upon etiology. Lesions of the subarachnoid III nerve may cause partial palsies that conform to the superior (67-69) or inferior divisions of the nerve (63).

III nerve palsy, hemorrhage affecting subarachnoid course.This 64 year old woman had been seen initially for a stroke from atrial fibrillation and rheumatic heart disease. She was anticoagulated, but then presented 5 months later with a new painful right III nerve palsy.
MRI susceptibility images showed the hypointense signal (arrow) consistent with hemorrhage adjacent to the course of the III nerve as it passes from the midbrain, through the interpenduncular cistern, and to the cavernous sinus.

The most important lesions causing subarachnoid III nerve palsies are aneurysms of the basilar artery or the posterior communicating artery (Figure C.IV.d). Aneurysms occur in young or middle-aged adults (mean age 50 years) (8), and seldom in children (70-73). They are usually acute painful palsies. Posterior communicating artery (ICA-PCA) aneurysms occur at the junction of this artery and the internal carotid artery (Figure C.IV.b). Knowledge of the correct form of the “pupil rule” is imperative for determining which patients with III nerve palsies require imaging. Rupture of ICA-PCA aneurysms is preceded by warning signs such as a III nerve palsy 70% of the time, with the time between initial symptoms and subarachnoid hemorrhage being 30 days on average (74). Delay in treating an ICA-PCA aneurysm increases the mortality rate from 20% to 67% (4). These aneurysms can be treated with either surgical clipping or endovascular coiling: small series differ in their opinion over whether III nerve recovery is better or the same after clipping compared to coiling (75, 76). Ocular motor recovery may be poorer with diabetes, older age, and complete palsies (76). III nerve palsy is also a common complication of surgical resection of basilar and superior cerebellar artery aneurysms, and its likelihood correlates with the size and direction of the aneurysm (77). Besides aneurysms, dolichoectatic basilar arteries can occasionally compress the III nerve, and are now detectable with high-resolution MRI (78).

Ischemic III nerve palsies are more frequent in older patients, with a mean age of 61 years (8) (Figure C.IV.a). Most are presumed to affect the subarachnoid nerve, though electrophysiologic evidence of abnormal masseteric reflexes has suggested a central location in some (79). They are due to microvascular disease and such patients often have hypertension and diabetes (6, 80), though in half diabetes is discovered after the III nerve palsy (8). Sildenafil or cocaine (81, 82), giant cell arteritis (83) and severe carotid stenosis can also cause a typical vascular III nerve palsy (84-86). Simultaneous central retinal artery occlusion and contralateral hemiparesis point to carotid occlusion (87). Microvascular palsy presents as a sudden onset painful III nerve defect with frequent sparing of the pupil. Some progression of weakness commonly occurs within the first two to three weeks (24, 88), with recovery beginning 1 to 2 months later (89). III nerve palsies that do not start to recover by 2 months should be imaged to exclude tumors and atypical aneurysms, regardless of the state of the pupil (24). Spontaneous recovery does not always prove a microvascular cause, as it can happen after several weeks or months with posterior communicating artery aneurysms (90) and lymphoma (91). Recovery from compression or trauma can even occur after several years, for unknown reasons (92).

Traumatic III nerve palsy occurs with head injuries sufficient to cause loss of consciousness or skull fractures. The degree of head injury is usually more severe than that associated with IV or VI nerve palsies (93). Minor head trauma may cause a III nerve palsy that unmasks a previously unsuspected aneurysm (94) or tumor in the sellar or clivus area, such as a chordoma or meningioma (95). Transtentorial uncal herniation compresses the ipsilateral III nerve, with early and frequent pupillary dysfunction. Sometimes the contralateral III nerve is compressed, causing a false localizing sign. With progression, both III nerves are affected, due to a combination of compression and hemorrhage into the midbrain affecting the III fascicle (54). Tumors of the III nerve such as neurinomas and schwannomas are increasingly recognized as causes of palsy (96, 97). Unfortunately the III nerve does not do well with resection of these. Inflammatory conditions such as Lyme disease (98) and sarcoidosis (99) are unusual.

Figure: III nerve, partial inferior divisional palsy. Nine cardinal gaze positions show partial paresis of depression, adduction and pupilloconstriction of the left eye, in a 28 year old man with Tolosa Hunt syndrome.

Cavernous sinus lesions often affect several or all of cranial nerves III, IV V and VI, but can cause mononeuropathies. Pituitary apoplexy with sudden severe headache is a rare but important cause of sudden painful isolated III nerve palsy (100-102). If the lesion is located in the anterior sinus it may cause a divisional paresis of either the superior (103) or inferior subdivisions of the III nerve (Figure C.IV.e). A divisional palsy should always be investigated for a cavernous sinus mass, although partial lesions of the III fascicle, subarachnoid or intra-orbital III nerve (69, 104) can also cause them. More benign causes of divisional palsies include dural arteriovenous malformations (105), viral or flu-like infections (106) and sphenoid sinusitis (107).

[Above] III nerve palsy, from parasellar meningioma.This 63 year old man was followed for 4 years after presenting with several months of diplopia. Examination showed a subtle partial III nerve palsy, with mild limitation of elevation, adduction and ptosis.
MRI T1-weighted with contrast is shown, with axial and coronal images. Arrow indicates the enhancing mass that on axial shows the characteristic tapering tail of a meningioma. The mass was stable over the years of follow up, though the ocular motor limitations very slowly progressed.

III nerve palsy, from cavernous sinus metastasis.This 67 year old woman had a history of breast cancer 1 year prior, when she presented with a partial left III palsy.
Coronal T1 weighted MRI without contrast shows the metastatic mass in the region of the left cavernous sinus (arrow).
She died from further metastatic complications 9 months later.
Pediatric III nerve palsies
Congenital palsies

These account for a third to a half of pediatric III nerve palsies (70, 108-111). These are usually incomplete and unilateral, and many have synkinetic signs (108, 110). Other neurologic signs are more common than with congenital IV or VI palsies (112). Certain rare congenital syndromes have specific patterns. Adduction palsy with synergistic divergence is an incomplete III palsy with anomalous innervation of the lateral rectus, so that a gaze shift requiring adduction of the paretic eye leads instead to abduction of both eyes. In vertical retraction syndrome, synkinetic co-contractions cause the eye to retract during attempted vertical gaze.

In cyclic oculomotor paresis with spasms, the muscles supplied by the III nerve cycle between periods of paresis lasting one to two minutes and periods of abnormal contraction lasting 10 to 30 seconds (113). It is almost always unilateral and the paresis can be total or partial, with sparing of the lid or medial rectus most common. Any or all III nerve functions can participate in the spasms, though the most obvious cycling occurs in pupillary diameter and lid position. Attempted adduction, elevation, or accommodation may provoke spasms. In most cases the palsy is apparent at birth or develops within the first year, and the cyclic spasms are seen at the time the palsy is diagnosed or shortly after. The disorder is permanent. The leading pathophysiologic hypothesis is that early damage to the peripheral III nerve causes retrograde degeneration of nuclear neurons prior to the maturation of supranuclear inputs to the nucleus. Subsequent regeneration of these damaged neurons is associated with abnormal central inputs and a denervation supersensitivity to subthreshold stimulation from these abnormal central connections (113).

Acquired pediatric III nerve palsies

Among these, aneurysms are distinctly rare, with five reports of posterior communicating artery aneurysms in patients under age 20, the youngest at age 7 (70-73). As with all ocular motor palsies, trauma causes a larger proportion of acquired III nerve palsies in children than in adults (110, 111, 114). Tumors occur with a similar frequency of 15% (111, 114). Slowly progressive III nerve palsies in children with initially normal investigations may eventually prove to be tumors (115), especially if they lack the signs of aberrant regeneration so common in congenital palsies (108). Repeated imaging every two years is recommended (115).

Ophthalmoplegic migraine occurs mainly in children, with onset often under the age of 10 years (116). Unlike other neurologic symptoms associated with migraine, the III nerve palsy follows the headache, lasting from a day to a week. Usually the palsy is either complete or preferentially affects the superior division. MRI shows transient enhancement and thickening of the subarachnoid portion of the nerve (117) (116). Some advocate steroid treatment of the acute phase in the hopes of resolving episodes more promptly and possibly averting a more permanent palsy, although there is little data for this yet (116). Permanent III nerve palsy with or without aberrant regeneration can develop after multiple episodes. In the differential diagnosis, schwannoma of the oculomotor nerve can mimic ophthalmoplegic migraine, and may require high-resolution MRI to detect it (118) (119).

Strabismic amblyopia complicates more than a third of pediatric III nerve palsies (110, 111), and requires patch therapy to maintain the acuity at presentation. Surgery can improve the appearance but it is hard to restore binocular fusion (110, 111).