Clinical Vignette

A 37-year-old woman presented with a 2-day history of “blurry” vision on upward gaze, and headache. One month previously, when she had experienced the same symptoms, sinusitis was diagnosed, and an antibiotic was prescribed; symptoms had resolved in 5 days.

Examination demonstrated impaired upward, downward, and medial movement in the right. There was mild right-sided ptosis, and the pupil was slightly larger and reacted poorly compared with the left.

Magnetic resonance imaging (MRI) yielded normal results, but catheter angiography demonstrated a posterior communicating artery (p-com) aneurysm. At craniotomy the same night, the neurosurgeon reported fresh and old clot around a 10-mm aneurysm compressing the right oculomotor nerve. The aneurysm was clipped, and patient had an uneventful recovery with gradual resolution of the neuro-ophthalmologic findings.

Oculomotor palsy is most often associated with microvasculopathy due to diabetes mellitus, hypertension, or advanced age, so that its pool of potential victims is large. It is sometimes the harbinger of urgent, dangerous disease such as expanding berry aneurysm. Even in idiopathic cases, the diplopia it typically produces is not only distressing for the patient but also disrupts daily activities. Even in cases where ptosis is severe enough to eliminate diplopia by blocking the vision of the affected eye, the impact on patients, both on an emotional and practical level, is severe.

The oculomotor nerves course from the ventral midbrain to the orbits. CN-III provides the general somatic motor efferent innervation controlling upper lid elevation and most of the extraocular movements upward, medially, and downward. In addition, CN-III carries the general visceral motor (parasympathetic) efferent innervation responsible for pupillary constriction and accommodation (near focus) of the crystalline lens.

CN-III begins at its nucleus in the midline upper midbrain. The nucleus is a lepidopteroid collection of nine subnuclei located in the center of the rostral midbrain at the level of the superior colliculi (Fig. 5-1). The most ventral of these subnuclei is the central caudate nucleus, a midline structure that innervates both levator palpebrae muscles. Uniquely, axons from the medial subnuclei or columns decussate completely to innervate the contralateral superior rectus muscles. The other six subnuclei, three left-and-right pairs, innervate ipsilateral extraocular muscles. The ventral subnucleus, intermediate column, and dorsal subnucleus, respectively, control the medial rectus (eye adduction), inferior oblique (intorsion and some elevation), and inferior rectus (depression).

Figure 5-1 Oculomotor (III), Trochlear (IV), and Abducent (VI) Nerves: Schema.

Sometimes considered a subnucleus of CN-III, the Edinger–Westphal nucleus abuts the others rostrodorsally, residing at the ventral edge of periaqueductal gray matter. The Edinger–Westphal nucleus supplies the cholinergic efferents producing pupillary constriction and ciliary muscle contraction (lens accommodation). Afferents from the pretectal nuclei mediate the pupillary light reflex, whereas inputs influencing pupil constriction and lens accommodation in response to near visual stimulus originate from striate and prestriate cortex and the superior colliculus. When the pupillary fibers join the oculomotor nerve, they move exteriorly and dorsally within the nerve, a clinical continuation of the spatial relation of the Edinger–Westphal nucleus to CN-III.

The CN-III nucleus receives numerous afferents, including inputs from the paramedian pontine reticular formation for horizontal eye movement, the rostral interstitial nucleus of the medial longitudinal fasciculus for vertical and torsional movements, and the vestibular nuclei. Other afferents come from the superior colliculi, the occipital cortex, and the cerebellum.

Axons from the CN-III nucleus gather into a fascicle that sweeps ventrally in an arc curving toward the medial surface of the cerebral peduncle, then passes through the red nucleus.

The nascent oculomotor nerve emerges from the medial surface of the cerebral peduncle to enter the interpeduncular cistern. It crosses the cistern for approximately 5 mm, passing under the posterior cerebral artery. The fibers subserving pupillary constriction are located externally at the caudal aspect of the nerve and are less prone to microvascular changes as deeper fibers are. This arrangement is thought to explain the pupil’s resilience to ischemia affecting CN-III and to its susceptibility in compression. The nerve follows beneath the posterior communicating artery (p-com) for 10 mm and then pierces the dura underneath the p-com before it passes the internal carotid artery (ICA) en route to the cavernous sinus.

The cavernous sinus is part of the intracranial venous system. It receives blood from the ophthalmic vein and sphenoparietal sinus, transmitting this flow to the superior and inferior petrosal sinuses. The left and right cavernous sinuses are connected via the intracavernous plexus; they also communicate with the basilar sinus and the pterygoid and foramen ovale plexuses. The cavernous sinus resides lateral to the pituitary gland, resting atop the roof and lateral wall of the sphenoid sinus. Besides venous blood, the space contains the intracavernous portions of CN-III, -IV, and -VI; the ophthalmic branch of CN-V and its maxillary nerve posteriorly; the ICA; and the sympathetic nerve fibers investing the adventitia of the ICA. CN-III, -IV, and -VI and the ophthalmic nerve all leave the cavernous sinus to enter the orbit via the superior orbital fissure.

Given the confluence of multiple structures into this relatively small sinus, cavernous lesions are prone to produce multiple cranial nerve palsies often with pain or numbness in the ophthalmic distribution of CN-V. If the pathologic process is extensive, signs of venous obstruction in the orbit also develop (proptosis and chemosis).

CN-III typically divides into superior and inferior branches within the anterior cavernous sinus, thus entering the orbit as two distinct structures. The superior branch supplies the superior rectus and levator palpebrae muscles. The inferior branch provides somatic innervation to the medial and inferior recti and the inferior oblique, and it supplies the parasympathetic pupillary input to the ciliary ganglion, located superolaterally to the optic nerve. The parasympathetic axons from the Edinger–Westphal nucleus synapse here, with the postsynaptic neurons providing visceral motor control to the iris sphincter and the ciliary muscles via the short ciliary nerves.

Etiology and Pathogenesis

Etiologies for CN-III are broadly divided into two groups: those due to microvascular nerve infarction (e.g., diabetes mellitus) and those due to compression. There are also other, less frequent etiologies.

In the patient presenting with acute, severe headache and pupil-involved CN-III palsy, an expanding aneurysm, usually of the posterior communicating artery (p-com), is the most important cause (Fig. 5-2). The location of these aneurysms is the origin of p-com at the ICA (Fig. 5-3) and 90% of these aneurysms present with CN-III palsy. Aneurysm in other nearby arteries can likewise present as CN-III palsy, with up to 30% of acquired CN-III palsies being caused by aneurysms.

Figure 5-2 Ophthalmologic Manifestations of Cerebral Aneurysms.

Figure 5-3 Aneurysms Causing Oculomotor Nerve Palsy.

However, the majority of acquired CN-III palsies will be due to vascular compromise of some portion of CN-III, commonly affecting patients with known risk factors for vasculopathy or microvascular disease. In 60–80% of microvascular CN-III palsy cases the pupil is spared. Typically, these palsies have a favorable prognosis and uncomplicated recovery within 2–4 months. Although common vasculopathies secondary to diabetes and hypertension are seen most frequently, attention should be paid to the possibilities of other systemic vasculitides, temporal arteritis, clotting disorder, and infiltrative processes.

Third-nerve palsies due to lesions of the nucleus or fascicle within the midbrain are usually part of a larger midbrain syndrome (see below). The usual etiologies of such palsies are stroke for older patients and inflammatory or demyelinating disease (i.e., multiple sclerosis) in the young.

Open or closed head injuries may lead to traumatic oculomotor nerve palsy. The suspected mechanism is traction or shearing where the third-nerve root is relatively fixed at its origin and at its entrance into the dura.

Typically, traumatic CN-III palsy is associated with severe frontal deceleration impact with loss of consciousness and, usually, skull fracture (e.g., unrestrained occupant in a motor vehicle accident). In cases where pupil-involving CN-III palsy is discovered after seemingly trivial injury, neurovascular imaging to detect a possible underlying skull base tumor, often meningioma, or aneurysms should be performed.

Cavernous sinus thrombosis may produce a cranial polyneuropathy that features CN-III palsy. Often it is a septic complication of central facial cellulitis and a dreaded clinical entity typically producing proptosis, ophthalmoplegia, and optic neuropathy. Septic phlebitis of the facial vein or pterygoid plexus is the usual intermediary between cellulitis and infectious thrombosis.

Tolosa–Hunt syndrome is a painful ophthalmoplegia caused by idiopathic cavernous sinus inflammation, with most instances considered within the spectrum of inflammatory pseudotumor. It typically involves multiple cranial nerves and varies in degree over days. MRI of the cavernous sinus is needed to confirm the diagnosis, and treatment with high-dose corticosteroids is indicated once tumor and infection have been excluded.

Intrinsic, extrinsic, and metastatic tumors can cause third-nerve palsy. Carcinomatous or granulomatous meningitis can affect multiple cranial nerves in succession, often simulating Tolosa–Hunt syndrome.

Clinical Presentations

The classic presentation of a complete CN-III palsy is unmistakable: because of the unopposed actions of the superior oblique and lateral rectus muscles, the eye is turned outward and usually down. Upper-lid ptosis often requires that the lid be held up by the examiner to assess ocular motility.

The presence or absence of ipsilateral mydriasis (“pupil-involvement” or “pupil-sparing,” respectively) has traditionally been considered a major diagnostic consideration. CN-III palsies of compressive origin have pupillary involvement in the vast majority of cases and, if acute with severe headache, strongly suggest aneurysm as the etiology. Pupil-sparing usually implies temporary CN-III palsy due to microvascular ischemia. Patients with microvascular oculomotor palsy may report a mild ache in the ipsilateral brow, but occasionally the pain can be severe.

Motor involvement of CN-III palsies are generally characterized as complete, incomplete (where the innervated muscles show subtotal palsy), and, since the CN-III divides into superior and inferior rami just before its entrance into the orbit, divisional. “Superior division” CN-III palsy involves ipsilateral dysfunction of the superior rectus and levator palpebrae muscles, whereas an “inferior division” palsy has impaired downgaze, medial gaze, and on occasion, loss of pupillary constriction. Divisional palsies would seem to imply an orbital or anterior cavernous sinus pathologic site; however, more proximal intracranial disease is often responsible. Many cases will have negative imaging and recover well, and are then assumed microvascular in etiology.

Incomplete CN-III palsies show partial losses of up-, down-, and medial-gaze, along with partial ptosis with some CN-III-innervate muscles more affected than others. In such cases—as the clinical vignette illustrates—recognition that the patient’s ocular misalignment is a form of third-nerve palsy can be challenging. It is generally agreed that the presence of the pupil-sparing in such cases does not rule out compressive etiology.

A patient with an isolated medial rectus dysfunction (inability to adduct the eye) should not be considered to have an incomplete CN-III palsy. Most often, this condition is caused by internuclear ophthalmoplegia (see below). It may also be seen in cases of myasthenia gravis or from orbital disease involving the horizontal rectus muscles.

When the origin of third nerve palsy is at the nucleus, the presentation is one of ipsilateral medial rectus, inferior rectus, and inferior oblique dysfunction, with contralateral superior rectus weakness because of the decussation of axons from the medial column subnucleus. Because of bilateral lid innervation by the central caudate subnucleus, the eyelids exhibit either bilateral blepharoptosis or are normal, depending on the extent of the insult. In clinical practice, such cases are exceedingly rare.

With insult to the third-nerve fasciculus, clinical localization is often aided by the presence of other signs of midbrain dysfunction. CN-III fasciculus lesions at the red nucleus present as oculomotor palsy with crossed hemitremor, Benedikt syndrome. If the lesion extends to the medial lemniscus, there is also contralateral hypesthesia. Similar lesions with caudal extension into the brachium conjunctivum produce ipsilateral cerebellar ataxia or Claude syndrome. When damage extends ventrally into the basis pedunculi and the corticospinal tract, hemiplegia contralateral to the CN-III palsy occurs (Weber syndrome).

In comatose patients, unilateral mydriasis (“blown” or Hutchinson pupil) is indicative of supratentorial increased intracranial pressure (ICP), sufficient to force the uncus of the temporal lobe laterally and caudally to compress the third nerve against the anterior edge of the tentorial foramen (uncal herniation). In fact, using oculocephalic maneuvers, additional evidence of compressive CN-III palsy can be uncovered. Pupil checks and oculocephalic maneuvers need to be monitored frequently in any unresponsive patient, since uncal herniation can be rapidly fatal if not detected and addressed at its earliest sign. The laterality of the blown pupil does not always correlate with the side of the lesion.

Although a few cases exist of mydriasis as a possible sign of compressive third-nerve palsy in patients who are awake and alert, this remains exceedingly unlikely without evolving signs of altered consciousness and usually indicates another etiology, such as pharmacologic pupillary mydriasis or Adie tonic pupil (below).

Whereas microvascular CN-III palsy is generally followed by full recovery, the prognosis for traumatic or postoperative compressive CN-III palsy is guarded. If recovery occurs, it is usually marked by aberrant regeneration and synkinesis. The best-known example is the pseudo–von Graefe sign: the branch of CN-III that normally innervates the inferior rectus now synkinetically innervates the levator palpebrae, causing the upper lid to lift on downward gaze (clinically simulating the lid lag, or von Graefe sign, of Graves orbitopathy). Internal motor efferents can likewise be involved, resulting in a change of pupil size as gaze is shifted.

Occasionally, primary aberrant regeneration (aberrant regeneration without history of prior palsy) will be encountered. This finding is due to chronic compression of the third nerve, typically within or near the cavernous sinus usually due to meningioma and occasionally from an aneurysm of the intracavernous ICA. Adie tonic pupil is another example of aberrant regeneration affecting a facet of CN-III function with a probable intraorbital location within the ciliary ganglion and is discussed further in the section pertaining to pupils.

As opposed to the preceding discussion of isolated CN-III disease, the oculomotor nerve can be involved in cranial polyneuropathies, in which case the accompanying deficits typically help localize the etiology. Cavernous sinus syndrome typically affects CN-III, -IV, and -VI and the ophthalmic branch of CN-V. When the intracavernous carotid artery wall is also involved, sympathetic pupil dysfunction (Horner pupil) will result, producing miosis; the Horner pupil will be unnoticeable if CN-III-related mydriasis obscures it. The clinical history in the case of slowly expanding tumor in the cavernous sinus often includes chronically increasing diplopia, sometimes with pain or numbness in the CN-V ophthalmic distribution; in cases of inflammation or infection, the onset is usually dramatic and painful. Superior orbital fissure syndrome is often indistinguishable from cavernous sinus syndrome.

Lesions producing diminished vision, internal (i.e., pupillary involvement) or external ophthalmoplegia, orbital pain, and corneal hypesthesia characterize orbital apex syndrome. In simplified terms, this syndrome is clinically characterized by findings of superior orbital fissure syndrome with a concomitant compressive optic neuropathy. It must be distinguished from pituitary apoplexy where sudden, painful visual loss due to chiasmal compression by pituitary hemorrhage is often accompanied by unilateral or bilateral CN-III palsy as impingement upon the adjacent cavernous sinuses evolves.

Differential Diagnosis

Myasthenia gravis, a disorder of somatic neuromuscular junction failure that does not affect the pupil, will occasionally simulate pupil-sparing third-nerve palsy. A history of diurnal variability, findings of inducible fatigability, and resolution of the “palsy” during intravenous administration of edrophonium chloride is often sufficient to expose the diagnosis, which can then be confirmed by serum antibody testing and electromyography.

Chronic, progressive external ophthalmoplegia (CPEO) presents as slowly progressive bilateral ptosis and loss of extraocular movements, usually without diplopia. CPEO has been associated with specific mutations of mitochondrial and nuclear DNA and can be part of a larger syndrome, oculopharyngeal dystrophy. The Kearns–Sayre variant of CPEO includes pigmentary retinopathy with nyctalopia, and hormonal dysfunction.

The Miller Fisher variant of Guillain–Barré syndrome produces an external ophthalmoplegia that may be initially confused with CN-III palsy; the presence of viral prodrome, ataxia, areflexia, cerebrospinal fluid albuminocytologic dissociation, and positive serum anti-GQ1b IgM and IgG antibodies will confirm the diagnosis.

Patients with internuclear ophthalmoplegia have inability to move the ipsilateral eye into adduction when attempting horizontal gaze to the contralateral side. The responsible lesion is in the medial longitudinal fasciculus, interrupting the interneurons traveling from the CN-VI nucleus to the CN-III ventral subnucleus that innervates the medial rectus (see discussion of CN-VI anatomy, below). Such patients are often assumed to have a “medial rectus palsy”; however, such a variant of CN-III palsy is rarely if ever seen clinically, and the preservation of adduction during convergence to near stimulus (mediated by the mesencephalon) in internuclear ophthalmoplegia serves to confirm its central nervous system supranuclear origin.

Duane syndrome is an example of a congenital aberrant innervation. In affected individuals, prenatal abducens nerve dysgenesis or injury causes subsequent misdirected CN-III innervation of the lateral rectus. Therefore, attempted lateral eye movement results in simultaneous stimulation of the medial and lateral recti, causing variable eye movement, measurable globe retraction into the orbit, and consequent pseudoptosis. In type II Duane syndrome, the combination of poor adduction and pseudoptosis during globe retraction may simulate CN-III palsy. The congenital nature of this condition is most easily deduced by the absence of symptomatic diplopia in lateral gaze despite the presence of incomitant strabismus.

Patients with isolated ptosis are often screened for the presence of CN-III palsy. The most common cause of ptosis, typically encountered in patients older than age 50 years—but occasionally seen in younger patients with a history of frequent eye rubbing—is aponeurotic ptosis, a lengthening of the tendon (aponeurosis) connecting the levator palpebrae muscle to the upper lid. Aponeurotic ptosis is particularly common in patients who have undergone cataract surgery. In those patients who, in addition, experienced intraoperative iris injury with postoperative mydriasis, erroneous suspicion of a partial compressive CN-III palsy can be easily prompted.

Marcus Gunn jaw-winking is a syndrome of congenital aberrant innervation of the levator palpebrae muscle by the motor neurons of CN-V that innervate the pterygoid muscles of the mandible. The typical patient will have ptosis that partially resolves with lateral and forward jaw movements with costimulation of the levator.

In the traumatic setting, ophthalmoplegia due to CN-III palsy must be distinguished from that due to orbital disease (e.g., orbital floor fracture with entrapment of the inferior rectus muscle).

Diagnostic Approach

Whether a spared pupil in otherwise complete CN-III palsy reliably excludes an aneurysm deserves discussion. Certainly, with instances of an incomplete extraocular CN-III palsy, the absence of pupil involvement must not be considered evidence of a benign etiology; however, total pupil-sparing in otherwise complete CN-III palsy due to acute compression seems exceedingly rare.

In 1985, neurovascular imaging of patients with isolated, complete, pupil-sparing CN-III palsy was not recommended for patients older than age 50 years. This recommendation was based in part on the frequency of microvascular palsies in this age group, the relative danger of intracranial catheter angiography, and the lack of noninvasive neurovascular imaging modalities. With the emergence of detailed CTA and gadolinium-enhanced magnetic resonance angiography, the number of patients with acute CN-III palsy who should be excluded from imaging is vanishingly small.

Once aneurysm has been excluded in those patients without clear precipitants, testing for diabetes mellitus, hypertension, vasculitis and other inflammatory disease, clotting disorders, spirochetal disease (syphilis and Lyme disease) and myasthenia gravis is recommended. Even in patients with microvascular CN-III palsy without evidence of causative disease, consideration may be given to reevaluate already defined cerebrovascular risk factors.

Any patient presenting with diplopia, initially thought to be related to a cranial mononeuropathy, must have careful examination of the adjacent cranial nerve to exclude their involvement. Also, patients with apparently isolated CN-III palsy should be checked for signs of ataxia, areflexia, or contralateral rubral tremor, hemiparesis, or hypesthesia. Similarly, patients presenting with new upper facial pain or numbness must always be checked for impaired eye movements and corneal hypesthesia to exclude early cavernous sinus syndrome.

Management and Therapy

The management of symptomatic intracranial aneurysm is usually urgent, via endovascular or surgical intervention if the general state of the patient permits (see Chapter 57). Management of microvascular palsy usually centers on prevention of recurrent events via reduction of risk factors. Optimization of any causative disease, such as diabetes, is crucial, and daily aspirin is often recommended. Therapy for other underlying causes of CN-III palsy will vary, appropriate to etiology.

Visual management of nonhealing CN-III palsies is complicated by the number of paretic extraocular muscles involved, as ocular misalignment changes significantly depending on the direction of gaze. Prismatic spectacles are often unavailing, except in cases of minimal residual misalignment. Strabismus surgery, often involving two or three staged procedures, has the limited goal of stable relief of diplopia in primary gaze only. Often the simplest management tool, if acceptable to the patient, is a patch on the affected eye to eliminate diplopia, if the ptosis does not already accomplish that.

Clinical Vignette

A workman, bent over his work, sustained left occiput blunt head trauma and scalp laceration when a coworker dropped a tool from above. Diplopia and headache subsequently developed.

Examination revealed poor depression of the right eye in leftward gaze. Prismatic spectacle lenses were prescribed to alleviate the diplopia. After a few months, the patient reported that his vision had returned to normal.

This vignette describes isolated trochlear nerve (CN-IV) injury with relatively mild closed head trauma. Often the most benign of the cranial neuropathies, particularly those related to extraocular muscle function, it tends to recover fully over a period of weeks or months.

The CN-IV nuclei are located at the level of the inferior colliculi in the lower midbrain off midline at the ventral edge of the periaqueductal gray. The nuclei are crossed; the left trochlear nucleus innervates the right superior oblique and vice versa.

Axons emanating from the trochlear nucleus arc dorsally around the periaqueductal gray into the tectum of the midbrain, where they cross the midline and then emerge laterally beneath the inferior colliculus at the medial border of the brachium conjunctivum as CN-IV. It then completely decussates and exits the brainstem from its dorsal aspect, a unique feature among the cranial nerves. It passes through the quadrigeminal and ambient cisterns and then runs along the free edge of the tentorium. It enters the orbit via the superior orbital fissure and innervates a singe extraocular muscle, the superior oblique.

The superior oblique is chiefly a depressor of the globe and is most active when the eye is adducted and depressed. It has a secondary function of intorting the eye during ipsilateral head tilt and is a weak abductor of the eye in downgaze (Fig. 5-4). Therefore, CN-IV palsy will produce ipsilateral loss of depression (hyperopia) and excyclotorsion of the globe.

Figure 5-4 Extraocular Muscles and General Function.

Etiology and Pathogenesis

Trauma is the most frequent cause of CN-IV palsies. Traumatic palsies may be bilateral, but most often one side is spared or recovers so that patients are left with unilateral dysfunction. The frequent association of trauma with CN-IV palsy may imply that the thin dorsal tectum is vulnerable to traumatic forces causing shear between the emerging nerves and the colliculi or the cerebellar tentorium or direct injury from a hydraulic pressure wave transmitted through the aqueduct. MRI demonstration of tectal subarachnoid hematoma in traumatic trochlear palsy supports this theory. In addition, a pathologic study has shown that, with sufficient force, avulsion of the CN-IV root from the pons can occur.

The nucleus and fasciculus of the trochlear nerve lie within the pons; in this location, CN-IV palsies may result from stroke, demyelination, and tumor. Lesions of the fascicle, rarely seen clinically, produce a contralateral CN-IV palsy and an ipsilateral Horner syndrome due to coinvolvement of the descending first-order pupillary sympathetic axons passing through the pontine tegmentum. The trochlear nerve fasciculi decussate just dorsal to the sylvian aqueduct, and tumors or stroke in this area will produce bilateral trochlear palsies.

In the subarachnoid space, CN-IV can be affected by carcinomatous meningitis, by aneurysm (especially of the superior cerebellar artery; Fig. 5-2), or by dolichoectasia of the basilar artery. The nerve itself may be the site of schwannomas. Once within the dural canal leading to the cavernous sinus, the nerve may be affected by tumor, especially meningioma. Compression of CN-IV can occur at the cavernous sinus itself, by dissections or aneurysm of the carotid artery, by extension of sellar and orbital tumors, and by metastases. Typically CN-IV, -III, -VI, and the ophthalmic branch of CN-V are involved in cavernous sinus lesions.

In cases where imaging reveals no structural cause of CN-IV palsy and where there is no history of trauma, microvascular ischemia is the usual assumed etiology. Patients with diabetes, hypertension, vasculitis, sarcoidosis, or treponemal infection may present with seemingly “idiopathic” palsies.

Clinical Presentations

Patients with trochlear palsy have hypertropia or impaired ability to depress the eye on the involved side. Weakness of depressor function of the superior oblique is exaggerated with medial downward gaze or when the head is tilted toward the side of palsy

Normally during head tilt to one side, the ipsilateral superior oblique is activated to accomplish incyclotorsion of the eye, keeping the retina relatively level despite the head shift. The medial rectus is activated simultaneously, so that the incyclotorsion of the superior oblique is not accompanied by usual depressing of the globe. In trochlear palsy, then, when the head is tilted toward the palsied side, abnormal excyclotorsion is emphasized, magnifying both the hypertropia and diplopia. This pattern of incomitant strabismus is summarized as “hypertropia worse with gaze away and with tilt toward the affected side.”

Patients with CN-IV palsy often adopt a secondary torticollis, offering a diagnostic clue. Patients prefer a chin-down posture with the head tilted away from the palsy, so that the affected eye is in up and out, where the superior oblique normally has the least action, and its palsy matters the least. Because this posture minimizes the visual consequences of a CN-IV palsy, congenital CN-IV palsies are often undiagnosed for decades. A diagnosis in adulthood may be made after intermittent diplopia develops from progressive asthenopia or when treatment for torticollis is sought. The presence of the characteristic head tilt in childhood photographs often confirms the congenital nature of the palsy.

In most cases of CN-IV palsy, there is a history of trauma. A high frontal head impact with contrecoup forces at the dorsal tectum, occipital impact producing more direct injury, or coccygeal impact transmitted up a straight spinal column are all encountered. Occasionally, the appearance of vertical diplopia after frontal head trauma will prompt suspicion of orbital floor “blow-out” fracture before CN-IV palsy is uncovered.

The amount of force needed to produce traumatic CN-IV palsy seems variable, and, in contradistinction to traumatic CN-III palsy, impact sufficient to produce alteration in consciousness is not required. An acquired trochlear palsy after minor head trauma should still, however, prompt suspicion of an undiagnosed mass lesion, producing a “pathologic” palsy in an already damaged nerve.

Patients with bilateral CN-IV palsy complain of rotational instead of vertical diplopia. Loss of incyclotorsion for both eyes causes images seen by the left eye to rotate clockwise compared with those seen by the right eye. Most patients with bilateral involvement will note occasional vertical diplopia: right eye image above left eye image with left head tilt or rightward gaze, and vice versa. Often, esotropia is seen in downgaze as well, because of loss of the abducting action of the superior obliques. They may adopt a chin-down head position without horizontal tilt.

A lesion interrupting both the predecussation trochlear fasciculus and the ipsilateral central tegmental (pupillary sympathetic) tract within the tectum produces an ipsilateral Horner syndrome with crossed CN-IV palsy. CN-IV palsy has occurred in the setting of idiopathic intracranial hypertension and after lumbar puncture—presumably because of tractional mechanisms—both with CN-VI coinvolvement. It can also occur in conjunction with CN-III involvement in spontaneous intracranial hypotension.

Perhaps because of their relatively fixed location within the lateral wall of the cavernous sinus, the trochlear and trigeminal nerves can be injured concomitantly. Patients with a posteriorly draining carotid–cavernous fistula may present with painful superior oblique dysfunction along with an oculomotor nerve palsy, presumably due to local cavernous distention.

Differential Diagnosis

Other entities that produce vertical binocular diplopia with hypertropia may be initially confused with CN-IV palsy; myasthenia gravis is one such mimic. However, the pattern of changing misalignment in different directions of gaze will usually serve to distinguish true trochlear palsies from its simulators.

Restrictive diseases affecting the inferior rectus muscle (such as thyroid-related orbitopathy, orbital floor fracture with entrapment of the muscle, or injury from local anesthetic for cataract surgery) produce vertical diplopia; such diplopia, however, worsens in upgaze. Restrictive disease of the inferior oblique is a far better mimic, as patients would have ipsilateral hyperopia with excyclotorsion and worsening on attempted downgaze.

Injury to the orbital trochlea (through which the superior oblique tendon passes) typically produces Brown tendon sheath syndrome, with the eye shooting into downgaze on adduction because the tendon remains tight even when the muscle relaxes; however, on occasion, the injured trochlea will not allow the tendon to retract in response to superior oblique retraction, perfectly simulating CN-IV palsy. History of orbital trauma and trochlear abnormality on orbital imaging will serve to clarify the diagnosis.

Skew deviation due to imbalance of the otolithic inputs to the vestibulo-ocular system can also produce vertical misalignment. In such cases, reclining the patient to a supine position may eliminate the hypertropia.

Diagnostic Approach

Diagnosis of unilateral CN-IV palsy is made when ipsilateral hypertropia is demonstrated to worsen in downward gaze, contralateral gaze, and ipsilateral head tilt. Cases of bilateral trochlear palsies may present the seeming paradox of no hypertropia in primary gaze when the head is straight. However, these patients demonstrate a left hypertropia on right gaze and left head tilt, and right hypertropia on left gaze with a right head tilt.

Blood testing for infection, abnormal clotting, and systemic inflammation is usually done in nontraumatic cases. Patients with isolated CN-IV palsies may be observed for spontaneous improvement over 3 to 4 months if the history indicates a likely etiology (e.g., trauma or known diabetes); otherwise, neuroimaging is done upon diagnosis. Even in cases with a presumed etiology, nonresolution over time usually prompts imaging unless congenital CN-IV palsy is strongly suggested by history and examination findings (e.g., vertical fusional amplitude greater than 4 diopters and photographic evidence of life-long compensating head tilt).

Management and Therapy

Therapy directed at the cause of CN-IV palsy (when a cause other than trauma can be identified) will be dependent on the pathologic entity encountered. Symptomatic diplopia in nonhealing trochlear palsies may be reduced by the use of prismatic glasses to shift “second images” to line up with primary images. However, the utility of prismatic glasses in CN-IV palsy may be limited because such spectacles do not correct image tilt and because only one prismatic strength can be ground into the spectacles, but different strengths are needed for different gaze directions. Many patients prefer strabismic surgical treatment of nonresolving palsies; it offers correction of excyclotorsion and greater range of gaze without diplopia.

Clinical Vignette

A 68-year-old hypertensive, diabetic patient presented with isolated sixth cranial nerve (CN-VI) palsy, manifesting as inability to abduct the involved eye. No imaging was initially requested, given the presumed microvascular etiology. Four days later, the patient developed severe headache, and 2 days after that presented to the emergency room where computed tomographic scan revealed a hemorrhagic pituitary fossa mass.

Two days later the patient expired due to hyperthermia from hypothalamic compression. It is argued that the sellar hemorrhage was in fact present at the time of the patient’s initial symptoms and that this patient represents a case of pituitary apoplexy presenting with painless, isolated CN-VI palsy.

The sixth cranial nerve (CN-VI) innervates a single extraocular muscle, the lateral rectus, which is the primary abductor for the eyes.

The CN-VI nucleus, located just beneath the facial colliculi in the inferior pons is enveloped by the turning CN-VII fascicular fibers of the facial genu and contains two physiologically—but not topographically—distinct groups of neurons (Fig. 5-5). One group innervates the ipsilateral lateral rectus; the other sends axons across the midline to the contralateral medial longitudinal fasciculus (MLF). These latter axons ascend in the MLF to the ventral nucleus of the contralateral CN-III nuclear complex. These internuclear neurons connect the nuclei of CN-VI and -III, producing the almost simultaneous stimulation of the contralateral medial rectus during ipsilateral abducens nerve stimulation to produce lateral horizontal gaze.

Figure 5-5 Central Control of Eye Movements.

From its position laterally abutting the paramedian pontine reticular formation, the CN-VI fasciculus first travels medially (toward the MLF, temporarily with the interneuron axons) and then turns ventrally, passing through the paramedian pontine reticular formation and the undecussated corticospinal tract to reach the ventral surface of the brainstem at the inferior lip of the pons.

On exiting the ventral pons, the abducens nerve ascends between the pons and the clivus within the subarachnoid pontine cistern. After it enters the dura, CN-VI continues up the clivus to the posterior clinoid. It travels over the petrous ridge to lie beneath the inferior petrosal sinus and then enters the cavernous sinus via the Dorello canal just medial to the Meckel cave, which houses the gasserian ganglion.

After CN-VI is within the cavernous sinus, it passes forward, adjacent to the internal lateral aspect of the carotid artery. Here, it likely carries the majority of the tertiary sympathetic pupillary axons the short distance from the carotid artery to the ophthalmic branch of the trigeminal nerve. The sympathetics then follow the ophthalmic nerve via its nasociliary branch to the ciliary ganglion; the sympathetic fibers pass through the ganglion without synapsing, entering the eye via the short ciliary nerves. Additional sympathetic fibers bypass the ciliary ganglion, entering the eye as the long ciliary nerves.

Etiology and Pathogenesis

Microvascular palsy, associated with risk factors such as hypertension or diabetes, is the most common cause of acquired, isolated CN-VI palsy. In some cases, advanced age is the only identifiable risk factor and the palsy is considered idiopathic. However, occasionally sixth-nerve palsy will be the presenting sign of other vasculitides such as temporal arteritis or treponematosis.

Within the brainstem, cranial nerve palsies can be caused by tumor, stroke, and demyelination. Often, other neurologic signs localizing to the pons will be present, but isolated abducens palsies can be seen.

The sixth nerve has the longest intracranial course of all the cranial nerves. It may suffer compression along this path from tumors at a number of locations, including at the cerebello-pontine angle, the clivus, the petrous bone, and the cavernous sinus. Tumors include acoustic neuroma, meningioma, hemangioma, lymphoma, chondrosarcoma, eosinophilic granuloma, and nasopharyngeal carcinoma, as well as various other carcinomas, both local and metastatic. Midline tumors of the skull base, such as chordoma, can cause bilateral CN-VI palsies by compressing both nerves as they ascend the clivus. Isolated unilateral palsy is, in rare cases, due to abducens schwannoma.

Within the cavernous sinus, the sixth nerve is often involved by disease of the carotid artery, including aneurysm, dissection, dolichoectasia, and carotid–cavernous fistula. The cavernous sinus is also a frequent location of hemangiomas, septic thrombosis, idiopathic inflammation (Tolosa–Hunt syndrome), and metastatic carcinoma that can affect the sixth nerve. Pituitary apoplexy can cause CN-VI palsy by compressing against the cavernous sinus. Often, the other cranial nerves of the cavernous sinus will also be involved, along with the tertiary pupillary sympathetic neurons.

Traumatic CN-VI palsy is seen in the setting of a significant impact, severe enough to cause change of consciousness or bone fracture. CN-VI can also be injured during skull-based neurosurgery and can be seen after percutaneous radio-frequency ablation of CN-V for trigeminal neuralgia.

Vincristine produces CN-VI palsies, presumably from direct neuropathic action on the nerve. Reports of CN-VI in patients using vitamin A and its analogs must probably relate to increased ICP secondary to retinoid-induced pseudotumor cerebri.

Raised ICP alone, whether due to medication, tumor, obstructive hydrocephalus, meningitis, or idiopathic intracranial hypertension, can produce unilateral or bilateral CN-VI palsy. Such abducens palsy is a falsely localizing sign, suggesting impinging upon the sixth nerve, when in fact the causative tumor may be remote from the CN-VI territory, or there may be no tumor at all. The course of CN-VI between the internal auditory artery and the anterior inferior cerebellar artery makes it vulnerable to such palsy. As ICP begins to rise, downward brainstem herniation causes stretching of CN-VI, and perhaps compression against either artery. Similarly, downward shift of the pons in relation to the petrous ridge is thought to account for CN-VI palsies sometimes seen in spontaneous or post–lumbar puncture intracranial hypotension.

Clinical Presentations

Patients with CN-VI paresis have an inward deviation of the affected eye and a noncomitant esotropia. Temporal eye movement beyond midline is lost or reduced. Patients with partial or mild abducens palsies adopt a posture with the head turn toward the affected side to minimize diplopia by keeping the eye adducted. In more severe palsies, this strategy often fails or is uncomfortable, so patients present with one eye shut, or covered.

The typical patient with microvascular CN-VI palsy will report painless, sudden-onset, horizontal binocular diplopia. Such patients typically show complete, spontaneous resolution within 2–4 months of onset.

Patients with unilateral or bilateral CN-VI palsy from high ICP will present with the symptoms of headache, worsening with recumbency, and visual symptoms ranging from mild dimming to 1–2 seconds of bilateral visual obscurations to profound visual field loss. In cases of obstructive hydrocephalus, gait instability, urinary incontinence, and change in mental status are present. Primary nuclear CN-VI lesions typically have concomitant ipsilateral facial nerve involvement, because of the contact between the abducens nucleus and the genu of the facial fasciculus. For example, stroke of the inferior medial pons produces both ipsilateral gaze palsy and CN-VII as part of Foville syndrome. These deficits are accompanied by contralateral hemiplegia from more extensive involvement of the corticospinal tract prior to its decussation.

As Foville syndrome demonstrates, lesions of the CN-VI nucleus do not, in fact, result in clinical CN-VI palsy but rather an ipsilateral gaze palsy with inability to move both eyes to the affected side. This gaze palsy occurs because the CN-VI nucleus contains both the motor neurons headed for the lateral rectus muscle and the interneurons going to the contralateral third-nerve nucleus via the MLF. The pontine localization of the gaze palsy can be inferred from the finding that such “lower” gaze palsies, in contradistinction to “higher” gaze palsies from frontal lobe disease, cannot be overcome with vestibulo-ocular reflex (e.g., doll’s-eyes maneuver), caloric labyrinthine stimulation, or optokinetic stimulation.

Larger lesions affecting the CN-VI nucleus and extending rostrally into the ipsilateral MLF interrupt the crossed internuclear neurons from the opposite CN-VI nucleus coursing up toward the CN-III nucleus, with consequent inability to adduct the ipsilateral eye in horizontal gaze. This combined lesion of ipsilateral gaze palsy and internuclear ophthalmoplegia is known as the Fisher “one-and-a-half” syndrome: As with other internuclear ophthalmoplegia variants, convergence (the ability to adduct both eyes simultaneously for near vision) is spared as neither the upper midbrain pathways producing convergence nor the CN-III nuclei are affected.

Paramedian basilar artery branch occlusion causes infarction of the medial and ventral structures of the inferior pons, producing ipsilateral gaze palsy (paramedian pontine reticular formation involvement), hemifacial paralysis (CN-VII), limb ataxia and nystagmus (involvement of middle cerebellar peduncle and possibly vestibular nuclei efferents), crossed paralysis (corticospinal tract), and crossed tactile hypesthesia (medial lemniscus). More focal lesions may produce Raymond syndrome (abduction palsy and crossed hemiplegia) from abducens fascicular injury at the corticospinal tract in the basis pontis, whereas similar lesions with some lateral extension also involve the facial fasciculus, adding ipsilateral facial palsy to the presentation (Millard–Gubler syndrome).

Anterior inferior cerebellar artery occlusion typically produces more lateral damage characteristically to the vestibular nuclei, the auditory nerve, CN-VII, the paramedian pontine reticular formation, the spinothalamic tract, and the middle cerebellar peduncle and possibly extending dorsally to the cerebellar hemisphere and rostrally to the CN-V nucleus. The combined deficits produce a lateral inferior pontine syndrome of nystagmus (with beats or fast phase directed ipsilaterally), vertigo, gaze palsy, facial paralysis and hypesthesia, deafness, and ataxia, all with crossed body analgesia.

CN-VI, the carotid artery, and sympathetic pupil fibers are situated closely within the cavernous sinus, and an expanding intracavernous carotid dissection or aneurysm can compress these structures, producing painful abducens palsy with an ipsilateral Horner syndrome. Other pathologic processes, such as carotid cavernous fistula (CCF) and granulomas within this region sometimes produce a similar clinical picture. Patients with CCF may have additional feature of headache, enlarged conjunctival vessels, proptosis, and an audible bruit over the orbit.

Processes that affect the anterior midline brainstem also deserve consideration in the differential diagnosis, including various posterior fossa tumors or inflammatory processes that affect the abducens nerve during its ascent of the clivus. Chordomas, slowly growing tumors that favor the midline skull base, occasionally present as isolated or bilateral CN-VI palsy as do durally based meningiomas.

Gradenigo syndrome is characterized by a painful abducens palsy resulting from mastoiditis and petrositis complicating chronic otitis media. The infectious process erodes the bone, affecting the abducens nerve and the gasserian ganglion and, at times, the CN-VII as it passes through the mastoid bone en route to the stylomastoid foramen. A combined trigeminal-abducens-facial nerve syndrome can be produced by other entities, particularly tumors, that affect this region.

Differential Diagnosis

Möbius syndrome is a congenital, bilateral CN-VI and CN-VII palsy. MRI typically shows pontine hypoplasia in the region of the affected CN nuclei. The characteristic elongated, expressionless lower facies of these patients is usually sufficient to suggest the diagnosis, and such patients usually do not have symptomatic diplopia. However, Chiari malformation with syringomyelia can produce a similar, acquired picture.

Duane syndrome, a congenital condition of misdirected CN-III innervation of the lateral rectus, can also simulate abducens palsy. In patients with type I Duane syndrome, attempted lateral gaze reveals lack of abduction. Again, the chief clues to this diagnosis are life-long history and absence of symptomatic diplopia in lateral gaze despite the presence of noncomitant strabismus.

Inability to abduct the eyes, a seeming bilateral CN-VI palsy, can be seen in Wernicke encephalopathy resulting from thiamine depletion. Confusion, confabulation, ataxia, and history of alcoholism suggest the diagnosis, which is confirmed by low serum thiamine levels. Occasionally, sudden onset of esotropia simulating bilateral CN-VI palsy occurs because of divergence palsy, probably due to microvascular ischemia at the putative mesencephalic “divergence center.” Spontaneous improvement in 2–3 months is expected. Divergence palsy can be differentiated from the more common, frequently psychogenic, convergence spasm by the miosis that accompanies convergence spasm as in normal close vision.

Myasthenia gravis may simulate CN-VI palsy but can be diagnosed by history of diurnal variation, variable ocular misalignment, presence of serum antibodies to acetylcholine receptors or striated muscle, and positive response to intravenous edrophonium chloride.

Traumatic fracture of the medial orbital wall (the lamina papyracea of the ethmoid sinus) with entrapment of the medial rectus muscle produces a restrictive esotropia that may at first suggest traumatic CN-VI palsy. Similarly, thyroid-related ophthalmopathy, which often preferentially restricts the medial rectus muscle, or orbital tumor may lead to restrictive esotropia and consideration of abducens palsy. Force duction testing (see below) will be normal in myasthenia, but positive—the eye resists the attempted movement—in cases of restrictive strabismus. Orbital imaging will confirm restrictive esotropia.

Diagnostic Approach

Complete palsies if CN-VI are usually evident, with cursory examination revealing esotropia that lessens with gaze away from the affected side (direction in which the lateral rectus is usually least active). Abduction of the affected eye past midline is not possible, and the movement from adducted to midline position is slow.

Partial abducens palsies can be subtler, especially as only one muscle, and one plane of eye movement, is affected. Having the patient describe the diplopia will usually clarify that it is the binocular diplopia of ocular misalignment, and not the monocular diplopia or “ghosting” experienced when problems of the eye’s optical system (e.g., cataracts) are present. The history should seek to uncover symptoms of myasthenia gravis, thyroid disease, or temporal arteritis, as well as any chronic or ongoing medical conditions that may suggest etiology (e.g., diabetes in microvascular palsies, cancer in compressive or infiltrative ones).

Alternately covering each eye with the patient refixating on a distant object each time will reveal the amplitude of the corrective saccade needed to compensate for the misalignment. This “alternate cover test,” repeated in different directions of gaze, will confirm an incomitant (different in different gaze directions) esotropia, worse with ipsilateral horizontal gaze, in the case of an abducens nerve palsy. This test will also serve to detect other directions of ophthalmoplegia in cases of multiple nerve involvement.

Forced-duction and force-generation testing are used clinically to differentiate paralytic abduction deficit from that due to restriction of the medial rectus muscle. The forced duction test is the passive movement of the eye into the apparently paralytic field of gaze; if the eye moves easily, there is no restriction and the diagnosis of palsy is supported. In the force-generation test for CN-VI palsy, the affected eye is passively adducted, and then the patient is instructed to shift gaze to attempt to abduct the eye. If no significant abducting force can be felt by the examiner, palsy is again suggested.

A screening examination of the other cranial nerves is then made, as structural lesions affecting CN-VI can also affect (depending on location and size of the responsible lesion) CNs II, III, IV, V, VII, and VIII. Fundus examination to exclude papilledema is particularly important.

At this point, for patients for whom the history of present illness, past medical history, review of systems, or examination has suggested a specific diagnosis, directed diagnostic tests will be recommended. Chief among these tests is often an MRI of the brain and orbits with gadolinium contrast, and attention to the entire course of CN-VI.

However, a sudden-onset, painless, isolated CN-VI palsy in a patient with known vasculopathic risk factors, a presumptive diagnosis of microvascular CN-VI palsy can be made. If the patient has no obvious risk factors for microvascular cranial mononeuropathy except age, blood pressure testing, as well as screening blood tests—complete blood count, hemoglobin A1-C, erythrocyte sedimentation rate, angiotensin-converting enzyme titer, and serologies for syphilis and Lyme disease—may be performed. In young patients, imaging will often be added to the initial workup, because of the relative rarity of microvascular palsy in this population. Isolated CN-VI palsy with negative neuroimaging that improves spontaneously over 2–3 months is seen in children and can be presumed “viral” in origin.

Traditionally, patients given a presumptive microvascular CN-VI diagnosis are followed expectantly for 2–4 months without imaging. If spontaneous resolution does not occur in that time frame, neuroimaging (MRI, as described above) typically is performed. However, that standard is today under discussion because of recent case reports similar to this section’s clinical vignette.

Management and Therapy

As with other ocular motor palsies, management of the cause of CN-VI palsy, when one can be identified, will depend on the specific etiology. Therapies may range from strategies to mitigate vasculopathic risk factors in microvascular cases, to neurosurgical interventions for those cases due to tumor, aneurysm, or high ICP.

Therapy for nonhealing CN-VI palsies can include the use of prismatic spectacles or strabismus surgery, both of which are most effective in cases with some preserved abducens function. In cases of persistent total sixth-nerve palsy, muscle-splitting surgery (dissecting out portions of the superior and inferior rectus muscles to fabricate a new abducting extraocular muscle) or vertical muscle transposition surgery can be attempted and frequently result in a good cosmetic and acceptable functional result. At times, however, cases of complete CN-VI palsy will be at last managed by use of a patch or obscuring lens in front of one eye to eliminate binocular diplopia in a dependable, if inelegant, fashion.

Examination

The pupillomotor examination is an assessment of two of the three internal motor functions of the eye, pupil constriction and dilation (the third is lens accommodation). The motor assessment is often supplemented by slit-lamp observation of the iris, which may reveal abnormalities of iris structure. Such iris defects can cause abnormalities of pupillary function that are unrelated to any neuropathy.

To examine pupillomotor functions, seat the patient comfortably with his or her gaze directed at a distance (12–20 ft forward). The examiner should position in front, and slightly to one side, so that the pupils may be observed without interrupting the patient’s fixation. For examination of the light reflex, the room should be dim, and the examination light bright. The traditional stimulus is the ophthalmologic Finoff scleral transilluminator (“muscle light”), which features a shielded, directed beam of variable brightness, making it ideal for isolated illumination of one eye with minimal “scatter” illumination to the fellow eye. Any nonmedical light source with similar features will do as well.

Ideally, the examination of the light reflex requires the patient to be wearing their distance correction, as an unfocused distance fixation-target may stimulate pupillary contraction via the near triad—convergence, lens accommodation, and miosis—should the patient attempt to focus. This consideration is perhaps most important in young patients, whose ability to accommodate is significant. However, especially if the lenses are thick, the patient’s use of spectacles may obscure the pupil to the examiner.

In dim illumination, the pupil’s shape (degree of roundness) is noted, its size is measured, and both are recorded. A “pupil gauge” (a printed card with full- or half-circles of given sizes, usually in 1-mm increments) is helpful, but a simple ruler may also be used. A dimmest-visible slit-beam directed from 45° degrees temporally can also be used to measure the pupil at the slit-lamp biomicroscope, if care is taken to avoid patient fixation on the slit-lamp or examiner. Alternatively, the pupil can be measured in dark conditions using a quantitative (scaled) infra-red pupillometer; this device has become much more readily available in recent years because of the need to assess maximum pupil dilation at night in patients considering refractive corneal surgery.

Bright-light stimulus is then applied to one eye, and the pupil response of that eye (direct response) is observed. The final size of the pupil in response to light and the speed or briskness of that response is recorded. The normal pupillary light reaction is a brisk, uniform concentric constriction; when the light stimulus is removed, an equally brisk redilation is seen.

When light stimulation is prolonged, normal constriction is followed after about a second by minimal redilation. In some patients, cycles of small-amplitude redilation and reconstriction are seen, and are termed hippus. Hippus can be quantified clinically: it can often be induced or emphasized with special lighting conditions (“edge lighting” at the slit-lamp), so that the frequency of the redilation/reconstruction cycles can be measured to give a “pupil cycle time” value. A prolonged pupil cycle time may suggest disease of the optic nerve or the pupilloconstrictive neural efferents.

Light stimulus is then applied to one eye while assessing the indirect pupillary response in the fellow eye. In healthy individuals, the indirect pupillary response should be clinically equivalent to the direct response. However, in many clinical settings, actual observation of an unilluminated pupil in a dim room is impractical. Instead, the swinging flashlight test is generally utilized to better document the indirect response by comparing it to the same eye’s direct response.

The swinging flashlight test begins with the light directed to one eye; the direct response is observed. The flashlight is then quickly swung over to the other eye. Normally, the second pupil begins to dilate during the short time that neither is illuminated, but once it is directly stimulated a slight, brisk contraction is seen. If a large contraction or a continued dilation is seen after the flashlight has been swung, a relative afferent pupillary defect (RAPD) is suggested (see below).

Next, the reaction to near is checked; often in the clinical setting, the near reaction is only checked if the light reaction is found to be abnormal. The patient is asked to shift visual attention from the far fixation target to a minimally illuminated near fixation target, perhaps 6–10 inches away. The normal reaction of the pupil to near stimulus is a brisk, uniform constriction that may be of slightly greater amplitude than the light response. When gaze is redirected to the distant target, brisk redilation is normally observed. It should be noted that although the light reaction is involuntary, the near reaction requires voluntary triggering of the near triad and so is dependent on patient alertness, attention, and cooperation.

Notation of the complete clinical pupillary exam then consists of a description of the shape and measurement of the size of the pupil in dim lighting with distance fixation; speed of the reaction (both constriction and redilation) and final size of the light-stimulated pupil; presence (and severity) or absence of a RAPD; and reaction speed and final size of the near-stimulated pupil, especially if the light reaction is abnormal in any way.

Abnormalities of Pupil Function

Light Reflex Abnormalities, Afferent Limb

Light is detected at the retina, and the signal sent via the optic nerve to the brain. Although the majority of visual information is transmitted to the lateral geniculate nucleus, the pupillary afferent fibers reach the pretectal nucleus via an extrageniculate pathway. The input from each eye reaches both the left and right nuclei, so that stimulation of one retina results in both the ipsilateral and contralateral pupillary constriction, producing a direct and consensual pupillary response, respectively (Fig. 5-6). Because of this anatomic property, disease of the pupillary afferents, even if unilateral, does not produce pupils that are unequal in size (anisocoria).

Figure 5-6 Parasympathetic Pupillary Innervation and the Light Reflex Pathway.

When the light-stimulated neural signal sent to the pretectal nucleus by one eye is significantly different from the other, an RAPD will result. Clinically, a RAPD is seen during the swinging flashlight test when, rather than reconstricting, the affected pupil continues to dilate when the light is swung to that eye; the lack of reconstriction demonstrates that the (abnormal) direct pupillary response in the affected eye is not as strong as the (normal) indirect response produced by stimulating the fellow eye. When the flashlight is swung back to the normal eye, a larger-than-usual constriction is seen, as the direct response in that eye is greater than its consensual response.

It should be noted that a RAPD will only be detected if one eye’s afferent system is appreciably more abnormal than that of the fellow eye. When, for example, both eyes have suffered extensive optic atrophy, the eyes will display light-near dissociation (absent light response with preserved near response; see below) as well as severe visual loss—but no RAPD.

The reasons for a detectable RAPD are legion. Although mild optical and cataract problems cannot cause an RAPD, a unilateral dark cataract may cause it, especially if the fellow eye has had its cataract removed. Retinal and optic nerve disease are the usual causes and typically can be correlated to defects in central and peripheral vision and to objective structural changes in the funduscopic examination. With complete optic tract lesions causing contralateral complete homonymous hemianopia, the contralateral eye (with temporal visual field loss and “bow-tie” optic atrophy) shows an RAPD, likely because that eye has lost more peripheral field (i.e., the temporal field of each eye is greater than the nasal) and a corresponding greater percentage of optic nerve fibers (53% loss in the contralateral optic nerve vs. 47% loss ipsilaterally).

Rarely, one encounters disease that has affected the extrageniculate pupillary afferent fibers only, after they separate from the geniculate-bound vision fibers. In those cases, the patient will show a clear afferent pupillary defect without any visual defect. A reverse case, with unilateral visual loss, optic atrophy, and no RAPD, has not yet been reported.

Efferent Limb Abnormalities: Sympathetic

The sympathetic innervation of the pupillary dilator muscle involves a three-chain pathway. The primary neuron runs from the hypothalamus to the ciliospinal center of Budge and Waller at the junction of the thoracic and cervical spinal cord; the secondary neuron starts there, crosses over the lung apex and synapses in the superior cervical ganglion; and the tertiary neuron follows the ICA to the cavernous sinus, eventually reaching the eye after passing through the ciliary ganglion without synapsing (Fig. 5-7).

Figure 5-7 Sympathetic Pupillary Innervation.

A pupil that has lost its sympathetic innervation will sluggishly redilate when light stimulus is removed (redilation lag), and will not open past mid-dilation even in darkness; in mesopic lighting, it is miotic compared to a normal pupil. The sympathetics innervating the facial arteries, sweat glands, and the Mueller muscle of the lid travel with the pupillary sympathetic; therefore, sympathetic-denervation leads to miosis often accompanied by ipsilateral ptosis and hemifacial anhydrosis (Horner syndrome). Hemifacial flushing can also be present (harlequin syndrome).

Pharmacologic Diagnosis of Pupillary Dysfunction

The diagnosis of anisocoria or of bilateral pupillomotor abnormality can be sharpened by the use of topical pharmacologic agents. Strong mydriatics or miotics override neural influences, so that any remaining anisocoria (or subnormal response) indicates iris disease, whereas elimination of anisocoria (or normal response) indicates a neural cause of the pupillary dysfunction.

For example, incomplete (or asymmetric) response to standard pharmacologic dilation (phenylephrine 2.5–10% with tropicamide 1%) suggests an iris structural abnormality, which may be more easily detected at slit-lamp after attempted dilatation. Conversely, incomplete miotic response to pilocarpine 1–2% may suggest previous pupillary sphincter trauma, or recent exposure to an anticholinergic agent (topically to the eye if unilateral, and perhaps systemically if bilateral).

In contrast, weak mydriatic or miotic agents can be used to highlight denervation supersensitivity when it exists. Within days of sympathetic denervation of the iris, the dilator muscle will exhibit supersensitivity to weak alpha-1 adrenergic agonists (epinephrine 0.1%, phenylephrine 1%, or most recently apraclonidine 0.5–1%); such agents (or cocaine, below) are often used to distinguish Horner pupil from physiological anisocoria. Similarly, a weak cholinergic agonist (pilocarpine 0.06–0.12%) can demonstrate the cholinergic supersensitivity found in Adie tonic pupil.

Two additional agents are classically employed in the diagnosis of Horner pupil. Cocaine 10% solution has the unique property of preventing presynaptic norepinephrine reuptake; because of the steady baseline release of small amounts of norepinephrine into the neuromuscular cleft of the pupillary dilator muscle, the normal response to topical cocaine is pupillary dilatation. When baseline norepinephrine release is absent (because of either absence of the tertiary neuron or its neurochemical silence), cocaine will fail to dilate the Horner pupil.

Topical hydroxyamphetamine 1% causes release of stored presynaptic norepinephrine at the dilator’s neuromuscular junction. Therefore, lack of dilation in response to hydroxyamphetamine suggests absence of the tertiary neuron, helping to “localize” the lesion in the pupillary sympathetic chain.