The nuclear complex of the third (oculomotor) nerve lies beneath the aqueductal gray matter of the rostral midbrain at the level of the superior colliculus (Fig. 2). The medial longitudinal fasciculus (MLF) passes just lateral to the oculomotor nuclei, and the fourth (trochlear) cranial nerve nucleus is contiguous caudally. The organization of the oculomotor nuclear complex into distinct motor cell pools subserving individual extraocular muscles was investigated by Warwick,¹ from whose schema (Fig. 3) the following points are especially noteworthy: (1) both lid levators are served by a single dorsal-caudal midline nucleus; (2) the motor cell pool of the superior rectus muscle sends fibers across to the contralateral oculomotor nerve; (3) a nucleus for convergence (Perlia) has not been consistently demonstrated in primates, including humans; and (4) at the caudal aspect of the oculomotor complex is the trochlear nucleus, whose axons turn dorsally to cross in the anterior medullary velum and innervate the contralateral superior oblique. Therefore, the nuclear motor pools of the superior rectus and superior oblique muscles are contralateral to the eye that they move. Warwick proposed that each muscle (intrinsic and extrinsic) innervated by the oculomotor nerve is subserved by a single, circumscribed mass of cells called a subnucleus. Modern tracer techniques have, to date, confirmed this concept for all the extrinsic muscles except the medial rectus, which has three definable subnuclei^2,3; there are also afferent fibers to the ipsilateral trigeminal ganglion. Results of elegant axonal tracer studies mapping the intricate connections of the visceral nuclei of the oculomotor complex have been summarized by Burde.⁴

From the oculomotor complex the efferent fibers exit ventrally and pass through the red nucleus and medial aspect of the cerebral peduncles. The fascicles emerge in the interpeduncular space anterior to the midbrain as the paired oculomotor nerves. The oculomotor nuclei obtain their vascular supply from the terminal bifurcation of the basilar artery. Multiple arteries perforate the median mesencephalon in the interpeduncular space.

The sixth (abducens) nucleus is situated in the caudal portion of the paramedian pontine tegmentum, beneath the floor of the fourth ventricle (see Fig. 2). Facial nerve fibers loop around the abducens nucleus before exiting in the cerebellopontine angle. This intimate relationship accounts for frequent concurrent damage seen clinically. Although lateral to the third nuclear complex in the rostral mesencephalon, the MLF passes medial to the abducens nucleus. There are two populations of neurons with cell bodies within the abducens nucleus.^5,6 One group forms the sixth nerve; these abducens fibers pass ventrally to exit at the pontomedullary junction. The other internuclear neurons send fibers to join the contralateral MLF, with projection to the medial rectus subnucleus. Therefore, lesions involving the sixth nucleus produce an ipsilateral conjugate gaze palsy (i.e., ipsilateral lateral rectus and contralateral medial rectus).⁷

The abducens, trochlear, and oculomotor nuclei are integrated via the MLF, which also has major connections with the vestibular nuclear complex (see Fig. 1). Lesions involving the MLF typically result in internuclear ophthalmoplegia (see Chapter 10), which consists of faulty adduction of the ipsilateral eye (observed especially with attempted saccades) and dissociated nystagmus greater in the abducting eye on attempted lateral horizontal gaze (Fig. 4). In addition, some degree of vertical nystagmus in upward gaze is often present, and skew deviation may account for vertical diplopia.⁸ Internuclear ophthalmoplegia, usually bilateral, is by far the most common ocular motor disturbance of demyelinative origin. As a rule, unilateral ophthalmoplegia is usually due to a vascular incident, but bilateral involvement should not be considered rare in brain stem infarction.⁹

The peripheral course of the third nerve is as follows (Fig. 5): as the nerve exits ventrally from the midbrain into the interpeduncular space, it passes beneath the origin of the posterior cerebral artery and lies parallel and lateral to the posterior communicating artery. Klintworth¹⁰ pointed out that, in instances where the basilar artery bifurcates at a low level, the oculomotor nerve may be angled downward at the point where the posterior cerebral artery crosses the nerve, and vascular grooving of the superior aspect of the nerve is present in approximately one third of normal brains. The nerve runs between the free edge of the tentorium and the lateral aspect of the posterior clinoid, where it pierces the dura to enter the cavernous sinus. The oculomotor trunk occupies the superior aspect of the cavernous sinus (see ahead to Fig. 17) and separates into superior and inferior divisions at 4 to 5 mm before the superior orbital fissure. Fiber count of the superior division is about one-third that of the inferior,¹¹ and it has been suggested that relative pupil sparing in cavernous sinus or orbital apex lesions may reflect preservation of the inferior branch. The inferior branch supplies the medial and inferior recti, inferior oblique, and parasympathetic root to the ciliary ganglion (pupil sphincter); the superior branch innervates the superior rectus and levator palpebrae.

According to Kerr,¹² the pupillomotor fibers are superficial in the oculomotor nerve trunk, lying just internal to the epineurium. It is thought that this superficial position makes the pupillomotor fibers especially vulnerable to compression. In more anterior segments (e.g., cavernous sinus), however, pupillomotor fibers may be preferentially spared even in the presence of total oculomotor palsy. It is likely that involvement or “sparing” of the pupil reflects the nature and acuteness of the lesion, rather than which specific segment of the oculomotor trunk is compromised.

The trochlear fascicles pass dorsally, lateral to the aqueduct, and the nerve exits the midbrain and crosses the contralateral fourth nerve in the anterior medullary velum, just caudal to the inferior colliculi. The fourth nerve is the only cranial nerve to exit the brain stem dorsally. The nerve continues laterally around the midbrain tectum, crosses the superior cerebellar artery, and reaches the free edge of the tentorium, where it enters the dura and runs forward into the cavernous sinus (see Fig. 5). The fourth nerve enters the orbit through the superior orbital fissure, but above the annulus formed by the origin of the recti muscles, and innervates only the superior oblique muscle.

The abducens nerve emerges from the brain stem at the lower border of the pons in the pontomedullary sulcus, approximately 1 cm from the midline. The nerve ascends the ventral face of the pons for a short distance, is crossed by the anterior inferior cerebellar artery, and pierces the dura of the clivus approximately 2 cm below the posterior clinoids (see Fig. 5). The sixth nerve traverses or passes above the inferior petrosal sinus, runs beneath the petroclinoid ligament (Gruber), and enters the cavernous sinus. The sixth nerve lies freely within the body of the cavernous sinus, unlike the oculomotor and trochlear nerves that are supported in the lateral wall of the sinus. Some sympathetic fibers are briefly attached to the abducens, passing onward to the ophthalmic trigeminal.¹³ From the cavernous sinus, the nerve passes through the annular segment of the superior orbital fissure and innervates only the lateral rectus.

Milisavljevi and associates¹⁴ demonstrated penetration of oculomotor trunks by circumflex mesencephalic arteries or branches of the posterior cerebral perforating vessels, but clinical implications of such anatomic anomalies are not clear.

According to the anatomic review by Lapresle and Lasjaunias,¹⁵ there are three arterial “systems” that vascularize the cranial nerves: the inferolateral trunk arises from the intracavernous siphon of the internal carotid artery and nourishes cranial nerves III, IV, VI, and V-1; the middle meningeal system supplies nerves VII and V-2,3; and the ascending pharyngeal system supplies nerves IX through XII. The oculomotor nerve is also vascularized by the basilar artery system in the region of the posterior perforated substance, and in the supracavernous region by the artery of the free tentorial margin (Bernasconi). The clinical correlation of ischemic cranial neuropathies with these arterial territories is not entirely clear.

TABLE 1. Causes of Abduction Deficits

  Sixth nerve palsies
  Graves' myopathy (fibrotic medial rectus)
  Myasthenia gravis
  Orbital pseudotumor/myositis
  Orbital trauma (medial rectus entrapment)
  Congenital defects (Duane, Möbius syndromes)
  “Convergence spasm” (spasm of the near reflex)

ETIOLOGY

The causes of actual sixth nerve palsy are legion (Table 2). As noted previously, the peripheral course of the abducens nerve is a lengthy one that predisposes this cranial nerve to involvement at all levels, from the brain stem and base of the skull, through the petrous tip and cavernous sinus, to the superior orbital fissure and orbit.

TABLE 2. Causes of Sixth Nerve Palsies

  Nonlocalizing
  Increased intracranial pressure
  Intracranial hypotension
  Head trauma
  Lumbar puncture or spinal anesthesia
  Vascular, hypertension
  Diabetes/microvascular
  Parainfectious processes (postviral; middle ear infections in children)
  Basal meningitis
  Localizing
  Pontine syndromes (infarction, demyelination, tumor); contralateral hemiplegia; ipsilateral facial palsy, ipsilateral horizontal gaze palsy (± ipsilateral internuclear ophthalmoplegia); ipsilateral facial analgesia
  Cerebellopontine angle lesions (acoustic neuroma, meningioma): in combination with disorders of the eighth, seventh, and ophthalmic-trigeminal nerves (especially corneal hypoesthesia), nystagmus, and cerebellar signs
  Clivus lesions (nasopharyngeal carcinoma, clivus chordoma)
  Middle fossa disorders (tumor, inflammation of medial aspect of petrous): facial pain/numbness, ± facial palsy
  Cavernous sinus or superior orbital fissure (tumor, inflammation, aneurysm): in combination with disorders of the third, fourth, and ophthalmic-trigeminal nerves (pain/numbness)
  Carotid-cavernous or dural arteriovenous fistula

Lesions in the area of the abducens nucleus produce an ipsilateral horizontal gaze paresis, since both the internuclear neurons and the motor neurons of the sixth nerve originate in this nucleus. Although it is not certain whether the horizontal gaze palsy that occurs from damage to the abducens nucleus is always symmetric, it is clear that isolated lateral rectus pareses should never be considered nuclear in origin.

The fascicular (intrapontine) portion of the abducens nerve may be involved along with adjacent structures (see Fig. 2) to produce (1) ipsilateral paralysis of abduction (ipsilateral gaze palsy if sixth nucleus and/or pontine paramedian reticular formation [PPRF] is affected); (2) ipsilateral facial palsy; (3) ipsilateral Horner syndrome; (4) ipsilateral facial analgesia; (5) ipsilateral peripheral deafness; and (6) contralateral hemiparesis. These signs constitute the dorsolateral and ventral pontine syndromes (Foville, Millard-Gubler) at the level of the abducens fasciculus in the distribution of the anterior inferior cerebellar artery or its paramedian perforating arteries.

As the sixth nerve ascends the clivus in the subarachnoid space it is vulnerable to various insults, including neoplasms in the prepontine basal cistern (e.g., clivus chordoma, intraforaminal extension of nasopharyngeal carcinoma), compression by downward or forward movement of the brain stem (e.g., transtentorial herniation from supratentorial space-occupying lesions, head trauma, posterior fossa masses or structural anomalies, intracranial hypotension from cerebrospinal fluid leaks), and meningitis. It is here also that the nerve is probably affected by changes in intracranial pressure. Unilateral or bilateral abducens palsies can develop in association with pseudotumor cerebri or the syndrome of spontaneous intracranial hypotension,¹⁶ as well as after the following procedures: lumbar puncture, shunting for hydrocephalus, contrast myelography, spinal anesthesia,¹⁷ and treatment of cervical fractures.¹⁸

Before entering the cavernous sinus, the abducens nerve lies in relationship to the medial aspect of the petrous bone. Inflammation of the petrous bone and its dura may occur secondary to middle-ear infections, with involvement of the facial nerve (facial palsy), the trigeminal ganglion (pain in the eye or face), and the abducens nerve (lateral rectus palsy). These signs and symptoms constitute the now rare Gradenigo syndrome. The combination of sixth and seventh nerve palsies, even bilateral, is not uncommon in closed-head trauma, especially when the skull is compressed in its horizontal diameter (Fig. 6); this results in transverse fractures of the temporal bone. Leakage of blood or spinal fluid from the external ear canal, hemotympanum, or mastoid ecchymosis (Battle's sign) may be further evidence of basal fracture.

In the cavernous sinus, the abducens nerve may be involved in combination with the ophthalmic-trigeminal, third, or fourth nerves. Abducens monoparesis is frequent with cavernous sinus lesions, perhaps related to the nerve's location within the sinus, inferolateral to the carotid artery and unsupported by the dural wall of the sinus.^19,20 Isolated abducens palsy occurs with carotid-cavernous fistulas (especially with spontaneous dural shunts²¹) and intracavernous aneurysms²⁰ (Fig. 7), and is the earliest indication of contralateral spread of cavernous sinus thrombosis. Sixth nerve palsy accompanied only by ipsilateral Horner's syndrome also points to the cavernous sinus, since the ocular sympathetics from the carotid plexus may be simultaneously involved.²²

Lesions involving abducens nerve function at the superior orbital fissure or orbital apex regularly involve other motor nerves to the eye, or produce proptosis and/or visual compromise.

Keane²³ provided an analysis of 125 cases of bilateral sixth nerve palsies. Unlike the many isolated, unilateral abducens palsies that wander in the limbo of “vascular disease,” more accurate pathoanatomic diagnoses were made where bilateral palsies existed. One fourth of the patients in this series demonstrated deficits of other cranial nerves, and many had additional neurologic signs and symptoms, as well as spinal fluid abnormalities.

ISOLATED ABDUCENS PALSY

As noted previously, all patients with abduction defects do not have sixth nerve lesions per se, and additional diagnostic techniques such as forced ductions/generations and intravenous Tensilon tests are mandatory. If the onset of diplopia is associated with acute eye, orbital, or head pain, then neither Graves' disease nor myasthenia is a likely cause. In addition to the ocular motor (III, IV, VI) nerves, the function of cranial nerves V (especially corneal sensation), VII, and VIII should be examined.

The question now arises as to how one should proceed in the workup of the patient with a truly isolated sixth nerve palsy. In the elderly, as well as in younger adults (see later discussion), vascular disease (hypertensive or otherwise) has been considered a cause of sixth nerve palsies, and remitting abducens palsies are regularly encountered in the adult diabetic population. Therefore, a history of hypertension or diabetes should be sought. Considering the latter, a fasting and 2-hour postprandial glucose level or glycosylated hemoglobin should be obtained. There is no correlation between severity of glucose metabolism defect and occurrence of cranial nerve palsies; thus, an isolated sixth, fourth, or pupil-sparing third nerve palsy may signal the presence of otherwise occult diabetes. Diabetic retinopathy is frequently absent in these cases.

Although it would be rather extraordinary for cranial arteritis to present as an isolated sixth nerve palsy, an erythrocyte sedimentation rate is a reasonable laboratory study in patients 65 years of age or older. Of the neurologic complications of systemic lupus erythematosus, both sixth and third nerve palsies, and brain stem motility disorders, are recognized.²⁴ Because of the propensity for nasopharyngeal carcinoma to spread through the extradural space via basal skull foramina, basisphenoidal sections should be included in gadolinium-enhanced magnetic resonance imaging (MRI) (Table 3).

TABLE 3. Diagnostic Studies for Isolated Abduction Palsy

  Tensilon test
  Forced ductions/forced generations
  Serum glucose: fasting or after glucose load, or glycosylated hemoglobin
  Erythrocyte sedimentation rate
  Imaging studies*

  Contrast-enhanced CT: axial and coronal views, especially of orbital apex, cavernous sinus, sella, and clivus
  Contrast-enhanced MRI: cavernous sinus, clivus

When associated orbital and cranial signs and symptoms are absent, and when laboratory and appropriate radiologic studies are normal, the most prudent and practical course to follow is continued observation. An examination by a neurologist is comforting, but even Tensilon testing may be postponed. In this specific clinical situation, neuroimaging is infrequently productive, and its application in the elucidation of acute or subacute isolated sixth nerve palsies is moot. However, further radiologic evaluation must be undertaken if pain persists or develops, if other cranial nerves become involved, or if the palsy does not begin to improve over a 3- to 4-month period. Although it is true that some isolated “chronic” sixth nerve pareses last longer than 6 months, yet follow a completely benign course,²⁵ others are indeed caused by potentially treatable basal tumors.²⁶ Volpe and Lessell²⁷ reported seven patients with relapsing or remitting sixth nerve palsies, which were ultimately identified to be secondary to extramedullary compression of the abducens nerve by skull-based tumors. No patients had diabetes or vascular disease, and all recovered completely at least once (and in one case in five separate episodes) without surgical intervention, radiotherapy, or chemotherapy before a definitive diagnosis was made. Lesions included chordomas (Fig. 8), chondrosarcomas, and presumed meningiomas.

When pain persists and all radiologic and orbital investigations are unrevealing, a trial of corticosteroids (e.g., 60 mg prednisone orally for 5 days) may result in prompt and dramatic relief, in which case a tentative diagnosis of nonspecific inflammation of the superior orbital fissure or cavernous sinus may be made. However, the “response to steroid trial” may produce relief of pain with neoplasms as well as inflammation (see below, Combined Ocular Motor Palsies and Painful Ophthalmoplegia). Certainly, unrelenting eye or orbital or facial pain is an indication for exquisite visualization of the cavernous sinus and parasellar area by thin-section MRI scanning and either magnetic resonance or conventional angiography, if vascular abnormalities are suspected.

Isolated sixth nerve palsies in children often resolve spontaneously. Newborns may rarely manifest a transient lateral rectus weakness, with resolution occurring by 6 weeks.²⁸ Knox and colleagues²⁹ called attention to transient isolated abducens palsy of presumed postviral origin developing in children 1 to 3 weeks after nonspecific febrile or respiratory illness. The age range of the patients reviewed was 18 months to the early teens; recovery of abducens function occurred within 10 weeks (one case continued for 9 months). A similar pattern may be seen with specific viral illnesses such as varicella,³⁰ after immunization,³¹ or in association with Epstein-Barr viremia.³² A spate of reports indicates that some patients have multiple recurrences of these isolated “benign” sixth nerve palsies and that these recurrences have no serious implications.^31,33–36 A 35-year-old with cluster headaches also experienced three consecutive right lateral rectus palsies, on each occasion beginning a day or two after onset of pain, with recovery within 2 weeks³⁷; radiologic studies were unremarkable, suggesting the possibility of migrainous abducens palsy.

Robertson and co-workers³⁸ found a high incidence of brain tumor in his Mayo Clinic series of children with sixth nerve paresis. Although referred to as cases of “isolated” sixth nerve paresis, this definition signifies only that no other ocular motor nerves were defective. Indeed, of the children with neoplasms, one-third had papilledema and one-half demonstrated nystagmus at the time of initial examination. Of the patients with tumor who truly presented with only isolated abducens palsy, additional signs appeared within a few weeks or, rarely, within 2 to 3 months. Harley,³⁹ in his series of children with sixth nerve palsies of all causes, whether isolated or not, noted that approximately one third had suffered trauma and one fourth had underlying tumors; the total clinical picture in these cases is not described.

In the child with an isolated sixth nerve palsy without other neurologic signs, including papilledema, headaches, or ataxia, the following approach is suggested: (1) rule out middle-ear infection; and (2) obtain a peripheral blood count (lymphocytosis may be considered an indication of recent viral infection). The child must be reexamined at regular intervals until the paresis clears, and the parents must be advised to observe for new signs or symptoms. If the paresis persists or worsens, MRI is mandated. A persistent sixth nerve paresis in childhood may be the first clinical sign of a pontine astrocytoma or other posterior fossa mass lesion.

In a 10-year series of 49 “younger adults” (age range, 15 to 50 years) with isolated sixth nerve palsy, Moster and colleagues⁴⁰ reported that about one third had diabetes and/or hypertension; 8 had basal tumors; 6 had isolated abducens palsies as the initial sign of multiple sclerosis (all with subsequent clinical or spinal fluid abnormalities), usually with spontaneous resolution; and 11 had no specific etiology disclosed, but did have a sanguine outcome. This series excluded patients with a positive Tensilon test, abnormal forced ductions, other known neurologic disease, or with bilateral palsies.

Larger series of sixth nerve palsies reported^41–43 are helpful in reviewing the causes, although these patients were somewhat preselected. The largest number of cases fell into the nonspecific “vascular” category (37%, 7%, and 18%, respectively) and the “undetermined” category (24%, 21%, and 29%, respectively). All three series included a modest number of patients with multiple sclerosis (13%, 7%, and 4%, respectively; also 12% in the Moster⁴⁰ series), but abducens palsy in demyelinative disease has been exceedingly rare in our personal experience. Nevertheless, with the advent of MRI, acute sixth nerve palsies with multiple sclerosis may be more frequently discovered, with abnormal signals in the pons.⁴⁴

Minimal abduction paresis may herald increased intracranial pressure, such that the patient complains of horizontal diplopia when viewing distant objects. Clinically, these symptoms and findings may mimic divergence insufficiency. Kirkham and co-workers,⁴⁵ using electro-oculographic techniques, have demonstrated reduced abduction saccadic velocities, which suggest bilateral minimal sixth nerve dysfunction. Although neurons that discharge with divergence (and convergence) have been found in the mesencephalic reticular formation of the monkey,⁴⁶ the existence of a “divergence center” in the brain stem still remains controversial.

Symptomatic treatment of an acute sixth nerve palsy includes the use of Fresnel prisms, or alternate patching to avoid diplopia and possible medial rectus contracture. The injection of botulinum toxin type A (Botox) into the ipsilateral medial rectus is quite effective at preventing muscle contracture and improving fusion in the primary position of gaze. However, this procedure carries the disadvantage of significant crossed diplopia (exotropia) in contralateral gaze. Definitive surgical correction of a sixth nerve paresis should be employed when the deviation has been stable for at least 6 months. The primary consideration in these cases is the amount of residual abducting power of the lateral rectus, since moderate to good abduction is associated with successful ipsilateral recess/resect procedures (perhaps combined with contralateral medial rectus recession). However, if residual abduction is poor or absent, ipsilateral medial rectus recession may be combined with either a full- or partial-thickness tendon transplant procedure of the superior and inferior recti, or a Jensen procedure. The latter may have a decreased risk of anterior segment ischemia in susceptible patients.

Divergence paralysis is characterized by acute comitant esotropia at distance, normal fusion at near, and full ocular ductions. Of 11 patients with nontraumatic cause, Krohel and associates⁴⁷ found 3 with neurologic disease and other findings. Otherwise, there was no tendency to late evolution of neurologic sequelae. Stern and Tomsak⁴⁸ reported a young adult with a lower pontine lesion and also provided a useful overview of “divergence paralysis.” Divergence paralysis has been reported in association with the Arnold-Chiari malformation; in some cases, fusion returns to normal after neurosurgical correction.⁴⁹ In general, however, the process is idiopathic and benign, and neuroimaging is neither useful nor necessary. When surgical correction is indicated in these cases, lateral rectus resection, without medial rectus recession, effectively eliminates diplopia.

Superior oblique palsies may present spontaneously in late childhood and possibly represent “decompensated” congenital fourth nerve palsies. This diagnostic concept (i.e., that fusional mechanisms decompensate in later life) has also been applied to otherwise healthy adults with spontaneously acquired, unremitting superior oblique palsies of unknown origin (Fig. 9). A similar, often transient, occurrence of superior oblique palsy has been reported during pregnancy.⁵¹ These adults complain of reading difficulties, principally momentary diplopia, and show all of the attributes of superior oblique palsy. Old photographs may document tilting of the head, and further inquiry may uncover a forgotten history of childhood squint. Patients with congenital trochlear palsies commonly show increased amplitudes of vertical vergence.⁵² Normally, only 2 to 4 prism diopters (D) of vertical fusional amplitude are found, but patients with congenital superior oblique pareses may be able to fuse a 10-D or even a 30-D deviation. However, the presence of large vertical fusional amplitudes does not necessarily imply a congenital etiology, because vertical fusional vergence may increase in adults within weeks or months after an acquired vertical strabismus.

The cause of most congenital superior oblique palsies is unknown; however, agenesis of the trochlear nucleus has been described in association with agenesis of other cranial-nerve nuclei,⁵³ but never in the situation of an isolated congenital fourth nerve palsy. Dysplasia (aplasia) of cranial nuclei may occur after perinatal peripheral injuries to nerves, with secondary “dying back.” Also, axonal death, with selective elimination and preservation, is an established phenomenon during neurogenesis of all cranial nerves.⁵⁴ Absence of the superior oblique tendon has been observed during surgery to correct putative isolated congenital superior oblique palsies. This phenomenon may be more common in patients with craniofacial dysostoses.⁵⁵ Indeed, Helveston et al⁵⁶ reported congenital absence of the superior oblique tendon in 18% of patients with congenital superior oblique palsy, in whom a tuck of the superior oblique had been contemplated, and in another subgroup of patients with congenital superior oblique pareses, abnormally lax superior oblique tendons have been described. Bilateral congenital superior oblique palsies (particularly asymmetric pareses), as with bilateral acquired superior oblique palsies, may initially appear to be unilateral until corrective surgery “unmasks” the contralateral palsy.

Other than in the context of trauma, acquired isolated fourth nerve palsy occurs far less frequently than abducens or oculomotor palsies. In a retrospective study of 412 patients,⁵⁷ third and sixth nerve palsies were seven times more common than fourth nerve palsy. As with isolated abducens palsy, many spontaneous trochlear palsies are classified as “unknown” or “vascular.” In the older age group, isolated fourth nerve palsy is frequently associated with diabetes. Keane⁵⁸ provided an excellent overview of fourth nerve palsy among 215 patients, with head trauma representing the cause in more than 50%; no tumors showed isolated palsies, but were accompanied by other defects related to lesions in the cavernous sinus. In comparison, 149 patients with ocular myasthenia did not show isolated superior oblique palsies. Bilateral fourth palsies occurred in 19%; again, the majority of these cases were due to head trauma. Herpes zoster ophthalmicus may be associated with isolated trochlear palsy,⁵⁹ with variable recovery, but meningitis produces other signs and symptoms.⁵⁸ Although extremely rare, intracranial aneurysms (e.g., superior cerebellar artery) have been documented to cause superior oblique palsy as well.⁶⁰ Autosomal-dominant inheritance of superior oblique palsy, some bilateral, is also documented.⁶¹ The causes of fourth nerve palsies are listed in Table 4.

TABLE 4. Causes of Superior Oblique Paresis

  Fourth nerve palsy

  Traumatic (may be bilateral)
  Vascular mononeuropathy
  Diabetic
  Decompensated congenital paresis
  Posterior fossa tumor (rare)
  Cavernous sinus/superior orbital fissure syndromes
  Neurosurgical procedures
  Herpes zoster

Susceptibility of the trochlear nerve to injury in closed head traumas has been attributed to the position of the nerves with respect to the tentorial edge. According to Lindenberg,⁶² the tectum of the midbrain is subject to contrecoup contusion at the tentorial notch when the forehead or skull vertex strikes a stationary object, with the impact force directed toward the tentorium. The fourth nerves may be injured as they sweep laterally around the midbrain or dorsally in the anterior medullary velum, or in the substance of the lower midbrain. In these situations, bilateral fourth nerve palsies are common. Lindenberg also pointed out that, in blows to the base of the occiput or even in falls on the buttocks, forces are transmitted such that the cerebellum is thrust against the tentorium from below. In contrast to Lindenberg's neuropathologic material, fourth nerve palsies may result from minimal, if not insignificant, trauma. Radiographic documentation of the site of damage to the fourth nerve is unusual after trauma, but MRI of the posterior fossa has greatly increased the possibility of identifying minor intra- and extra-axial lesions in these cases.

As a rule, the diagnosis of an acute superior oblique palsy is not difficult (Fig. 10). Many patients rapidly learn to tilt the head toward the side opposite the defective eye. Such head tilting is not an exclusive sign of trochlear palsy, but it is seen more consistently here than with other vertical muscle pareses.⁶³ Nevertheless, it must be cautioned that a number of patients will have no consistent head tilt, or may even show a tilt toward the palsied side, possibly to achieve greater subjective image separation so that the more peripheral image can be ignored.

According to the data accumulated by Khawam et al,⁶³ all patients with unilateral superior oblique palsies show vertical deviation in the primary position, with an increase in deviation on adduction of the involved eye. A common pattern wherein the vertical deviation is greatest in adduction and elevation is seen with secondary inferior oblique overaction. With time, the vertical deviation often becomes comitant. In patients with bilateral palsies, almost all due to head trauma, the vertical deviation in primary position tends to be smaller. Anomalous head positions were present in half of the unilateral palsies and 70% of the bilateral palsies, but more than 90% of all patients demonstrated greater vertical deviation with the head tilted toward the side of the paretic muscle (i.e., a positive Bielschowsky forced head-tilt test; see Fig. 10). Sydnor and colleagues⁶⁴ concurred that unilateral fourth nerve palsies have large hypertropias and more vertical than torsional diplopia, whereas bilateral palsies show small hypertropias in primary gaze, large V-pattern esotropias, a compensating chin-down position that permits fusion in upgaze, and excyclotorsion greater than 10° to 12°. Lee and Flynn⁶⁵ noted that bilateral superior oblique palsies should be suspected when the Bielschowsky test is positive with head tilt in both directions, especially after a relatively severe head trauma.

In the clinical dilemma of acquired verticle deviations, Trobe⁶⁶ provided practical data regarding cyclotorsional defects: excyclodeviation occurred in 30 of 33 patients with trochlear palsies, 8 of 15 patients with Graves ophthalmopathy, and 1 of 13 patients with myasthenia, but did not occur in any case of skew deviation. Keane⁶⁷ provided an excellent summary of the vertical diplopia syndromes seen during a 15-year inpatient hospital experience, including oculomotor palsy (579 cases), trochlear palsy (133 cases), skew deviation (434 cases), myasthenia (94 cases), and others, such as Guillain-Barré syndrome, orbital floor fracture, and Graves ophthalmopathy.

In the patient with an isolated superior oblique palsy, without antecedent trauma and with a negative Tensilon test, forced duction, and serum glucose tests, observation is the rule. Radiologic studies are of minimal value. Most of these patients spontaneously recover in less than 6 months.⁴³ If the deviation is stable, prisms can be incorporated into spectacles, but this may fail because of torsional defects or persistent incomitance. After measurements remain stable for at least 6 months, surgical correction may be undertaken with a high rate of success. In general, ductional defects when present should be addressed: for example, if the superior oblique is underactive, a tendon-tucking procedure is preferred; with significant inferior oblique overaction, inferior oblique myectomy or recession is quite effective. Depending on the degree and pattern of the vertical misalignment, recessions of the ipsilateral superior rectus and/or contralateral inferior rectus using the adjustable suture technique may be employed. These procedures have worked well in cases of congenital absence of the superior oblique tendon⁶⁸ or in cases of bilateral superior oblique palsies. For bilateral cases, surgery should be commensurate with the relative degree of symmetry between the two eyes. In cases of persistent V-pattern esotropia and excyclodeviation, after bilateral superior oblique tucks, bilateral inferior rectus recessions often yield significant improvement.⁶⁹ Finally, in cases where there is minimal vertical deviation but excyclodiplopia is the chief complaint, advancement of the anterior superior oblique tendon fibers (Harada-Ito procedure) may improve the torsional diplopia without disturbing vertical ocular alignment.

Acting as a pseudopalsy of the inferior oblique, Brown's syndrome refers to an anomalous articulation between the trochlea and superior oblique tendon sheath, resulting in a restrictive strabismus showing lack of elevation in adduction. This is most often a congenital disorder, in which diplopia is infrequent and good fusion is the rule. Many patients enjoy spontaneous improvement by late childhood or early adulthood.⁷⁰ When surgery is required for large hypotropia in the primary position, or for disfiguring chin-up posture in order to promote fusion, superior oblique tenectomy with or without ipsilateral inferior oblique weakening is the most commonly employed procedure. Other surgical techniques include introduction of a silicone tendon expander and superior oblique and trochlear luxation.⁷¹ A form of secondary Brown's syndrome may also be acquired after orbital trauma⁷² or with orbital metastasis.⁷³ It has been described in association with systemic collagen vascular disease, such as juvenile rheumatoid arthritis,⁷⁴ systemic lupus erythematosus,⁷⁵ and hypogammaglobulinemia. Such cases typically respond well to oral steroids or nonsteroidal agents. Local injection of depot steroids in the region of the trochlea can produce improvement as well, but may cause secondary scarring and fibrosis. Brown's syndrome has also been described as a transient phenomenon in the postpartum period.⁷⁶

Superior oblique myokymia (see also Chapter 11) consists of spasms of cyclotorsional and vertical eye movements. These are often difficult to appreciate on gross examination, but are easily seen with the slit lamp or ophthalmoscope. There is an initial intorsion and depression of the affected eye, followed by irregular torsional oscillations of minor amplitude. This phenomenon is strictly unilateral, and generally occurs in the absence of neurologic disease. Brazis et al⁷⁷ have reported a long-term follow-up of 16 patients. Therapeutic options include carbamazepine or propranolol. If medical treatment is ineffective or intolerable, superior oblique tenectomy combined with inferior oblique myectomy to avoid iatrogenic trochlear paresis has been documented to be an effective treatment.

TABLE 5. Causes of Oculomotor Palsies

  Nuclear
  Infarction
  Demyelination
  Metastatic tumor
  Fascicular
  Infarction
  Demyelination (rare)
  Tumor
  Interpeduncular
  Aneurysm
  Trauma
  Meningitis
  Cavernous Sinus
  Carotid-cavernous fistula
  Granulomatous inflammation (Tolosa-Hunt syndrome)
  Intracavernous aneurysm
  Extrasellar extension of pituitary tumor
  Meningioma
  Sphenoid sinus carcinoma
  Metastatic tumor
  Mucormycosis (other fungus)
  Herpes zoster
  Orbit
  Nonspecific inflammation (pseudotumor)
  Trauma
  Tumor
  Ischemic (diabetic) Ophthalmoplegia
  Miscellaneous
  Polyneuritis (Guillain-Barré-Fisher syndrome)
  Cyclic oculomotor palsy (Bielschowsky)
  Migraine
  Arteritis

NUCLEAR LESIONS

Disorders of the oculomotor nerve at its nuclear source may be encountered in rare instances. Based on Warwick's anatomic configuration of the third nerve nuclear complex (see Fig. 3), the following clinical rules are applicable:

1. Conditions that cannot represent nuclear lesions
   1. Unilateral external ophthalmoplegia (with or without pupil involvement) associated with normal contralateral superior rectus function
      
   2. Unilateral internal ophthalmoplegia
      
   3. Unilateral ptosis
      
   
   
2. Conditions that may be nuclear
   1. Bilateral total third nerve palsy
      
   2. Bilateral ptosis
      
   3. Bilateral internal ophthalmoplegia
      
   4. Bilateral medial rectus palsy
      
   5. Isolated single muscle involvement (except levator and superior rectus)
      
   
   
3. Obligatory nuclear lesions
   1. Unilateral third nerve palsy with contralateral superior rectus and bilateral partial ptosis
      
   2. Bilateral third nerve palsy (with or without internal ophthalmoplegia) associated with spared levator function
      
   
   

Because ocular myasthenia, and in some instances, Graves myopathy, may mimic various patterns of oculomotor nerve dysfunction, Tensilon testing and forced ductions should be considered in cases of painless ophthalmoplegia where pupils are normal. Supranuclear lesions involving midbrain structures near the third nerve nucleus may closely simulate direct damage to the nucleus. If ocular motility improves with vestibular stimulation (oculocephalic reflex, calorics) or with Bell's phenomenon, a supranuclear lesion is present. Failure of ocular motility to improve with any of these stimuli indicates the presence of a nuclear or infranuclear lesion, but does not exclude additional supranuclear abnormalities.

Several clinicopathologic studies have supported Warwick's schema. There are documented instances of isolated bilateral ptosis, with discrete foci in the nuclear complex of the third nerve, in the midline at the level of the central caudal nucleus.⁷⁸ Keane et al⁷⁹ described a case of unilateral oculomotor palsy, complete except for near-normal levator function; at autopsy, a solitary midbrain metastasis was seen involving the rostral ipsilateral third nerve nucleus, but sparing the central caudal levator nucleus. The MRI findings in two instances of levator-sparing nuclear oculomotor palsies, with contralateral elevator palsy, defined focal rostral midbrain infarcts.⁸⁰ In several patients, isolated extraocular muscle palsies (e.g., isolated inferior rectus palsy) have been ascribed on clinical grounds to small lesions of the oculomotor nuclear complex.⁸¹

Acquired bi-nuclear total ophthalmoplegia is occasionally seen (Fig. 11), as reported by Masucci.⁸² These findings are the result of thrombotic or embolic processes at the level of the basilar bifurcation, with occlusion of the median mesencephalic perforating arteries. Congenital bilateral total ophthalmoplegia with or without levator and pupil sparing has been reported and may be associated with dysplasia of the corpus callosum.⁸³

FASCICULAR LESIONS

Deficits of the oculomotor fasciculus are usually identified by the accompanying brain stem signs. Oculomotor palsy with contralateral hemiplegia (Weber syndrome) indicates involvement of the corticospinal tracts. Contralateral ataxia and intention tremor (Benedikt syndrome) indicates involvement of the red nucleus (see Fig. 2). Nothnagel syndrome is an eponym given when signs of both Weber and Benedikt syndromes are present. Midbrain vascular accidents account for most fascicular defects.

Ksiazek⁸⁴ shed some light on the fascicular arrangement of the oculomotor nerve based on two patients with partial oculomotor paresis, each with pupillary mydriasis, significant inferior rectus paresis, and medial rectus paresis. Neuroimaging revealed a lesion in the fascicular portion of the nerve, thus indicating the proximity of these fibers in the fasciculus. Monocular elevator paresis (superior rectus and inferior oblique) in mass compression of the oculomotor fasciculus has also been reported.⁸⁵ In this regard, Castro and associates⁸⁶ proposed the mediolateral somatotopy of the oculomotor fascicular fibers within the mesencephalon with the inferior oblique and superior rectus muscles being most lateral, and the pupilloconstrictor fibers and inferior rectus being most medial. The levator palpebrae fascicles are in an intermediate location between the superior rectus and medial rectus fascicles.

INTERPEDUNCULAR LESIONS

Basal lesions, including the rare rostral basilar artery aneurysm, may encroach on the oculomotor nerves as they exit in the interpeduncular space. Such slow-growing aneurysms, either saccular or fusiform, may present as partial oculomotor palsies with or without involvement of pyramidal tracts, and without subarachnoid hemorrhage.⁸⁷ Aneurysms of the posterior communicating artery, on the other hand, are probably the most common lesions causing acute spontaneous oculomotor palsies (Fig. 12). According to Hyland and Barnett,⁸⁸ the oculomotor palsy that occurs with posterior communicating aneurysm is not necessarily due to mass effect per se, but rather is attributed to hemorrhage that suddenly enlarges the aneurysmal sac to which the oculomotor nerve is adherent, or to hemorrhage into the substance of the nerve itself. Most patients present, therefore, with an intensely painful, complete unilateral oculomotor palsy in association with other signs and symptoms of subarachnoid hemorrhage. Few patients with symptomatic posterior communicating aneurysms are found in office waiting rooms: they are usually obtunded or comatose in emergency rooms.

Involvement of pupillary fibers is such a consistent finding in third nerve palsies due to bleeding aneurysms that most clinicians concur in this useful dictum: a pupil-sparing, but otherwise complete, third nerve palsy is very unlikely to be due to posterior communicating aneurysms. Careful pupil evaluation may disclose subtle abnormalities in “apparent pupil-sparing,” especially in cases of aberrant regeneration or with chronic cavernous sinus lesions. Generally, in patients at least 50 years of age or older, an acute, isolated, painful oculomotor palsy that spares the pupil is caused by intraneural ischemia; nevertheless, these patients must be carefully observed for further evolution. In our opinion, an acute complete oculomotor palsy with moderate to major mydriasis, even when diabetes is present, is an indication for cerebral arteriography. It should be emphasized that magnetic resonance angiography may not detect aneurysms smaller than 3 to 4 mm.⁸⁹

The clinical management of patients with relative pupil-sparing third nerve palsies remains in debate. Observation alone arguably is appropriate management of such patients; however, since practically every conceivable combination of partial ophthalmoplegia and pupillary abnormality has been reported in aneurysmal compression of the third nerve, it is better to err on the side of caution and perform angiography more frequently. It is incumbent upon the physician to evaluate carefully the proportion of ophthalmoplegia and ptosis in relation to the degree of pupillary abnormality when deciding appropriate workup of these patients. Again, the increasing sensitivity of magnetic resonance angiography has not yet entirely replaced formal angiography. Certainly, neurosurgical intervention requires conventional cerebral arteriography before surgical treatment. Capó and colleagues⁹⁰ pointed out that the interval from onset to maximal ophthalmoplegia does not differentiate between microvascular (3.3 days) and aneurysm (3 days), but that failure to recover within 4 to 8 weeks requires further evaluation.

Other partial oculomotor palsies occur regularly with cavernous sinus masses and parasellar syndromes (see below), accompanied by variable pupillary findings. Furthermore, both acute and chronic lesions may produce incomplete palsy of the superior division (supplying levator palpebrae and superior rectus muscles) or of the inferior division (medial and inferior recti, inferior oblique and pupillomotor fibers). If pain or first trigeminal division numbness are absent, and if the pupil is uninvolved, such fractional oculomotor pareses are regularly misinterpreted as myasthenia or local orbital inflammations. Guy et al⁹¹ described five patients with isolated ptosis and elevator paresis in abduction, consistent with selective “superior division” involvement. They also discussed five previously reported cases with the following respective diagnoses: (1) intracavernous aneurysm (usually with associated Horner's syndrome) and basilar artery aneurysm; (2) diabetic ophthalmoplegia; (3) meningitis; (4) dural lymphoma; and (5) postsurgical manipulation of parasellar structures. In essence, there was little anatomic correlation with the physical separation into superior and inferior oculomotor trunks that occurs in the cavernous sinus. Moreover, two patients sustained superior division palsies during surgical manipulation of the subarachnoidal portion of the oculomotor nerve trunk. A number of cases of inferior rectus paresis, isolated or in combination with ipsilateral or contralateral superior rectus paresis, have been construed as focal lesions involving the rostral portion of the oculomotor nuclear complex.^80–82

Oculomotor palsy following head trauma is not rare, but probably occurs less frequently than traumatic fourth nerve palsies. As a rule, such closed-head injury causes loss of consciousness and is accompanied by skull fracture, but this is not invariable. Injury to the ocular motor nerves in road accidents was studied by Heinze,⁹² who dissected the cadavers of 21 fatal cases. He found that the relationship of frontal or temporal fractures to neural damage was unpredictable. In fact, intact nerves were encountered adjacent to gross fracture sites. The oculomotor nerve was damaged at three locations: (1) avulsion of the rootlets at their ventral exit from the brain stem; (2) contusion necrosis of the most proximal portion of the nerve trunk; and (3) intraneural and perineural hemorrhage of the nerve trunks at the level of the superior orbital fissure. Of great interest are Heinze's findings of focal hemorrhages in extraocular muscles, usually associated with fractured orbital bones.

Eyster et al⁹³ reported three patients with large basicranial tumors, who presented with oculomotor palsies precipitated by mild blows to the head that were insufficient to cause fracture or loss of consciousness. The oculomotor nerves were encased and stretched by tumor, which apparently rendered these tethered nerves vulnerable when innocent head blows abruptly shifted the brain. The authors pointed out that such atypical presentations of intracranial tumors may further mimic aneurysms, since subarachnoid hemorrhage does occasionally occur with tumors. Neetens⁹⁴ reported an additional three cases of oculomotor nerve palsies after minor trauma in the presence of basal intracranial tumors; the trochlear nerve was involved in all three cases, and in two cases the oculomotor nerve was partially affected. Walter et al⁹⁵ reported two instances of minor head trauma resulting in complete third nerve palsies attributed to occult posterior communicating artery aneurysms. We have seen a 45-year-old school teacher who experienced an immediate right abducens palsy when playfully slapped on the back of the head; within weeks, other cranial nerve palsies announced the presence of diffuse meningeal spread of carcinoma.

In the United States, basilar meningitis is rare, but was formerly encountered with tuberculosis and syphilis. When the third nerve is involved in such cases, progressive defects are the rule and other cranial nerve palsies are commonly found. Oculomotor palsy may especially occur with meningitides in infants, including instances of viral and bacterial (e.g., Streptococcus pneumoniae, Haemophilus influenzae) infections.⁹⁶

Oculomotor nerve compression by the proximal segment of the posterior cerebral artery, or by the uncus against the petroclinoid ligament, can be seen with increasing cerebral edema or with an ipsilateral expanding supratentorial mass, and it is often heralded by unilateral pupillary dilation (Hutchinson pupil). Progression rapidly leads to complete ocular motor nerve palsy. Keane⁹⁷ reviewed the ocular motor signs of tentorial herniation, which include anisocoria and parasympathetic pupillary abnormalities, unilateral or bilateral ptosis, internuclear ophthalmoplegia, vertical gaze paresis, and partial third nerve palsies.

CAVERNOUS SINUS LESIONS

The oculomotor nerve may be involved by inflammatory disease, tumor, aneurysm, arteriovenous fistula, or thrombosis at the level of the cavernous sinus. The third nerve is usually involved in combination with the fourth, sixth, and ophthalmictrigeminal nerves, and accompanying sympathetic paresis may minimize pupillary dilation. The syndrome of the cavernous sinus, therefore, includes multiple ocular motor nerve palsies and pain or numbness in the first trigeminal division. In practice, lesions involving primarily the superior orbital fissure produce signs and symptoms that, with the possible exception of proptosis, cannot be distinguished from those of the anterior cavernous sinus. In particular, dural carotid cavernous fistulas that drain primarily into the inferior petrosal sinus may cause third nerve pareses without significant orbital congestion.⁹⁸

Third nerve palsies due to lesions in the cavernous sinus tend to be partial in that all muscles innervated by the oculomotor branches need not be involved. This is especially true of pupillomotor fibers, such that the pupil may be normal or minimally involved. This “pupil- sparing” is offhandedly attributed to the superimposition of sympathetic paresis (Horner syndrome), but appropriate pharmacologic tests rarely substantiate this explanation (see below, Parasellar Syndrome). More likely, slowly expanding masses (e.g., infraclinoid aneurysm, meningioma) functionally spare the pupilloconstrictor fibers in the intracavernous portion of the oculomotor nerve. In addition, the levator, superior, inferior, and medial recti may be involved in unequal degrees, but progressive paresis evolves. (Once again, myasthenia must be suspected in any nonpainful, pupil-sparing, nonproptotic ophthalmoplegia, with or without ptosis.) Cavernous sinus lesions are further discussed below.

Primary neurinoma of the oculomotor nerve is a relatively rare lesion that should be considered in children or young adults with insidious third nerve palsy. These may occur in the cavernous or interpeduncular portion of the nerve (Fig. 13).^99,100

ORBITAL LESIONS

Oculomotor nerve palsies with orbital lesions are usually accompanied by abducens weakness and proptosis. In the absence of proptosis, anterior cavernous sinus lesions may not be distinguishable from those involving the superior orbital fissure or orbital apex. Nonspecific inflammations of orbital tissues (orbital pseudotumor) may produce palsies of extraocular muscles in variable combinations, but other manifestations (e.g., pain, chemosis, ocular inflammation, proptosis) are usually present. Orbital trauma, unless overlooked or forgotten, usually presents no difficulty in diagnosis. Forced duction testing and orbital ultrasonography and/or enhanced CT imaging are indicated.

Clinically, patients with ischemic oculomotor palsy present with acute pain in and about the involved eye. The pain may precede actual ophthalmoplegia and can be so severe as to suggest a bleeding aneurysm (but without neck stiffness, photophobia, obtundation, etc.), or it may accompany the onset of ptosis or diplopia as a mild brow pain or headache. The pupil is almost always spared, in contradistinction to posterior communicating artery aneurysm (see above). Iridoplegia, when present, is moderate. Ophthalmoplegia may be partial, with some muscles spared entirely (Fig. 14). Recovery is predictable, occurring after several weeks and usually before 4 months.

Studies by Weber et al¹⁰⁴ and Asbury et al¹⁰⁵ have indicated the following: (1) the lesion is primarily a focal demyelinization with minimal axonal degeneration; (2) remyelinization is thought to be responsible for recovery without aberrant regeneration; and (3) ischemia due to closure of intraneural arterioles is thought to cause the demyelinative lesion, which may occur in the intracavernous¹⁰⁵ or subarachnoid¹⁰⁴ segment of the third nerve. However, the advent of MRI has clearly demonstrated that intraparenchymal midbrain lesions may be responsible for pupil-sparing ophthalmoplegia.^106,107

The key to diagnosis is threefold: a high level of suspicion should be entertained when a middle-aged or elderly person (1) presents with a pupil-sparing ophthalmoplegia involving all or most of the ocular muscles innervated by the third nerve only (with or without accompanying pain); (2) has elevated serum glucose levels either during fasting or after a measured glucose load; most recently, the American Diabetes Association has recommended¹⁰⁸ a more reliable assay of hyperglycemia, namely, glycosylated hemoglobin (GHb or hemoglobin A1c), reflecting mean glycemia over the preceding 2 to 3 months; and (3) has a documented recovery within 3 to 4 months. The significant proportion of cranial nerve pareses due to diabetes or another microvascular disease cannot be overemphasized. The Mayo Clinic has reviewed more than 4000 cases of third, fourth, or sixth cranial nerve palsy.⁴³ The order of frequency was as follows: abducens pareses (43.9%), oculomotor pareses (28%), trochlear pareses (15%), and multiple simultaneous oculomotor pareses (13.1%). Slightly more than 15% of all cranial neuropathies were attributed to vascular causes (e.g., diabetes, hypertension, atherosclerosis, vasculitis). Note, however, that these figures pertain to adults only: microvascular cranial neuropathies do not occur in the pediatric population.

The precise mechanism whereby oculomotor synkinesis occurs is controversial and unsettled. Sibony et al¹⁰⁹ reviewed the various hypotheses proposed to explain oculomotor synkinesis. Random misdirection of regenerating motor axons within an injured oculomotor nerve trunk, with erroneous muscle re-innervation, is the traditional explanation for oculomotor synkinesis, and indeed histopathologic, clinical, and experimental evidence may be cited in support of this hypothesis.¹¹⁰ But transient oculomotor synkinesis,^111–113 spontaneous “primary” oculomotor synkinesis,^{111,114–117} and synkinesis involving superior and inferior divisions of the third nerve after damage to only the superior division¹¹² have been observed and are difficult, but not impossible,¹⁰⁹ to explain by the hypothesis of indiscriminate axonal regeneration. Such clinical oddities prompted Lepore and Glaser¹¹¹ to challenge the concept that misdirection of regenerating oculomotor fibers is responsible for all oculomotor synkinesis, and to invoke two alternative mechanisms: ephaptic transmission (axo-axonal “cross-talk”), and synaptic reorganization of the oculomotor nucleus following retrograde axonal degeneration.

After acute ophthalmoplegia, clinical signs of dyskinesia begin at about 8 to 10 weeks, accompanying variable degrees of recovered function (Fig. 15). When recovery begins earlier, synkinesia is less frequent—and, of course, when there is no recovery, there is no synkinesia. Several paradoxic patterns may evolve: elevation of the upper lid on attempted use of the inferior (pseudo-von Graefe sign) or medial rectus muscles (“reverse Duane” syndrome) (see Fig. 13); adduction or retraction of the globe on attempted downward or upward gaze; and a light-near (or lateral gaze) pupillary dissociation with constriction of a larger than normal pupil occurring on attempted adduction. According to Hepler and Cantu,¹¹⁸ of 25 patients with aberrant oculomotor regeneration after posterior communicating artery aneurysms, 20 demonstrated the pseudo-von Graefe phenomenon of lid elevation on attempted downgaze. This critical sign is best appreciated by directing the patient's gaze first downward, and then slowly from side to side. Czarnecki and Thompson¹¹⁹ reported other pupillary anomalies, including asynchronous sectoral contractions with both light stimulation and eye movement.

Oculomotor synkinesis is frequently observed in congenital third nerve palsies.^39,120–122 The spontaneous and progressive development of oculomotor synkinesis in patients with no prior acute oculomotor palsy^{111,114–117} is seen most commonly with slowly growing lesions in the cavernous sinus, usually meningiomas or aneurysms, and has been termed primary oculomotor synkinesis. Varma and Miller¹²³ pointed out that although aneurysms typically present with acute, painful oculomotor pareses, they may produce painless third nerve palsies with primary aberrant regeneration. Secondary oculomotor synkinesis, that is, synkinesis following recognized acquired oculomotor palsy, most commonly occurs in association with trauma or aneurysms, but may rarely be seen with neoplasia or even ophthalmoplegic migraine.¹²⁴ Misdirection has not been documented after ischemic (diabetic) ophthalmoplegia or demyelinative syndromes.

Bilateral misdirection produces the extraordinary picture of gaze-dependent (adduction and/or depression) alternating lid retraction: that is, right lid retraction on left gaze, and left lid retraction on right gaze. An instance of apparent combined oculomotor-abducens synkinesis has been reported¹²⁵ in one unusual case of posttraumatic “total ophthalmoplegia”: on attempted adduction, the right eye slightly abducted, but adducted upon attempted abduction; in addition, attempted abduction produced pupillary constriction. An extraordinary case of trigeminal-abducens synkinesis has been reported¹²⁶ following head trauma. In a 29 year old woman, left eye abduction was enhanced by 30° when accompanied by tight jaw closure, attributed to misdirection of mandibular division motor fibers accessing the abducens sheath at the petrous bone.

Pallini and colleagues,¹²⁷ in their work in adult guinea pigs, noted frequent aberrant regeneration following oculomotor nerve repair after transection proximally at the tentorial edge, versus full recovery without aberrant phenomena when the nerve was severed distally at the orbital fissure. The presence of aberrant regeneration correlated inversely with reestablishment of normal topographic bias in the regenerated nerves.

Commonly, the disorder follows a febrile or “viral” illnesses, or is seen in association with infectious mononucleosis. Although the well-known cerebrospinal fluid protein elevation, in the absence of cellular response, is a sine qua non of this disorder, by no means is this dissociation a constant finding. Detailed nerve conduction studies in one patient with generalized Guillain-Barré syndrome¹²⁹ revealed that demyelination occurred first in the most distal nerve and progressed to the spinal root; during recovery, remyelination occurred initially at the spinal root level. This sequence may explain the typical interval of days to weeks between onset of symptoms and rise in cerebrospinal fluid protein, which probably increases only when the spinal roots become involved.

In 1956, Fisher¹³⁰ documented the ophthalmoplegic variant of acute idiopathic polyneuritis, characterized by oculomotor palsies, areflexia, and ataxia. Pathologic material published by Asbury et al¹³¹ demonstrated inflammatory infiltration of nerve roots, including peripheral and cranial nerves; these authors proposed that their findings suggest that the polyneuritis syndrome is related to a lymphocyte-mediated autoimmune reaction. The patient studied by Grunnet and Lubow,¹³² however, showed central chromatolysis in the nuclei of the third, fourth, fifth, and twelfth nerves, and of the anterior horn cells, with only sparse lymphocytic infiltration. Additional clinical evidence that Fisher's syndrome can indeed affect the central nervous system (CNS) includes the following: loss of voluntary saccades with preservation of pursuit; upgaze paresis with intact Bell's phenomenon; internuclear ophthalmoplegia; cerebellar ataxia; hemiparesis; extrapyramidal signs; and disorders of consciousness, including obtundation and electroencephalographic abnormalities.¹³³ Radiologic abnormalities include enhancing midbrain tegmental lesions in a case of bilateral internuclear ophthalmoplegia, vertical gaze palsy, ataxia, and hyporeflexia.¹³⁴

Although it is estimated that ophthalmoplegia occurs in 15% of patients with Guillain-Barré syndrome,¹³⁵ nonetheless, on the basis of both clinical and neuropathologic findings, Fisher's syndrome (ophthalmoplegia, ataxia, areflexia) may not always represent a variant of the Guillain-Barré syndrome, but could represent several disease states. In fact, ophthalmoplegia may accompany a third type of idiopathic demyelinative polyneuropathy characterized by a prolonged course of symmetric sensory and motor limb symptoms.¹³⁶ Acute ophthalmoparesis may be associated with high serum IgG antibody to GQ_1b ganglioside, with or without ataxia.¹³⁷ (See also Other Ocular Polyneuropathies, below).

In an extensive review of patients with Fisher's syndrome, Berlit and Rakicky¹³³ provided the following data:

  Male:female ratio: 2:1
  Mean age of onset: 43.6 years
  Percentage with a preceding viral prodrome: 72%, with a 10-day interval
  Symptoms: diplopia (39%), ataxia (21%), and areflexia (82%)
  Non-ocular nerve involvement included:
  seventh (46%), ninth and tenth (40%), and twelfth (13%) nerves
  Percentage with elevated CSF protein: 64%

Prognosis was considered good, with a mean recovery time of 10 weeks, but residual symptoms were present in 33% of cases. Therapy with corticosteroids or plasmaphoresis seemed without benefit.

Friedman et al¹³⁸ analyzed eight cases of ophthalmoplegic migraine culled from 5000 migraine patients. Ages at onset of the first ophthalmoplegic episode were as follows: 2, 2, 3, 3, 5, 8, 17, and 30 years; that is, six of eight patients experienced ocular palsy at age 8 years or younger. All patients had oculomotor nerve involvement, the majority of which involved the pupil. A typical episode consisted of pain in and about the involved eye, nausea, and vomiting. With the onset of ophthalmoplegia, the head pain often resolved. As a rule, paresis clears completely within 1 month, but residua may persist (Fig. 16D). Although patients can suffer multiple attacks, many years may intervene.

The mechanism of ophthalmoplegic migraine is obscure, but surely is peripheral in nature. Vijayan¹³⁹ observed sparing of the pupil in a single patient during three episodes of ophthalmoplegic migraine and, on reviewing the literature, reiterated that pupil sparing is not uncommon in this entity. He argued that this makes compressive neuropathy an unlikely mechanism, but proposed instead that “swelling of the walls of the carotid or basilar arteries leads to occlusion of the smaller vessels which supply the involved cranial nerves.” However, MRI has shown enhancement of the oculomotor nerve in acute ophthalmoplegic migraine, with normal appearance on repeat imaging after the attack.^140–142

The question of cerebral angiography is an important one. In the typical case of a young child with nausea, vomiting, and headache followed by third nerve palsy upon resolution of the premonitory symptoms, as well as a positive family history of migraine, perhaps no angiography is indicated. It is extremely unlikely than an intracranial tumor would present as a sudden painful third nerve palsy in a child, and aneurysms are quite rare among pediatric patients. A small perimesencephalic vascular anomaly was found angiographically in a 31-year-old patient with a partial oculomotor palsy and a 25-year history of recurrent ophthalmoplegic migraine.¹⁴³ The point that migrainous ophthalmoplegia and Tolosa-Hunt syndrome (see below) share many features is well taken,^141,144 but the argument that steroids should be used seems superfluous given the rapid resolution of pain and spontaneous recovery.

Osuntokun and Osuntokun¹⁴⁵ reported an extraordinarily high incidence of ophthalmoplegic migraine in Nigerians. Of practical importance is their finding of concurrent hemoglobin AS, and they suggested that hemoglobin electrophoresis be obtained in any black patient presenting with complicated migraine, including the ophthalmoplegic form.

Balkan and Hoyt¹²² cautioned that congenital third nerve palsies may not be monosymptomatic. Of their 10 patients with congenital third nerve palsies, 4 had associated focal neurologic deficits and 2 had generalized developmental delay. In children, isolated third nerve palsy may follow viral illness^123,146 or immunization,¹⁴⁷ but seems to occur much less frequently in this setting than sixth nerve palsy. Recall also that “cryptogenic,” progressive oculomotor pareses may be secondary to a neurinoma of the peripheral nerve or masses in the cavernous sinus, for which thin-section MRI is required.

Harley¹²³ provided a useful overview of “paralytic strabismus” in children, a retrospective analysis of the Wills Eye Hospital experience of 121 patients ranging in age from birth to 16 years. The common causes of isolated oculomotor palsy included 15 congenital cases (including 4 with double elevator palsies), frequently showing aberrant regeneration signs; 4 traumatic cases; and 3 migrainous cases. Of the abducens palsy cases, 21 were traumatic; 17 were associated with neoplasms, including brain stem gliomas, and posterior fossa astrocytomas and medulloblastomas. Although no further clinical data are supplied, in the tumor group surely other neurologic signs and symptoms were present, although the abducens may have been the predominant malfunctioning motor nerve to the eye. Of 18 trochlear palsy cases, 12 were congenital (including 5 bilateral cases) and 5 were the result of head trauma. Other patients in this series showed eye movement defects that were due to local orbital inflammation or tumor, but not strictly due to focal ocular motor palsies per se.

In the situation of nontraumatic, acquired, isolated oculomotor palsy in childhood, where the diagnosis is in doubt, it is reasonable to proceed with MRI scanning of basal structures including the orbits. In cases where meningitis or intracranial hemorrhage is suspected, cerebrospinal fluid examination is also mandatory.

One extraordinary case¹⁴⁹ showed involvement of the pupil and accommodation only, with no evidence of levator or extraocular muscle involvement. In another unusual case,¹⁵⁰ cyclic oculomotor palsy accompanied by oculomotor synkinesis was presumably caused by a supraclinoid aneurysm in an elderly woman.

TABLE 6. Combined Oculopareses

Combined ocular neural palsies are most commonly unilateral because lesions involve the superior orbital fissure or cavernous sinus. Orbital diseases producing oculoparesis usually also result in some degree of proptosis and congestion of the lids and conjunctiva. Minimal proptosis (2 to 3 mm) has been attributed to lack of tone of the extraocular muscle cone in the presence of profound oculomotor nerve palsy, but with such “neurogenic proptosis,” the globe may be easily retropulsed into the orbit by applying firm digital pressure through the closed lids. In the presence of an orbital mass lesion or Graves disease, increased orbital resistance prevents retropulsion of the globe.

Bilateral combined palsies may be seen in a variety of etiologic settings (see Table 6), including the following: acute infectious polyneuropathy (Fisher syndrome), enterovirus 70 infections, brain stem toxoplasmosis, infiltrative brain stem tumors, basicranial extension of nasopharyngeal carcinoma, basal sarcoidosis, carcinomatous seeding of basal arachnoid, clivus chordoma, extrasellar extension of pituitary tumor into both cavernous sinuses (may occur acutely with hemorrhage [i.e., “pituitary apoplexy”;]), sphenoid carcinoma, cavernous sinus thrombosis, or arteriovenous fistula. In a review of 4278 cases of ocular palsies encountered at the Mayo Clinic,¹⁰⁸ the abducens nerve was affected in 1918, oculomotor in 1225, trochlear in 657, and multiple cranial nerve palsies in 573. According to this series, in patients with simultaneous multiple ocular cranial neuropathies, neoplasm was by far the most common cause (35.3%). However, 4.1% of such patients had microvascular disease as the underlying etiology. These diverse clinical situations are usually differentiated by temporal course, associated signs and symptoms (including involvement of other cranial nerves), examination of the cerebrospinal fluid, and neuroimaging techniques that include CT, arteriography, and MRI, all performed with special regard to orbital and basicranial areas.

The combination of single or multiple ocular motor nerve palsies with pain in and about the eye, usually unilateral, constitutes the syndrome of painful ophthalmoplegia. This syndrome has a wide variety of underlying pathophysiologic mechanisms, ranging from benign ischemic oculomotor palsy to carcinoma involving the cavernous sinus (Table 7).

TABLE 7. Painful Ophthalmoplegia Syndromes

  Orbit
  Inflammatory pseudotumor
  Contiguous sinusitis
  Mucormycosis or other fungal infections
  Metastatic tumor
  Lymphoma
  Superior Orbital Fissure/Anterior Cavernous Sinus
  Nonspecific granulomatous inflammation (Tolosa-Hunt syndrome)
  Metastatic tumor
  Nasopharyngeal carcinoma
  Lymphoma
  Herpes zoster
  Carotid-cavernous fistula
  Cavernous sinus thrombosis
  Parasellar Area
  Pituitary adenoma
  Intracavernous aneurysm
  Metastatic tumor
  Nasopharyngeal carcinoma
  Sphenoid sinus mucocele
  Meningioma, chordoma
  Petrositis (Gradenigo's syndrome)
  Posterior Fossa
  Posterior communicating artery aneurysm
  Basilar artery aneurysm (rare)
  Miscellaneous
  Diabetic ophthalmoplegia
  Migrainous ophthalmoplegia
  Cranial arteritis

Of great clinical importance is the early recognition of an acute orbital inflammatory syndrome in the diabetic patient, which should immediately suggest an opportunistic fungal infection such as mucormycosis (phycomycosis). Contrary to popular opinion, uncontrolled acidosis need not be present, and in fact, orbitocerebral phycomycosis can occur in otherwise healthy patients.¹⁵³ Although the exception, mucormycosis may run a subacute or even chronic course. Retinal artery occlusion is highly suggestive, and classically a progressive and often fatal picture of cavernous sinus thrombosis rapidly evolves.

The basic pathophysiologic process by which mucormycosis produces orbital signs and symptoms is ischemic necrosis due to arterial thrombosis. All orbital structures may be involved, and there may also be occlusion of the cavernous sinus, other cerebral venous sinuses, the arterial circle, internal carotid artery, and central retinal artery. Rarely, orbital disease is minimal, but more commonly a full-blown orbital apex syndrome is observed. Premorbid diagnosis is dependent on a high index of suspicion and immediate sinus exploration with mucosal biopsy. Survival depends on the combined effort of the ophthalmologist, rhinologist, mycologist, and internist. Amphotericin B is the drug of choice, but adequate therapy also requires surgical débridement of necrotic tissue.

A major review by Yohai et al¹⁵⁴ analyzed survival factors in mucormycosis. Criteria related to a lower survival rate included delayed diagnosis and treatment, the presence of hemiparesis or hemiplegia, bilateral sinus involvement, leukemia, renal disease, and prior treatment with deferoxamine. Facial necrosis also played an important role in the clinical prognosis of these patients. Newer adjunctive therapies include local irrigation with amphotericin B and alteration of immunosuppressive regimens in patients being treated for transplants or malignancies. In addition, hyperbaric oxygen therapy had a favorable effect on prognosis.

Inflammatory orbital pseudotumor is a distinct, if somewhat difficult to define, clinical entity that may run an acute or indolent course. Usually associated with proptosis, orbital pseudotumor is a source of variable degrees of ophthalmoplegia and pain, but visual loss is infrequent. It occurs in all age groups; recurrences are common, and both orbits may be involved.¹⁵⁵ Orbital pseudotumor is an infrequent manifestation of the collagen vasculitides,¹⁵⁶ and in rare cases may be part of a syndrome of multifocal idiopathic fibrosclerosis.¹⁵⁷

Rootman and Nugent,¹⁵⁸ in their series of 17 patients with acute orbital pseudotumor, described five patterns determined by clinical and CT criteria: anterior, diffuse, posterior, lacrimal, and myositic. Of particular interest here is the myositis form of orbital pseudotumor (orbital myositis). This entity, like other forms of orbital pseudotumor, is characterized by inflammation of unknown etiology; may be associated with systemic collagen vascular disease; may be recurrent or chronic; occurs in all age groups; and shows a dramatic response to steroids. The patient typically presents with symptoms of acute periorbital pain, eyelid swelling, and diplopia with proptosis. Ocular echography and CT or MRI quickly exclude a number of diagnostic possibilities, such as carotid-cavernous fistula, infectious cellulitis, metastatic neoplasm, and cavernous sinus thrombosis.

Siatkowski et al¹⁵⁹ performed a large retrospective review of 75 patients (age range, 9 to 84 years) with orbital myositis. Female patients were affected more than twice as frequently as male patients; 68% of patients had single muscle involvement, the lateral and medial recti being affected most commonly. In almost half of these patients, affected muscles functioned normally, but in the other patients muscle function was equally distributed between paretic or restrictive, or combined “paretic-restrictive” myopathies. Early treatment with systemic corticosteroids was advocated to avoid permanent restrictive myopathies. Interestingly, in 9% of patients with typical unimuscular orbital myositis, classic thyroid eye disease later developed. Usually, the clinical distinction between these two entities is straightforward: myositis presents with pain, muscle enlargement, and involvement of the tendon insertion on CT or orbital echography, with low muscle reflectivity seen on standardized A-scan; thyroid myopathy is typically painless and spares the tendon, with notably high reflectivity echographically.

On relatively infrequent occasions, the clinical symptoms of cranial arteritis include defects of ocular motility. The incidence of subjective diplopia is uncertain, but it is estimated at 10% to 17%.¹⁶⁰ Ophthalmoplegia of any degree, however, may be obscured by the more dramatic symptoms of visual loss. In the only complete pathologic study of ophthalmoplegia occurring in cranial arteritis,¹⁶¹ the ocular motor system was unremarkable except for the extraocular muscles, which showed variable degrees of ischemic necrosis. It is also possible that some instances of diplopia may be due to cranial nerve infarctions, but pathologic confirmation of this mechanism is lacking.

Slowly progressive ophthalmoplegia, usually without pain, may occur rarely in amyloidosis, and intraductal (sclerosing) breast carcinoma produces a syndrome of insidious fibrous fixation (desmoplasia) of orbital soft tissues with atrophy and enophthalmos, despite infiltrative metastases.¹⁶²

Combined unilateral palsies of the third, sixth, or fourth nerves, or involvement of the trigeminal nerve (producing pain or hypoesthesia), suggest a lesion at the skull base, especially in the cavernous sinus or parasellar area. Keane¹⁶³ reviewed case material accrued at the Los Angeles County Medical Center and documented that 30% of such cases were due to tumors, two thirds of which were malignant.

The lesions responsible for the Tolosa-Hunt form of painful ophthalmoplegia have been pathologically confirmed in very few instances; these descriptions include nonspecific granulation tissue in the cavernous sinus¹⁶⁴ and pachymeningitis of the superior orbital fissure. Kline¹⁶⁸ provided a subject review with additional cases cited, and a patient with necrotizing inflammation of the intracavernous and intracranial portions of the internal carotid artery is documented.¹⁶⁹

The following criteria are suggested for the diagnosis of the Tolosa-Hunt (painful ophthalmoplegia) syndrome:

1. The patient has steady, boring pain in and about the eye (ophthalmic division of the trigeminal nerve).
   
2. There is ophthalmoplegia with partial or total palsy of the extraocular muscles innervated by nerves III, IV, or VI, in any combination.
   
3. The pupil may be partially dilated and sluggish, dilated and fixed, spared entirely, or small (because of involvement of the sympathetic nerves).
   
4. Sensory defects may be found in the distribution of the ophthalmic-trigeminal nerve (rarely the second division).
   
5. The optic nerve may rarely be involved.
   
6. Symptoms are acute or subacute and respond dramatically to large doses of corticosteroids (e.g., 60 to 100 mg prednisone).
   
7. Spontaneous remissions may occur with complete or partial regression of deficits.
   
8. Episodes may recur at intervals of months or years.
   
9. Diagnostic studies (CT, MRI, arteriography, rhinologic examination) show no evidence of involvement of structures outside of the cavernous sinus).
   

Radiologic findings may be relatively meager, but include soft tissue densities (Fig. 19) in the cavernous sinus,^170,171 some with resolution following corticosteroid therapy; sellar erosion,¹⁷² and, in a patient with painful ophthalmoplegia associated with diabetes and hypoadrenalism, enlargement of the hypophysis and infundibulum¹⁷³, biospy of which demonstrated chronic inflammation. Other various mechanisms that mimic Tolosa-Hunt include dural arteriovenous fistula,¹⁷⁴ ophthalmoplegic migraine with enhanced oculomotor nerves,^141,142 and lymphoma.¹⁷⁵

The clinician should be mindful that a diagnosis of Tolosa-Hunt syndrome is one made by default when exhaustive examination has seemingly ruled out other causes of painful ophthalmoplegia (see Table 7). More specific underlying processes may surface with the passage of time, and radiologic studies may bear repeating. If the preceding criteria are met, it is reasonable to begin corticosteroid therapy to alleviate severe pain while radiologic studies are being completed. If mucormycosis or other fungal infection is suspected, the use of corticosteroids is strictly contraindicated, and may indeed cause or hasten a fatal course.

The relationship between nonspecific inflammation involving the cavernous sinus or superior orbital fissure and idiopathic orbital pseudotumor is of interest. One may consider that these syndromes are indeed caused by the same process, in different locations. It is speculated that, on the basis of antineutrophil cytoplasmic antibodies, Tolosa-Hunt may represent a limited form of Wegener granulomatosis¹⁷⁶ in some instances. Also, idiopathic cranial pachymeningitis or fibrosclerosis may be related.¹⁷⁷ Concurrent autoimmune diseases such as Hashimoto's thyroiditis may be likewise incriminated.¹⁷⁸

Intracavernous aneurysms (see Fig. 7B and C) constitute only 2% to 3% of all intracranial aneurysms, but they may represent up to 15% of symptomatic unruptured aneurysms,¹⁹ and 20% to 25% of lesions producing a cavernous sinus syndrome.¹⁶⁶ The only other entities that are as frequently responsible for this syndrome are nasopharyngeal and metastatic neoplasms.^163,166,182 As Meadows¹⁸³ noted, intracavernous aneurysms “behave differently from aneurysms arising elsewhere in the skull by virtue of their position … and [they] tend to present themselves to ophthalmologists on account of ocular features.” Although Meadows wrote that “rupture may certainly occur,” with subsequent formation of an intracavernous arteriovenous fistula, this complication must be exceedingly rare. Fatal subarachnoid hemorrhage has been reported.¹⁸⁴ On occasion, uncontrollable nasal bleeding may be caused by erosion into the sphenoid sinus, but this phenomenon pertains to the post-traumatic, acquired intracavernous aneurysm.¹⁸⁵

The clinical features of intracavernous aneurysms may be summarized as follows¹⁸⁶:

1. There is usually slowly progressive diplopia first noted on eccentric gaze, due to variable involvement of the ocular motor nerves.
   
2. There is usually an abduction defect (abducens palsy) coupled with partial oculomotor palsy; pure abduction defects have been reported.^186,187
   
3. Less frequently, patients present with an abrupt and simultaneous onset of diplopia, unilateral ptosis, and severe ipsilateral periocular pain or trigeminal dysesthesia; however, pain may be minimal or absent, even in the presence of profound ocular motor palsies.
   
4. Ptosis may be minimal to complete.
   
5. The pupil may show sympathoparesis, parasympathoparesis, or (rarely) a combination that renders the pupil smaller (pharmacologic testing for Horner syndrome confirms the presence of sympathoparesis, whereas sluggish light reaction suggests parasympathoparesis).
   
6. “Primary misdirection” (see above) may be observed.
   
7. There is an unexplained higher frequency of these aneurysms in middle-aged and elderly women (Fig. 22).
   
8. Involvement of the optic nerve (visual loss and optic atrophy) is rare, and indicates encroachment of the aneurysm superiorly toward the ipsilateral anterior clinoid.
   
9. Thin-section, enhanced CT scanning of basicranial structures, or MRI, demonstrates the lesion, which may be confirmed by angiography or radionuclide dynamic flow studies.
   
10. Longstanding, unruptured aneurysms are compatible with long life, and indications for surgical intervention are indistinct, although intervention would seem reasonable to treat intractable trigeminal pain.
    
11. Cardiovascular disease, including hypertension, is commonly associated with these aneurysms.
    

Of 59 cavernous aneurysms reported with ocular motor involvement,¹⁸⁸ 17 involved the sixth nerve only, 5 involved the third nerve, and 37 involved multiple nerves, including 13 with complete unilateral ophthalmoplegia. The onset of oculomotor involvement was painful in all but three patients, and the conditions of all nine patients with sudden ophthalmoplegia improved spontaneously within 6 weeks.¹⁸⁸

Barr et al¹⁹ documented the pathologic changes of intracavernous aneurysms, including the disposition of the ocular motor nerves displaced on the medial convexity of the aneurysmal sac.

It is clinically valid to separate from the general category of middle fossa or sphenoid ridge meningiomas, a distinctive type whose center of growth, symptomatically and radiologically, is the cavernous sinus. Although meningiomas represent 15% to 20% of intracranial tumors, origin in the dura of the cavernous sinus is not acknowledged in most comprehensive series.¹⁸⁹ In all probability, these tumors derive from the meninges covering the floor of the middle fossa, but they are clinically unlike the tumors designated as “middle fossa meningiomas.” Typical middle fossa tumors, which constitute 2% to 15% of meningiomas, evidently originate at some distance lateral to the cavernous sinus, for they produce headaches, seizures, memory disturbances, hemiparesis, homonymous hemianopia, and papilledema before producing ophthalmoplegia. Meningiomas of the more medial sphenoid ridge frequently produce ophthalmoplegia, proptosis, and possible compromise of the optic nerve.

As with intracavernous aneurysms, “intracavernous” meningiomas may masquerade for years as slowly progressive unilateral ophthalmoplegia without pain, but commonly with proptosis, moderate ptosis, and occasionally primary aberrant regeneration phenomena.¹⁸⁶ Pupillary abnormality is usually of the parasympathoparetic type (i.e., somewhat dilated and with a sluggish light reflex). CT or MRI of the sellar area is typical, if not pathognomonic (Fig. 23).

Aside from histopathologic confirmation, surgery generally affords no relief of diplopia; the effectiveness of fractionated or stereotactic radiation therapy is moot.¹⁹⁰

In the Thomas and Yoss¹⁶⁶ series of 102 patients with parasellar syndrome, nasopharyngeal carcinoma was the most common cause, accounting for approximately 1 in every 5 patients. Also, according to Godtfredsen and Lederman,¹⁸² 20% of nasopharyngeal tumors present as a cavernous sinus syndrome and, conversely, 20% of cavernous sinus syndromes are due to malignant nasopharyngeal tumors. Although nasopharyngeal tumors may occur at any age, they most frequently do so in the seventh and eight decades and occur more frequently in males. Tumorous growth usually begins in the roof of the nasopharynx or in the lateral region about the ostium of the eustachian tube. Therefore, symptoms of tubal occlusion, including recurrent serous otitis, may be the initial sign of a nasopharyngeal tumor. Tumor extension commonly involves the basal foramina of the middle cranial fossa such that trigeminal involvement, especially maxillary division (e.g., pain or numbness in the cheek or side of the face), is common. According to Godtfredsen and Lederman,¹⁸² among patients with neuro-ophthalmic signs of nasopharyngeal tumors, the following frequencies of involvement are found: in 70%, neuralgias of the first and second trigeminal divisions; in 65%, ophthalmoplegia (most often affecting the abducens, then the oculomotor and trochlear nerves); in 17%, exophthalmos; in 12%, optic nerve defect; and in 16%, Horner syndrome. Although strictly ocular signs occurred alone in 25% of the patients, they were associated either with first- or second-division trigeminal defects or with varying lower cranial nerve palsies in 50% of the patients.

Because of the high rate of ophthalmologic signs and symptoms in nasopharyngeal tumors, and the large percentage of cavernous sinus syndromes due to such lesions, competent nasopharyngeal examination is mandatory in multiple ocular motor palsies or painful ophthalmoplegia. Since subtle submucosal extension of tumor occurs, “blind” nasopharyngeal biopsy may be positive in the absence of visible tumor mass, but CT and MRI studies of the paranasal sinuses often disclose evidence of soft tissue masses or bone erosion, in which case biopsy is performed at the indicated site.

Although associated with a more chronic variety of frontal and periocular headaches, sphenoidal sinus mucoceles (pyoceles) may also produce ophthalmoplegia. The review by Nugent et al¹⁹¹ indicates that approximately one in three patients with a sphenoidal mucocele evidences palsy of the oculomotor or abducens nerves. However, in the series by Valvassori and Putterman,¹⁹² no patient showed oculoparesis. One or both optic nerves are commonly involved, with a picture of chronically progressive visual loss and optic atrophy, but visual loss may be abrupt.¹⁹³ Occasionally, patients demonstrate chiasmal defects, usually with severe visual loss in one eye and a temporal hemianopic field defect in the other. It should be recalled that the sphenoidal sinus shares a common bony wall with the optic canal, tuberculum sellae, cavernous sinus, and superior orbital fissure (See Chapter 4, Fig. 5; Chapter 5, Fig. 32). With large expansion, exophthalmos may occur, as well as disc edema.¹⁹⁴

Patients harboring sphenoidal mucoceles may have a history of otolaryngologic disease, but many do not. The diagnosis rests on typical radiologic features best seen by CT scanning, and recovery of visual and ocular motor function is dependent on chronicity of symptoms.

Metastatic tumors to the cavernous sinus comprised 23% of the 102 parasellar lesions reviewed by Thomas and Yoss,¹⁶⁶ and 33% of all neoplastic disease. Other than the nasopharynx, common primary sites include lung, breast, prostate, and systemic lymphomas. In the series of 17 patients with cavernous sinus metastases reported by Post et al,¹⁹⁵ unilateral, rather severe periorbital pain was the initial symptom in 12; 9 patients, including most of those with pain, had decreased sensation in trigeminal distribution, the ophthalmic division alone or with the maxillary in six cases, with the mandibular division in two cases, and isolated maxillary division in one case; four patients also had ipsilateral optic nerve involvement. High-resolution, contrast CT scanning demonstrated an enhancing soft tissue mass that bulged the wall of the cavernous sinus laterally, and secondary bone invasion was often present (see also Kline et al¹⁹⁶). In 6 of 17 patients, the cavernous sinus syndrome was the initial presentation of occult malignancy, and it represented the first sign of metastases in 5 patients with known disease. Median survival was 4.5 months from onset of parasellar symptoms, but focal radiation therapy was useful in pain control.

Skin carcinoma, especially squamous cell, may spread centripetally from the face or neck via perineural routes to the orbital apex or superior fissure, and may present years after dermatologic excisions.¹⁹⁷ Patients may present with diplopia due to minimal ocular duction deficits with few orbital signs and can also have trigeminal hypoesthesia or pain, or facial neuropathies.¹⁹⁸ tenHove et al¹⁹⁹ documented nine such patients, noting that enhanced MRI of infraorbital and orbital nerves was helpful for confirmatory biopsy; in addition, radiation therapy may stabilize the diplopia in these patients, allowing for the possibility of strabismus surgery. Contiguous perineural and endoneural extension may also lead to meningeal carcinomatosis.²⁰⁰

Identification of specific pathologic entities causing the cavernous sinus syndrome is rarely possible by clinical criteria alone. The mode of onset, frequency of remissions, rate of progression, presence or absence of pain, pattern of neurologic deficit, and response to steroid therapy cannot reliably predict the precise nature of a cavernous sinus lesion. Nonetheless, it is often possible, on the basis of history, physical findings, radiography, and other clinical factors, at least to limit etiologic considerations and manage accordingly. Although it is true that ultimate diagnosis rests with biopsy, either transnasal or transcranial, in some instances even without histologic confirmation radiation therapy may be a better choice than craniotomy, especially if abnormal tissue is not encountered outside of the cavernous sinus. Surgery indeed may further jeopardize visual function or intensify general morbidity.

Although the nervous system is involved relatively infrequently in patients with systemic sarcoidosis, multiple cranial neuropathies, aseptic meningitis, hydrocephalus, disease of CNS parenchyma, peripheral neuropathies, and myopathies may all occur with neurosarcoidosis. Of cranial palsies, peripheral facial nerve weakness is most frequent,²⁰⁵ but the ocular motor nerves may also be involved as well as the optic nerves and chiasm (see Chapter 5). Of 50 cases of neurosarcoidosis, Oksamen²⁰⁶ found that the angiotensin-converting enzyme (ACE) level in the cerebrospinal fluid was elevated in 18 of 31 patients.

Ocular motor nerve palsies may be the initial presenting sign of CNS toxoplasmosis, a potentially treatable disorder. Toxoplasma gondii is an opportunistic, neurotropic organism that usually causes multifocal CNS lesions and frequently involves the thalamus and brain stem.²⁰⁷ We have observed several immunodeficient or immunosuppressed patients who presented with ptosis or diplopia due to toxoplasmosis involving the brain stem. Asymptomatic lesions are often found elsewhere in the brain. Other cranial nerve and brain stem functions may become progressively involved.

The acquired immunodeficiency syndrome (AIDS) provides the clinical substrate for cranial neuropathies secondary to infections and lymphomas (Table 8). Third and sixth nerve palsies may herald CNS infection with cryptococcosis and toxoplasmosis,²⁰⁷ as well as with large cell lymphoma.²⁰⁸ Other ocular motility disorders include conjugate gaze palsies and internuclear ophthalmoplegia.²⁰⁹

TABLE 8. The Potential Etiologies of Cranial Nerve Palsies with HIV Infection

  Infectious Meningitis
  Fungal

  Cryptococcus
  Histoplasmosis
  Mucormycosis

  Mycobacteria tuberculosis
  Listeria monocytogenes
  Treponema pallidum

  Herpes zoster/varicella
  Cytomegalovirus
  HIV meningitis

  Brain lymphoma
  Other malignancies

  Toxoplasmosis
  Cryptococcoma
  Tuberculomas and tuberculous abscess

Another infectious agent, enterovirus 70, causes acute hemorrhagic conjunctivitis that, in a number of cases, is associated with dysfunction of any of the spinal cord and/or cranial motor nerves.^210,211 One series²¹¹ yielded the following results: 50% of the patients showed cranial nerve disturbances; sole involvement of the seventh or fifth cranial nerves was most common, and when multiple cranial nerves were involved, these same two nerves were again most frequently affected; prognosis was related to both severity and type of cranial nerve dysfunction; and patients with mild initial weakness and involvement of cranial nerves VII, IX, and X showed complete recovery, whereas patients with severe weakness or involvement of nerves III, IV, VI, and V did not show significant improvement.

The spirochete Borrelia burgdorferi produces Lyme disease, which may manifest a variety of acute, subacute, and chronic ocular and neurologic symptoms, including conjunctivitis, scleritis, uveitis, panophthalmitis, neuroretinitis, fluctuating meningoencephalitis, peripheral radiculopathies, and cranial nerve palsies.²¹² By far, the facial nerve is most commonly affected, but other cranial nerve involvement, including the third, sixth, or optic nerve, is relatively rare even in endemic areas. Elevated serum IgM or IgG antibody titers are variably present, but false-negative results are common. The Western blot is a helpful confirmatory test, but cases of seronegative neuroborreliosis are well documented in the literature. Lyme disease is also a common cause of false-positive FTA-absorbed tests. Polymerase chain reaction may provide a sensitive tool for organism detection to complement immunologic techniques. The circular cutaneous lesion of erythema chronicum migrans is pathognomonic, as is the characteristic tick bite, but these phenomena may be unnoticed by the patient. The optimal treatment regimen for Lyme disease has not been defined, but a course of ceftriaxone (2 g/day) or cefotaxime (6 g/day) for 3 to 4 weeks is commonly prescribed. Intravenous penicillin and oral doxycycline (200 mg/day) for 2 weeks have been used successfully to treat Lyme meningitis, but these results require confirmation.

TABLE 9. Disorders of the Neuromuscular Junction and Ocular Muscles

  Myasthenia
  Myasthenia-like syndromes

  Eaton-Lambert syndrome (distant effect of neoplasia)
  Drug-induced myopathies

  Congenital
  Mitochondrial cytopathies

  Isolated ocular
  Oculofacial
  With pigmentary retinopathy
  Kearns-Sayre syndrome

  Spinocerebellar degenerations, heredoataxias
  Juvenile spinal muscular atrophy (Wohlfart-Kugelberg-Welander syndrome)
  Infantile spinal muscular atrophy (Werdnig-Hoffman syndrome)
  Abetalipoproteinemia (Bassen-Kornzweig syndrome)

  Progressive supranuclear (bulbar) palsy (Steele-Richardson-Olszewsky)
  Parkinsonism
  Rostral-dorsal midbrain syndrome

MYASTHENIA

The diagnosis of myasthenia is at times simple and straightforward, and on other occasions frustrating and elusive. Despite the well-publicized ocular signs, myasthenia ranks high on the list of “missed diagnoses,” simply because many physicians are unaware of the variations in presentation, do not know how to examine for subtle signs, and often do not think of this possibility, at any rate. Any puzzling acquired ocular motility disturbance—with or without ptosis, but with clinically normal pupils—should raise the question of myasthenia.

Myasthenia may be characterized as follows: weakness without other signs of neurologic deficit (no reflex changes, sensory loss, or muscle atrophy); variability of muscle function within minutes, hours or weeks; remissions and exacerbations (sometimes triggered by infection, fever, or trauma); and tendency to affect extraocular, facial, and oropharyngeal muscles. In addition, there is usually reversal or improvement of muscle function with cholinergic drugs. The onset of myasthenia may occur at any age, but before age 40, the disease is more common in women. Neonatal forms are rarely encountered, and the clinical course in children and infants differs from adults, demonstrating a wider spectrum of myasthenic syndromes.²¹³ (See also Chapter 13.) The association with thymoma is well known (approximately 10% of myasthenia patients), and in such patients morbidity tends to be more severe and mortality rates are higher. In addition, dysthyroidism is found in approximately 5% of myasthenic patients, such that ocular signs may be admixed (e.g., exophthalmos and ptosis, paretic and restrictive motility defects). There is also a distinct relationship between collagen vascular disorders, thymoma, and myasthenia, and a familial incidence of myasthenia has been reported.

Myasthenia gravis is an autoimmune disorder characterized by a reduction of available postsynaptic acetylcholine receptors on the end plates of the neuromuscular junctions of skeletal muscle. Antibody-receptor interactions block neuromuscular transmission and subsequently destroy the receptor complex. The humoral immune response (e.g., polyclonal IgG produced by B lymphocytes) apparently plays a critical role in producing this disease. Antiacetylcholine receptor antibody is said to be present in 85% to 90% of patients with generalized myasthenia gravis (GMG) but less in patients with myasthenia “restricted” to ocular muscles (OMG).²¹⁴ Indeed, given the “embryonic” type of acetylcholine receptor in ocular muscles, there is evidence for considerable immunologic heterogeneity between GMG and OMG.²¹⁵ This phenomenon may partially account for cases of “sero-negative” OMG. Although actual antibody titers correlate poorly with the severity of the disease, Drachman et al²¹⁶ demonstrated that the antibodies do accelerate degradation of acetylcholine receptors and increase the extent of receptor blockade. In turn, increased receptor degradation and blockade correspond closely with clinical status, and thus confirm the relevance of antiacetylcholine receptor antibodies in the pathogenesis of myasthenia. Thus, the concept of a “safety margin” is important in the pathophysiology of myasthenia. Normally, both acetylcholine receptors and acetylcholine molecules at the neuromuscular junction are in significant excess. Any aberration that decreases the likelihood of molecular interaction between these two entities reduces this safety margin and produces clinical symptoms. The cause of the autoimmune attack on acetylcholine receptors is not known, but the thymus regularly shows prominent germinal centers (presumably the source of antibody-forming cells), if not actual tumoral growth. Epithelial (“myoid”) cells normally present in the thymus do indeed histologically resemble skeletal muscle, complete with acetylcholine receptors; these cells may become antigenic.

Ocular muscle involvement eventually occurs in 90% of all myasthenia and accounts for the initial complaint in approximately 75%.²¹⁷ In a study involving 1487 patients,²¹⁸ more than 50% presented with manifestations limited solely to extraocular muscles and levator palpebrae; of those patients with strictly ocular involvement during the first month after onset, 34% continued to have clinically “ocular” myasthenia over a four-decade follow-up period. That is, in 14% of this series, clinical manifestations were limited to the ocular muscles during the entire observation interval (mean, 17 years). Generalized myasthenia evolved in 68% of the initially “ocular” group, 78% of whom had clinical evidence within 12 months. Bever et al,²¹⁹ in a similar study, reported that 49% of “ocular” myasthenia remains “ocular,” and that 82% of those patients who later developed generalized myasthenia did so within 2 years.

Since muscle fatigability and remissions are the hallmarks of the disease, it is not surprising that ocular signs may vary, lasting from a period of hours to a course of weeks or months. Although some degree of ptosis is almost invariable, it may at first be unilateral and noted only as the day or the fatigue progresses, or the ptosis may “shift” from eye to eye. Clinically, ptosis may be made more apparent by repeated eyelid closure or during sustained upward gaze (Fig. 24). In cases of unilateral ptosis, the contralateral upper lid may be retracted, but will assume a normal position if the eye with ptosis is occluded or if the ptotic lid is lifted with a finger (“curtaining” sign or “enhanced ptosis”). This represents an example of Hering's law of equivalent innervation to the lid levators, the intact lid responding to increased innervation evoked by the effort to raise the ptotic lid. Cogan²²⁰ described a “lid twitch” sign that is elicited by having the patient rapidly redirect gaze from the downward to the primary position. The lid will be seen to twitch upward and then resettle to its original ptotic position. Occasionally, fine fluttering vibrations of the lash margins are observed in myasthenic lids. Although this is not a pathognomonic sign, Cogan's lid twitch is only rarely associated with other causes of ptosis.

Authoritative consensus dictates that pupillary and accommodative musculature is clinically uninvolved by myasthenia, sporadic reports and laboratory data to the contrary, notwithstanding.^217,221 If pupillary signs are present, another diagnosis must be entertained.

Extraocular muscle involvement does not follow any set pattern, although some have suggested that upward movements may be involved earliest. In our experience, medial rectus weakness is quite common, but essentially any ocular movement pattern may develop, such that isolated muscle palsies, or even total external ophthalmoplegia, may evolve. The motility pattern can mimic central gaze palsies or even internuclear ophthalmoplegia, complete with nystagmoid movements in the abducting eye (Fig. 25).²²² Myasthenic “nystagmus” has been otherwise documented.²²³ Eye movement recordings may be helpful in the diagnosis of myasthenia, which tends to demonstrate hypometric large saccades, hypermetric smaller saccades, and intrasaccadic fatigue (resolved with edrophonium).²²⁴ Intersaccadic fatigue may result in the appearance of a bimodal saccade or very rapid small saccades (“lightning eye movements”) terminating in an apparent, small “quiver.” These movements are quite characteristic and may be observed clinically. That is, supernormal saccadic velocities are the rule in myasthenia, even when significant ductional defects are present. Weakness of the orbicularis oculi is a very consistent sign in ocular myasthenia (Fig. 26) and serves as a further clue in diagnosis. Rarely does corneal exposure occur, but lower lid ectropion is occasionally seen. The “peek” sign results from orbicularis fatigue during eyelid closure, resulting in one or both eyes slightly opening spontaneously as the patient appears to peek at the examiner.²²⁵

Although it is true that the diagnosis of myasthenia is made on the basis of history and careful physical observations, one of the most helpful and dramatic (if positive) tests in medicine is the Tensilon test (edrophonium infusion). However, Tensilon testing is complicated by the problem of interpretation of response. When deficits in lid elevation or ocular motility are moderate or marked, evaluation of response to anticholinesterase drugs is usually a simple matter. However, when signs are minimal or inconstant, edrophonium or neostigmine (Prostigmin) response is more difficult to assess. The patient's interpretation of change in diplopia pattern may be made easier by placing a red filter before one eye, but this technique shares the inadequacies of all subjective examinations. In fact, patients have reported “improvement” after intravenous saline placebo. Such artificial reactions may indicate a functional disorder, or “neurasthenia.” Before edrophonium is administered, lid weakness may be accentuated by prolonged upward gaze, but extraocular muscles are rarely weakened by exercise, with uncommon exceptions such as fatigue of sustained lateral gaze.²²⁶ The orbicularis strength should also be noted before and after administration of edrophonium (see Fig. 26).

False-positive reactions occur with both neostigmine and edrophonium, but are fortunately infrequent. False-negative tests are not uncommon. This is in part due to the physician's often rough evaluation of subtle and inconstant oculoparesis and ptosis, dependency on the patient's subjective impressions, day-to-day variability of signs, and inadequate observations of “end points.” Paradoxical edrophonium responses are recognized, including producing paresis of previously nonparetic muscles in myasthenics. Retzlaff et al²²⁷ believe such paradoxical reactions to be present in half of myasthenics subjected to Tensilon testing, using red-green glasses for diplopia assessment.

In the chronic or “fixed” form, ocular myasthenia may be confused with chronic progressive external ophthalmoplegia (CPEO), because either entity can demonstrate symmetric total external ophthalmoplegia, ptosis, facial weakness, edrophonium resistance, and pharyngeal symptoms. A slow, progressive symmetric course, without fluctuations or remissions and little or no complaints of diplopia, speaks strongly in favor of CPEO, as does familial incidence. The “fixed” type of chronic ocular myasthenia may also show mechanical resistance to attempted forced duction testing.

For the most part, intravenous edrophonium has replaced neostigmine in diagnostic testing for myasthenia, although neostigmine is useful in children or in adults with poor intravenous access. The Tensilon test is performed in the following manner: (1) ptosis and motility defects are evaluated as objectively as possible; (2) 1 mL (10 mg) edrophonium is drawn into a tuberculin or other small syringe and, after venipuncture, 0.2 mL of test dose is injected, but the needle is left in the vein; (3) tearing and fasciculations in the lids are indicators of cholinergic effect; and (4) if lid or extraocular muscle function is not improved within 30 to 60 seconds, the remaining 0.8 mL is slowly injected over similar intervals until a positive test result is observed, systemic effects (e.g., lid myokymia, tearing) occur, or the entire vial is injected, and the lid positions and eye movements assessed again.²²⁸ We have had no problem with the use of intravenous edrophonium, even in children. The effect of edrophonium is short lived, and all evaluations must be completed within 5 minutes. Many myasthenics show improvement within 30 to 45 seconds after doses as low as 0.3 mL. Rarely is the entire vial necessary to provoke a response, and in fact, large doses of edrophonium may paradoxically cause worsening of ocular motility in myasthenia.

The Hess diplopia screen (red-green glasses and matching projector lights) combined with intravenous edrophonium was used to test 10 normal control subjects, 12 nonmyasthenic patients with acquired strabismus, and 10 patients with acquired strabismus caused by OMG. A positive response to the edrophonium-Hess screen test was defined as a 50% or greater reduction in the strabismic deviation at the fixation point associated with maximum deviation within 1 minute of edrophonium infusion. All myasthenic patients had a 50% or greater reduction in the initial deviation within 1 minute of edrophonium infusion. Myasthenic patients had a statistically significant reduction in the average deviation up to 150 seconds after edrophonium infusion. In contrast, with or without edrophonium infusion, control subjects had a purely horizontal fluctuation in binocular alignment of less than or equal to 2° for the entire 4-minute period after edrophonium infusion. None of the 12 nonmyasthenic patients tested positive to the edrophonium-Hess screen test. These results suggest that clearly defined endpoint criteria make the edrophonium-Hess screen test a sensitive and specific quantitative study.²²⁹

Siatkowski et al²³⁰ performed Tensilon tests on 30 normal subjects and 14 patients with nonmyasthenic strabismus. There were no clinically significant changes in muscle balance after Tensilon injection in any of the subjects, although the normal subjects had a slight increase in their near exophorias (mean, 2 prism diopters). The strabismic patients tended to have a slight change in their vertical deviation (mean change, 1.7 prism diopters; maximum change, <5 prism diopters) which was neither clinically nor statistically significant. The mean dose of edrophonium required for systemic response was 7.1 mg.

Just as the Tensilon test may on occasion be positive when the Prostigmin test is negative, the Prostigmin test may be positive when the Tensilon test is negative. Miller et al²³¹ suggested that neostigmine be used in patients whose signs are minimal, particularly in those with diplopia but no ptosis. Arguably, the longer duration of neostigmine's effect allows more time for quantitative measurements of ocular motility. Such patients are usually pretreated with intramuscular atropine (approximately 0.6 mg) before receiving intramuscular injection of neostigmine (approximately 1.5 mg). Ocular motility is reassessed 30 to 45 minutes thereafter.

It should be emphasized that neurasthenia may masquerade as myasthenia, especially where the chronically fatigued or tired patient shows no real eye muscle involvement, the so-called findings being limited to variable limb weakness. A placebo injection of, for example, physiologic saline that produces increased muscle strength and/or rapid alleviation of fatigue will quickly provide a useful diagnostic distinction. A small pediatric scalp-vein needle permits alternate connection of syringes first with saline and then with edrophonium.

Diagnostic procedures that complement Tensilon and Prostigmin testing, particularly in generalized myasthenia, include (1) electromyography (EMG) of muscle action potentials evoked by repetitive supramaximal nerve stimulation (approximately 3 to 5 Hz), and for the presence of the jitter phenomenon on single muscle fiber studies; and (2) antiacetylcholine receptor antibody titer (see above). In OMG, testing of the orbicularis muscles may be helpful. The relative importance of several methods—stimulated single fiber EMG (stimulated SFEMG), repetitive nerve stimulation test (RNS) of orbicularis oculi muscle, and infrared reflection oculography (IROG)—was investigated.²³² Based on the results of the three neurophysiologic tests, the patients can be divided into three groups:

  Group 1: Those with an abnormal stimulated SFEMG, abnormal RNS, and/or abnormal IROG
  Group 2: Those with only a slightly abnormal stimulated SFEMG
  Group 3: Those with normal results in all three tests

The clinical diagnosis of OMG was made in all 11 patients in the first group; in 6 of 7 patients (86%) in the second group; and in 1 of 14 patients (7%) in the third group. This study emphasizes that the orbicularis oculi muscle is a suitable muscle for stimulated SFEMG in patients with suspected OMG. A seemingly simple “sleep test” was proposed,²³³ based on the phenomenon of myasthenic symptoms and signs improving after rest: patients are kept in a quiet room in a restful state for 30 minutes, and levator and extraocular muscle function is assessed before and after rest. In this series, the sleep test was positive in cases of known OMG.

A diagnosis or firm suspicion of myasthenia on the part of the ophthalmologist is an indication for thorough examination by a neurologist. Thin-section, contrast-enhanced CT scan or MRI of the mediastinum should be performed to search for occult thymoma, but in a significant number of patients with only hyperplastic or normal thymus glands,²³⁴ CT scan may suggest thymoma. Ideally, tests to determine thyroid function and the presence of collagen vascular disease should be performed.

The pharmacologic treatment of myasthenia, ocular or otherwise, is beyond the purlieu of even the interested ophthalmologist and is strictly the domain of an experienced neurologist, who would be more familiar with the response of myasthenics to medications, with the minor and major complications of the primary disorder, and with the difficulties of dose variations and medication schedules. The ophthalmologist should collaborate by reevaluating ocular motility and using press-on prisms and lid crutches when indicated. Large, variable, or incomitant deviations are best treated with an opaque lens. Ptosis surgery is dangerous because defective ocular motility can lead to problems of corneal exposure.

Therapy for myasthenia at present is somewhat individualized,²³⁵ but is based on one of the following options: (1) increasing the amount of acetylcholine available with cholinesterase inhibitors such as pyridostigmine (Mestinon); or (2) blunting the autoimmune response with corticosteroids, especially for the often-resistant ocular symptoms, or less frequently with immunosuppressive agents (e.g., azathioprine, cyclosporine), plasmapheresis, and/or thymectomy. Gamma-globulin therapy and plasmapheresis are rarely, if ever, indicated for purely ocular myasthenia. Other pharmacologic agents include ambenonium, a biquaternary compound that binds irreversibly to acetylcholinesterase, with a duration of approximately 8 hours.

Thymectomy is rarely used in OMG but often used in GMG. Remission postoperatively is well documented, although the benefit of surgery may be delayed from 1 to 3 years. For OMG, we have found that a combination of pyridostigmine bromide and oral corticosteroid provides salutary results, but some authors have reported improvement with the use of steroids alone.²³⁶

MYASTHENIA-LIKE SYNDROMES

The Eaton-Lambert syndrome is a paraneoplastic disorder of the neuromuscular junction that produces proximal limb weakness and fatigability resembling myasthenia in some aspects. In contrast to true myasthenia, ocular, facial, and oropharyngeal musculature is preferentially spared, a temporary increase in muscle power is seen after brief exercise, and deep tendon reflexes are diminished or absent.²³⁷ EMG diagnosis entails demonstrating a characteristic incremental response to repetitive nerve stimulation, which is precisely the opposite of myasthenia. Although patients with this disorder are sensitive to small doses of curare, as in true myasthenia the weakness is due to a presynaptic mechanism that causes impaired release of acetylcholine²³⁸ at both nicotinic and muscarinic nerve terminals. Specifically, antibodies to voltage-gated calcium channels in motor and autonomic nerve terminals disrupt calcium influx and reduce acetylcholine release. Approximately 70% of patients with Eaton-Lambert syndrome harbor malignant neoplasms, usually small-cell bronchogenic carcinoma; other instances are associated with autoimmune disorders, such as Sjögren's syndrome or discoid lupus,²³⁹ but in some cases no other primary disease can be discovered.

Ocular involvement is distinctly rare and, if present (particularly if there is isolated ocular involvement), practically excludes the diagnosis of Eaton-Lambert syndrome. Patients have been reported with ptosis and/or ocular motility disorders,²⁴⁰ as well as with documented abnormal eye movement recordings.²⁴¹ Breen et al²⁴² reported transient improvement of ptosis after sustained upgaze as a clinically useful sign in distinguishing Eaton-Lambert syndrome from myasthenia gravis. Grisold et al²⁴³ provided a general review of paraneoplastic neurologic syndromes in which detection of autoantibodies directed against central and peripheral nervous system structures has suggested an autoimmune etiology. The therapeutic results of 258 patients with paraneoplastic neurologic disease (e.g., paraneoplastic encephalomyelitis, sensory neuronopathy, cerebellar degeneration, motor neuron disease, stiff-man syndrome) were summarized. The results showed that in some entities, such as Lambert-Eaton syndrome, successful treatment can be expected. In other syndromes, such as subacute sensory neuronopathy or paraneoplastic cerebellar degeneration, therapeutic success varies from 5% to 10%.

Some pharmacologic agents may induce a clinical picture closely mimicking myasthenia. For example, D-penicillamine, given for rheumatoid arthritis, can produce isolated ocular signs and symptoms or generalized muscle involvement, and affected patients have elevated antiacetylcholine receptor antibodies, along with the same HLA antigens seen in true myasthenia.²⁴⁴ A number of antibiotics, including the polypeptides (Colistin, polymyxin B) and aminoglycosides (neomycin, streptomycin, kanamycin, azithromycin) can also induce weakness resembling myasthenia gravis.²⁴⁵ Diplopia, accommodative insufficiency, and bulbar muscle weakness may be encountered. The antineoplastic agents vincristine and vinblastine have special neurotoxic propensity, including ocular signs such as ptosis, external ophthalmoplegia, isolated muscle paresis, facial palsy, and lagophthalmos.²⁴⁶

Numerous other pharmacologic agents can decrease transmission at the neuromuscular junction,²⁴⁷ such as neuromuscular blockers, anticholinesterase agents, antiarrhythmics (procainamide and quinidine), anticonvulsants (phenytoin), β-blockers (propranolol, timolol), corticosteroids, cisplatin, lithium, and magnesium. Obviously, great care must be taken when patients with myasthenia or other disorders of neuromuscular transmission are exposed to or treated with these agents. Corticosteroids, for example, are commonly used to treat myasthenia and may exacerbate muscle weakness, in some instances to the point where respiratory support is necessary.

Toxins elaborated by scorpions, ticks, wasps, spiders, and bacteria (Clostridium botulinum, Clostridium tetani) also affect the neuromuscular junction. Botulinum toxin acts presynaptically to prevent release of acetylcholine and also destroys nerve endings, which require several months for regeneration. Ophthalmologic findings in botulism include ptosis, ophthalmoparesis, and dilated, poorly reactive pupils.^248,249 Of course, botulinum toxin is commonly used therapeutically to produce isolated transient paresis of the extraocular muscles and of the facial and neck muscles in treating strabismus, blepharospasm, hemifacial spasm (including Meige's syndrome) and torticollis.

THYROID-RELATED MYOPATHY (GRAVES DISEASE)

Restricted eye movement caused by pathologic changes in extraocular muscles commonly, but not exclusively, associated with dysthyroidism is an extraordinarily frequent cause of diplopia. Encountered in all age groups (but rarely occurring in those less than 20 years old), thyroid-related restrictive myopathy (TRM) is the most common cause of spontaneous double vision in middle age and early senescence. Like myasthenia, TRM ranks high on the list of frequently missed diagnoses; patients are constantly subjected to inappropriate, invasive, and expensive radiodiagnostic studies. The ophthalmologist and neurologist should learn well the subtle ocular signs that usually accompany TRM and should know how to perform the single most important office maneuver, the forced duction test, to establish the presence of mechanical resistance (Chapter 3, Fig. 6). Comments here are limited to those aspects of TRM pertinent to neuro-ophthalmology: that is, those findings that permit a clinical diagnosis and obviate further uncomfortable and costly studies.

In subtle cases of TRM, the striking clinical signs of congestive proptosis are absent, but spontaneous lid retraction (stare) or lag on downward gaze is observable (see Chapter 3, Fig. 11; Chapter 14, Fig. 4). These lid signs may be elicited by having the patient perform pursuit eye movements while fixating some object moved vertically at a moderately fast speed. As the eyes turn downward, one or both lids are noted to lag (or “hang up”). A peculiar “jelly roll” edema is often evident in the upper or lower lids, but at times is difficult to distinguish from the redundancy of lid tissue that accompanies aging.

Careful inspection of the globe itself may reveal the conjunctival vessels overlying the anterior aspect of the horizontal recti muscles to be dilated and tortuous. The hypertrophied extraocular muscles themselves are occasionally visible (Fig. 27).

The single most common ocular motility abnormality encountered in TRM is unilateral “elevator palsy” (Fig. 28), or a hypodeviation that increases on upward gaze. While mimicking a superior rectus palsy, the actual problem is fibrotic shortening of the inferior rectus, which restricts upward rotations. That the globe is tethered by a taut muscle is established by the palpable resistance to mechanical elevation (i.e., a positive forced duction test). If both inferior recti are involved, the patient shows an upward gaze palsy somewhat mimicking midbrain syndromes (Fig. 29). Similar fibrotic contraction of the medial rectus produces an abduction deficit that mimics a sixth nerve palsy, but the globe resists outward rotation when the insertion of the medical rectus is grasped. Downward gaze is limited when restrictive fibrosis of the superior rectus occurs. Isolated lateral rectus involvement, with abduction deficits, is uncommon, but all gaze functions may be reduced. In addition to the myopathy itself, impaired orbital venous outflow may play a role in the exophthalmos and strabismus of this disorder.²⁵⁰

Commonly, torsional movements of the globe are observed on attempted horizontal or vertical versions (see Fig. 29A and B). For example, on attempted right gaze, the right eye abducts incompletely and extorts slightly as it reaches the position of maximum abduction. This excyclotorsion is seen especially in the company of elevation deficits (tight inferior rectus).

In the early stages of the disease, an affected muscle may in rare cases appear paretic rather than restricted. Hermann²⁵¹ reported on two patients with diplopia with negative forced ductions, but with saccadic velocities consistent with inferior rectus paresis. We also have observed a patient with obvious Graves disease who presented with an inferior rectus paresis, including a positive three-step test and negative forced ductions; echography revealed a greatly enlarged inferior rectus muscle. Several months later the hypertropia converted to a hypotropia, as a typical restrictive pattern evolved. Such paresis is distinctly unusual, and may represent thyroid “myositis” as a precursor to muscle fibrosis. However, mechanical restriction by the involved muscle with positive forced duction testing is the rule.

An additional clue to the restrictive nature of TRM is the finding of elevation of intraocular pressure on attempted upward gaze.²⁵² This phenomenon, attributed to a fibrotic and taut inferior rectus muscle, may aid in establishing the cause of otherwise puzzling spontaneously acquired diplopia.

The diagnosis of TRM is not so difficult a task on clinical grounds, if the physician bears in mind the characteristic lid and orbital congestive signs, the typical patterns of motility disturbance, and the use of the forced duction test. Increase in extraocular muscle bulk, the hallmark of Graves orbitopathy, may be assessed by standardized A-scan ultrasonography,²⁵³ CT scanning, or MRI (Fig. 30). Usually multiple muscles in both orbits are enlarged, but asymmetry may be striking. To affirm the diagnosis in terms of biochemical tests of thyroid function is another problem altogether. Ocular manifestations may antedate laboratory or clinical evidence of dysthyroidism, but many patients present with ophthalmologic complications occurring months to years after surgery or radioactive iodine therapy for hyperthyroid states. At the time of ocular diagnosis, many of these patients are euthyroid by all parameters of multiple laboratory tests of thyroid function. However, hypothyroidism with elevated thyrotropin (thyroid-stimulating hormone, TSH) levels after radioactive iodine treatment appears to be an important adverse risk factor for development or exacerbation of ophthalmopathy.²⁵⁴ In addition to a history and physical examination, laboratory procedures to determine triiodothyronine (T₃), thyroxine (T₄), TSH, and T₃ resin uptake have assumed a fundamental role. T₄ and T₃ are the major circulating hormones produced by the thyroid. By increasing the sensitivity of analysis, radioimmunoassay (RIA) techniques have dramatically simplified thyroid hormone assessment. Furthermore, T₃ (RIA) and T₄ (RIA) levels are not influenced by inorganic iodine contamination from outside sources. Hence, the administration of iodinated radiologic contrast dye does not confound the evaluation of thyroid function when RIA methods are employed. Both the T₄ (RIA) and the previously widely used T₄ measurement by the Murphy-Pattee competitive protein-binding assay require simultaneous T₃ resin uptake determination. The T₃ resin uptake analyzes the unbound thyroxine-binding globulin. Numerous conditions (e.g., pregnancy, hepatitis, recent surgery, renal failure) and pharmacologic agents (e.g., estrogens, corticosteroids, phenytoin) may alter thyroxine-binding globulin affinity; therefore a computed value, the free T₄ index, is often used to estimate the amount of free thyroid hormone available to the tissues. The free T₄ index is calculated from the serum T₄ concentration and the T₃ resin uptake.

Although T₃ thyrotoxicosis is well recognized by internists and endocrinologists as a distinct clinical entity, ophthalmologists must be aware that T₄ determination alone does not completely evaluate peripheral blood thyroid hormone status. In addition, T₃ is often elevated out of proportion to T₄ in Graves disease. Long-acting thyroid stimulation determinations, although still available, have no currently recognized value in diagnosis or patient care.

Since approximately two thirds of patients with euthyroid Graves disease demonstrate an autonomously functioning pituitary-thyroid axis, this homeostatic system must be evaluated. An autonomous pituitary-thyroid axis indicates that the thyroid gland has escaped the normal feedback, regulatory control of circulating TSH; it is thus known as the autonomous thyroid gland. For many years, the Werner suppression test was employed to assess any “escape” of the thyroid from normal TSH control. This test involved the administration of oral T₃ (Cytomel) for 7 days with prior and follow-up determination of radioactive iodine uptake detected over the thyroid gland. With disruption of the pituitary-thyroid balance, the administration of oral T3 fails to suppress radioactive iodine uptake below 50% of the initial level, thereby indicating autonomous thyroid activity (provided that the initial uptake is at least 15%).

The intravenous thyrotropin-releasing hormone (TRH) test has now virtually supplanted the more cumbersome, time-consuming, and costly Werner suppression test. TRH is the hypothalamic regulatory factor controlling the release of TSH from the anterior pituitary gland. Normally, intravenous administration of TRH causes a four- to five-fold peak rise in blood TSH level within 20 to 30 minutes after injection. The TSH response to TRH is fairly constant, except in patients with Cushing's syndrome from either endogenous or exogenous excess corticosteroids. In addition, patients with an autonomous pituitary-thyroid axis will fail to show the expected increase in TSH response. A blunted or absent pituitary TSH response to TRH injection signifies a positive test, as found in approximately 50% of patients with Graves ophthalmopathy considered “euthyroid” by conventional testing.²⁵⁵ A normal TRH test is therefore seen in the remaining 50% of these patients and designates them truly euthyroid by currently available laboratory criteria.

Autoimmune abnormalities, such as thyroid-stimulating antibodies and thyroid-displacing activity, may be used in conjunction with the TRH test to detect occult thyroid disease. The collaboration of a competent endocrinologist is of obvious advantage. In addition, elevated serum IgE²⁵⁶ and anti-eye-muscle antibodies²⁵⁷ have been reported in patients with thyroid-related myopathy.

For the internist, a medical approach to therapy should be tempered by knowledge that thyroid-related orbitopathy is more or less a self-limited disease, and that emphasis should be placed on the prevention of serious ocular complications. It seems reasonable that rendering hyperthyroid patients euthyroid, and preventing them from becoming hypothyroid, is advantageous. If the euthyroid state is preferable, then no specific medical manipulation of euthyroid ophthalmopathic patients is indicated.²⁵⁵

Treatment of optic neuropathy in Graves disease is considered in Chapter 5. The strabismus in acute and subacute orbitopathy has been demonstrated to improve with both corticosteroid and radiation therapy,^258–260 but definitive surgical treatment should be postponed until deviations have been stable for a minimum of 6 months. Because of the incomitance of the strabismus, prisms are often inadequate to control patients' symptoms, necessitating extraocular muscle surgery. As a general rule, muscle resections should not be employed in this disease, because such procedures do not address the underlying mechanism of the restrictive strabismus and may, in fact, worsen it. Long-term results of rectus muscle recessions employing the adjustable suture technique are quite favorable,²⁶¹ and adjustable suspensions of the lower eyelid retractors may be employed concurrently to minimize lower eyelid retraction after inferior rectus surgery.²⁶² The surgeon should attempt initially to undercorrect the deviation, since late overcorrections are common in Graves' ophthalmopathy.²⁶³ Botulinum toxin has a limited role, if any, in Graves' ophthalmopathy, but may be used in those rare patients with extraocular muscle paresis in order to minimize or delay contracture of the antagonist muscle.

PROGRESSIVE (CHRONIC) EXTERNAL OPHTHALMOPLEGIA

There is considerable controversy regarding the precise nosologic classification of the “muscular dystrophies,” including the chronic external ophthalmoplegias (i.e., those not involving the internal ocular muscles of the pupil). Although they were once traditionally considered primary myopathies, later contributions have challenged this etiologic concept and have argued strongly in favor of another: primary neurogenic disorders or abnormal proliferation of mitochondria are believed to cause “ragged-red fibers” (so called because of their dark red color on modified Gomori trichrome stain), which are a hallmark of the severe biochemical defects in oxidative phosphorylation characteristic of many mitochondrial encephalomyopathies.²⁶⁴ Recent literature has focused on the importance of diffuse, systemic mitochondrial abnormalities (Table 10). In patients with progressive external ophthalmoplegia (PEO) or CPEO, light microscopic examination of extraocular muscle, orbicularis oculi, and at times other skeletal muscle reveals ragged-red muscle fibers admixed within a population of relatively normal muscle fibers. On electron microscopic examination, these same ragged-red fibers demonstrate strikingly abnormal mitochondria. Ragged-red fibers may be found in other diseases, and small numbers are indeed seen in the orbicularis and extraocular muscles of normal persons, but not in their limb muscles. Also, mitochondria are morphologically abnormal in skeletal muscle biopsies from PEO patients with or without ragged-red fibers.²⁶⁵ In the Kearns-Sayre variant, such abnormal mitochondria have also been observed in liver cells, sweat glands, and granular and Purkinje cells of the cerebellum.²⁶⁶ All recent studies have suggested that mitochondrial dysfunction plays an essential role in producing the multisystem involvement in many PEO patients. Mitochondrial dysfunction is associated with a variety of genetic defects due to nucleotide mutations.^264,267,268 Muscle mitochondrial DNA (mtDNA) deletions may be detected, localized, and quantitated by Southern blot analysis of transfer RNA (tRNA) genes in the mtDNA (+ RNA leucine, glutamine, isoleucine, and formylmethionine).²⁶⁹ Such techniques confirm the high frequency of mtDNA deletions or point mutations in PEO. At the onset of the disease, no clinical, morphologic, or molecular features can predict whether PEO will remain isolated or become part of a more severe multisystem disease. However, patients with mtDNA deletions are characterized by more severe ophthalmoplegia of earlier onset. Muscle alterations are roughly parallel in severity to the proportion of deleted mtDNA molecules in muscle. There are sporadic cases of patients with multitissue disease and mtDNA deletions; their clinical presentation usually closely resembles Kearns-Sayre syndrome.

TABLE 10. Manifestations of the Kearns-Sayre-Daroff Syndrome (“Ophthalmoplegia Plus”)

  Cardinal manifestations
  External ophthalmoplegia with onset in childhood
  Retinal pigmentary degeneration
  Cardiac conduction defects
  Elevated cerebrospinal fluid protein
  Abnormal muscle mitochondria
  Spongiform encephalopathy, including brain stem
  Negative family history
  Associated Manifestations
  Short stature
  Neurologic

  Deafness
  Cerebellar ataxia
  Mild Corticospinal tract signs
  “Descending” myopathy of face and limbs
  Subnormal intelligence
  Slowed electroencephalogram
  Aseptic meningitis (by history)
  Demyelinating radiculopathy
  Decreased ventilatory drive
  Hyperglycemic acidotic coma/death

  Diabetes mellitus
  Hypogonadism
  Hypoparathyroidism
  Growth hormone deficiency
  Adrenal dysfunction

Clinically, PEO is characterized by insidiously progressive, symmetric immobility of the eyes, which are fixed to oculocephalic or caloric stimulation. There is no pain and the pupils are spared, but the lids typically are ptotic and the orbicularis oculi weak (Figs. 31 and 32). Unlike Graves' ophthalmopathy, there is no lid retraction, proptosis, or congestive conjunctival signs. In longstanding PEO, however, fibrotic changes in extraocular muscles may produce mechanical resistance and a positive forced duction test. Chronic or “fixed” ocular myasthenia may be confused with PEO, because both disorders tend to demonstrate the following: symmetric total or subtotal external ophthalmoplegia; ptosis; normal pupils; orbicularis oculi, facial, and bulbar weakness; and resistance to Tensilon or other cholinergic agents. A slowly progressive symmetric ophthalmoplegia, without fluctuations or remissions, speaks strongly in favor of PEO (see below, hereditary form). Otherwise, electrophysiologic testing and muscle biopsy may be required to distinguish between chronic myasthenia and PEO.

Although not always an easy task, it is usually possible clinically to distinguish ophthalmoplegia due to CNS lesions from the PEO syndromes. Patients with PEO, however, do not demonstrate an increase in ocular motility when the doll's head maneuver is employed. On the other hand, cerebral gaze palsies are acute, usually asymmetric, and show retention of reflex eye movements, including oculocephalic deviations. Pontine gaze palsies are usually asymmetric and accompanied by other neurologic deficits, such as hemiparesis, hyperreflexia, and other ipsilateral cranial nerve palsies. Supranuclear gaze palsies that otherwise may simulate PEO (e.g., progressive supranuclear bulbar palsy, parkinsonism) are discussed in the next section.

Depending on the associated signs and symptoms, PEO may be classified into several subgroups (see Table 9). Accompanying the Kearns-Sayre form of PEO, a mild to moderate “salt and pepper” disturbance of peripheral retinal pigment epithelium has been described (Fig. 32B), especially in adolescents.²⁷⁰ Unlike retinitis pigmentosa, as a rule there is neither optic atrophy, arteriolar attenuation, nor visual disturbance to any real degree. Visual fields are grossly full, and electroretinography may be surprisingly normal. The major manifestations of Kearns-Sayre syndrome are as follows: childhood onset of PEO without family history; retinal pigmentary degeneration; cardiac conduction defects, often leading to complete heart block and Stokes-Adams attacks; ragged-red muscle fibers on skeletal muscle biopsy; elevated cerebrospinal fluid protein; and marked vacuolization (status spongiosus) of the cerebrum and brain stem.

A number of other findings are frequently, but not invariably, associated with this syndrome. Whether or not the Kearns-Sayre symptom complex represents an atypical (“slow”) viral, toxic, or multisystem genetic mitochondrial disturbance is currently unknown. Rowland²⁷¹ reviewed a number of reports of familial occurrence and found that “among the 70 cases, there has been only one family in which more than one person had the entire syndrome.” Administration of coenzyme Q-10, a component of the mitochondrial electron transport system, has been observed to normalize serum pyruvate and lactate levels and improve both atrioventricular block and ocular movements in a patient with Kearns-Sayre syndrome.²⁷²

Oculopharyngeal dystrophy of Victor is a rather benign hereditary condition, usually autosomal dominant, which has an onset in the fifth and sixth decades and involves the bulbar musculature. Temporalis wasting may be striking (see Fig. 31). Pathologically, ragged-red fibers with abnormal mitochondria are not described in this condition. Rather, there is marked reduction in the number of muscle fibers, and those fibers that remain show significant degenerative changes and characteristic nuclear inclusions.²⁷³ A large number of French Canadians are affected with this variety of PEO, which is traceable to a common ancestor from a Quebec isolate. Other variations, which may occur either sporadically or in an heredofamilial form, include involvement of muscles of the neck and upper extremities. Autopsy of one such case showed no pathologic changes in either the peripheral or the central nervous system.²⁷⁴ Some patients have ptosis and pharyngeal symptoms with relative sparing of ocular motility, and we have seen one case of profound ophthalmoplegia and pharyngeal involvement, but without ptosis.

Ionescu et al²⁷⁵ described the association between inherited ophthalmoplegia and intestinal pseudo-obstruction due to decreased motility of the stomach and small bowel. Ptosis and ophthalmoplegia begin in childhood, and gastrointestinal symptoms appear in adolescence; there is progressively worsening malnutrition, and death occurs before age 30 regardless of medical treatment. Abnormal synthesis of contractile proteins in muscle cells was demonstrated in the one case studied.

Mitochondrial myopathy, encephalopathy with lactic acidosis, and strokelike episodes (MELAS) syndrome is one of the mitochondrial encephalomyopathies that has distinct clinical features, including strokelike episodes with migrainous headache, nausea, vomiting, encephalopathy, and lactic acidosis.²⁷⁶ For example: A 27-year-old woman presented with a history of partial seizure, strokelike episodes including hemiparesis, hemianopia and hemihypesthesia, sensorineural hearing loss, migrainelike headache, and lactic acidosis. A brain CT scan showed encephalomalacia in the right parieto-occipital area and hypodensity in the left temporoparieto-occipital area with cortical atrophy. Muscle biopsy revealed ragged-red fibers and paracrystalline inclusions in the mitochondria. Genetic study revealed an A to G point mutation at nucleotide position (np) 3243 of mtDNA. External ophthalmoplegia and ptosis were also found during two exaggerated episodes in this patient. Therefore, the overlapping syndrome of CPEO in the MELAS syndrome was considered. This patient was also found to have a carnitine deficiency, and she responded to steroid therapy. Muscle biopsy revealed excessive lipid-droplet deposits. It was concluded that a carnitine deficiency may occur in MELAS syndrome with the A to G point mutation at np 3243, and it was recommended that patients with MELAS syndrome and carnitine deficiency be started on steroid or carnitine supplement therapy.²⁷⁶

Hereditary abetalipoproteinemia (Bassen-Kornzweig syndrome) refers to the association of PEO, pigmentary retinopathy, ataxia, and intestinal fat malabsorption. The laboratory assessment of patients with potential mitochondrial disease is extensive, as outlined by Johns²⁶⁴ (Table 11).

TABLE 11 Possible Laboratory Findings in Patients with Mitochondrial Diseases

  Ragged-red fibers in skeletal muscle-biopsy specimens
  Elevated lactate concentrations in serum and cerebrospinal fluid
  Myopathic potentials on electromyography
  Axonal and demyelinating peripheral neuropathy on
  nerve-conduction studies
  Sensorineural hearing loss on audiography
  Cardiac conduction defects
  Basal-ganglia calcification or focal signal abnormalities on magnetic resonance imaging
  Abnormalities on phosphorus-31 nuclear-magnetic-resonance spectroscopy
  Defective oxidative phosphorylation on biochemical studies
  Molecular genetic evidence of mitochondrial-DNA mutation

Regarding therapy, there is no pharmacologic relief for the weak muscles, including systemic or locally injected corticosteroids; in fact, in Kearns-Sayre syndrome systemic corticosteroids may precipitate hyperglycemic acidotic coma and death.²⁷⁷ If exotropia or diplopia develop, standard extraocular muscle surgery may be performed. However, these patients rarely complain of diplopia, perhaps in part because of slow onset of the disease, symmetry of the ophthalmoplegia, and comitancy of the strabismus. Surgical repair of ptotic lids should be approached with caution because, in the presence of poor ocular motility (specifically minimal upward movement), patients may experience severe complications of corneal exposure after lid-lifting procedures. Lid crutches are an excellent alternative (see Fig. 31C). In patients with an early onset, cardiac evaluation is mandatory to rule out complete heart block. A cardiac pacemaker is often indicated and may be lifesaving, although sudden neurologic deterioration and death can occur in Kearns-Sayre patients despite a functioning cardiac pacemaker.²⁷⁸

The ophthalmoplegia in progressive supranuclear palsy first affects volitional vertical gaze, especially downward. That the lesion is at first supranuclear can be demonstrated by full vertical deviations with oculocephalic (doll's head) maneuvers (Fig. 33). Pursuit movements may be preserved, such that optokinetic testing “draws” the eyes tonically in the direction of stimulus movement. Eventually, horizontal gaze is involved, with both saccadic and pursuit palsies. Although oculocephalic deviations may be demonstrable even late in the disease, marked neck dystonia makes doll's head maneuvers difficult to assess. Cold calorics show slow tonic deviation. Finally, all eye movements, including reflex movements, may be lost.

Therapy in these patients is generally directed at education and instruction regarding appropriate head movements; however, the use of idazoxan has proved useful in some patients.²⁸² Interestingly, although progressive supranuclear palsy is considered a supranuclear disorder, mitochondrial adenosine triphosphate production in the extraocular muscles has also been shown to be defective in these patients.²⁸³

Progressive supranuclear palsy is distinguished from Parkinson's disease by the pattern of ophthalmoplegia, lack of tremor, presence of pyramidal tract signs, dementia, and death, which usually ensues within 10 years. MRI is also helpful in distinguishing these two entities. In progressive supranuclear palsy, definitive atrophy of the midbrain and the region around the third ventricle is seen in more than 50% of cases. In Parkinson's disease, alterations in the pars compacta of the substantial nigra may be encountered.²⁸⁴ Levodopa does not alter eye movement but may alleviate rigidity.²⁸⁰ Since ocular symptomatology is marked, the ophthalmologist should be aware that defective vertical gaze movement may explain these patients' difficulty seeing objects in the inferior visual field. Bifocals are unsuitable, but single-vision reading glasses are indicated.

Patients with Parkinson's disease demonstrate a relative deficiency in spontaneous eye movements, which in association with infrequent blinking, produce a rather typical parkinsonian stare. As with progressive supranuclear palsy patients, blepharospasm and apraxia of lid opening may be seen. Upward gaze is more commonly initially involved and, along with convergence, may be weak or absent, even more so than those deficits associated with aging alone. Rapid volitional eye movements are fragmented into multiple saccades, and slow pursuit is accomplished similarly by a series of small amplitude saccades (“cogwheel” eye movements). Ophthalmoplegia in Parkinson's disease may well mimic progressive supranuclear palsy.²⁸⁵

Knox et al²⁸⁶ reviewed Whipple's disease, a rare cause of supranuclear ophthalmoplegia, dementia, and facial myoclonia, but not necessarily gastrointestinal symptoms of diarrhea. Pathological confirmation is provided by jejunal biopsy for periodic acid-Schiff—positive, foam-filled macrophages containing microorganisms.

A number of spontaneous and heredodegenerative CNS disorders characterized chiefly by ataxia tend to produce uncompensated small-angle heterotropias, with momentary diplopia, or frank ophthalmoplegia. These disorders include Friedreich's ataxia, cerebellar and spinocerebellar degenerations, familial or sporadic olivopontocerebellar atrophies, multisystem atrophy, and spastic or myoclonic ataxias.²⁸⁷

The lesions responsible for the Tolosa-Hunt form of painful ophthalmoplegia have been pathologically confirmed in very few instances; these descriptions include nonspecific granulation tissue in the cavernous sinus¹⁶⁴ and pachymeningitis of the superior orbital fissure. Kline¹⁶⁸ provided a subject review with additional cases cited, and a patient with necrotizing inflammation of the intracavernous and intracranial portions of the internal carotid artery is documented.¹⁶⁹

The following criteria are suggested for the diagnosis of the Tolosa-Hunt (painful ophthalmoplegia) syndrome:

1. The patient has steady, boring pain in and about the eye (ophthalmic division of the trigeminal nerve).
   
2. There is ophthalmoplegia with partial or total palsy of the extraocular muscles innervated by nerves III, IV, or VI, in any combination.
   
3. The pupil may be partially dilated and sluggish, dilated and fixed, spared entirely, or small (because of involvement of the sympathetic nerves).
   
4. Sensory defects may be found in the distribution of the ophthalmic-trigeminal nerve (rarely the second division).
   
5. The optic nerve may rarely be involved.
   
6. Symptoms are acute or subacute and respond dramatically to large doses of corticosteroids (e.g., 60 to 100 mg prednisone).
   
7. Spontaneous remissions may occur with complete or partial regression of deficits.
   
8. Episodes may recur at intervals of months or years.
   
9. Diagnostic studies (CT, MRI, arteriography, rhinologic examination) show no evidence of involvement of structures outside of the cavernous sinus).
   

Radiologic findings may be relatively meager, but include soft tissue densities (Fig. 19) in the cavernous sinus,^170,171 some with resolution following corticosteroid therapy; sellar erosion,¹⁷² and, in a patient with painful ophthalmoplegia associated with diabetes and hypoadrenalism, enlargement of the hypophysis and infundibulum¹⁷³, biospy of which demonstrated chronic inflammation. Other various mechanisms that mimic Tolosa-Hunt include dural arteriovenous fistula,¹⁷⁴ ophthalmoplegic migraine with enhanced oculomotor nerves,^141,142 and lymphoma.¹⁷⁵

The clinician should be mindful that a diagnosis of Tolosa-Hunt syndrome is one made by default when exhaustive examination has seemingly ruled out other causes of painful ophthalmoplegia (see Table 7). More specific underlying processes may surface with the passage of time, and radiologic studies may bear repeating. If the preceding criteria are met, it is reasonable to begin corticosteroid therapy to alleviate severe pain while radiologic studies are being completed. If mucormycosis or other fungal infection is suspected, the use of corticosteroids is strictly contraindicated, and may indeed cause or hasten a fatal course.

The relationship between nonspecific inflammation involving the cavernous sinus or superior orbital fissure and idiopathic orbital pseudotumor is of interest. One may consider that these syndromes are indeed caused by the same process, in different locations. It is speculated that, on the basis of antineutrophil cytoplasmic antibodies, Tolosa-Hunt may represent a limited form of Wegener granulomatosis¹⁷⁶ in some instances. Also, idiopathic cranial pachymeningitis or fibrosclerosis may be related.¹⁷⁷ Concurrent autoimmune diseases such as Hashimoto's thyroiditis may be likewise incriminated.¹⁷⁸

Intracavernous aneurysms (see Fig. 7B and C) constitute only 2% to 3% of all intracranial aneurysms, but they may represent up to 15% of symptomatic unruptured aneurysms,¹⁹ and 20% to 25% of lesions producing a cavernous sinus syndrome.¹⁶⁶ The only other entities that are as frequently responsible for this syndrome are nasopharyngeal and metastatic neoplasms.^163,166,182 As Meadows¹⁸³ noted, intracavernous aneurysms “behave differently from aneurysms arising elsewhere in the skull by virtue of their position … and [they] tend to present themselves to ophthalmologists on account of ocular features.” Although Meadows wrote that “rupture may certainly occur,” with subsequent formation of an intracavernous arteriovenous fistula, this complication must be exceedingly rare. Fatal subarachnoid hemorrhage has been reported.¹⁸⁴ On occasion, uncontrollable nasal bleeding may be caused by erosion into the sphenoid sinus, but this phenomenon pertains to the post-traumatic, acquired intracavernous aneurysm.¹⁸⁵

The clinical features of intracavernous aneurysms may be summarized as follows¹⁸⁶:

1. There is usually slowly progressive diplopia first noted on eccentric gaze, due to variable involvement of the ocular motor nerves.
   
2. There is usually an abduction defect (abducens palsy) coupled with partial oculomotor palsy; pure abduction defects have been reported.^186,187
   
3. Less frequently, patients present with an abrupt and simultaneous onset of diplopia, unilateral ptosis, and severe ipsilateral periocular pain or trigeminal dysesthesia; however, pain may be minimal or absent, even in the presence of profound ocular motor palsies.
   
4. Ptosis may be minimal to complete.
   
5. The pupil may show sympathoparesis, parasympathoparesis, or (rarely) a combination that renders the pupil smaller (pharmacologic testing for Horner syndrome confirms the presence of sympathoparesis, whereas sluggish light reaction suggests parasympathoparesis).
   
6. “Primary misdirection” (see above) may be observed.
   
7. There is an unexplained higher frequency of these aneurysms in middle-aged and elderly women (Fig. 22).
   
8. Involvement of the optic nerve (visual loss and optic atrophy) is rare, and indicates encroachment of the aneurysm superiorly toward the ipsilateral anterior clinoid.
   
9. Thin-section, enhanced CT scanning of basicranial structures, or MRI, demonstrates the lesion, which may be confirmed by angiography or radionuclide dynamic flow studies.
   
10. Longstanding, unruptured aneurysms are compatible with long life, and indications for surgical intervention are indistinct, although intervention would seem reasonable to treat intractable trigeminal pain.
    
11. Cardiovascular disease, including hypertension, is commonly associated with these aneurysms.
    

Of 59 cavernous aneurysms reported with ocular motor involvement,¹⁸⁸ 17 involved the sixth nerve only, 5 involved the third nerve, and 37 involved multiple nerves, including 13 with complete unilateral ophthalmoplegia. The onset of oculomotor involvement was painful in all but three patients, and the conditions of all nine patients with sudden ophthalmoplegia improved spontaneously within 6 weeks.¹⁸⁸

Barr et al¹⁹ documented the pathologic changes of intracavernous aneurysms, including the disposition of the ocular motor nerves displaced on the medial convexity of the aneurysmal sac.

It is clinically valid to separate from the general category of middle fossa or sphenoid ridge meningiomas, a distinctive type whose center of growth, symptomatically and radiologically, is the cavernous sinus. Although meningiomas represent 15% to 20% of intracranial tumors, origin in the dura of the cavernous sinus is not acknowledged in most comprehensive series.¹⁸⁹ In all probability, these tumors derive from the meninges covering the floor of the middle fossa, but they are clinically unlike the tumors designated as “middle fossa meningiomas.” Typical middle fossa tumors, which constitute 2% to 15% of meningiomas, evidently originate at some distance lateral to the cavernous sinus, for they produce headaches, seizures, memory disturbances, hemiparesis, homonymous hemianopia, and papilledema before producing ophthalmoplegia. Meningiomas of the more medial sphenoid ridge frequently produce ophthalmoplegia, proptosis, and possible compromise of the optic nerve.

As with intracavernous aneurysms, “intracavernous” meningiomas may masquerade for years as slowly progressive unilateral ophthalmoplegia without pain, but commonly with proptosis, moderate ptosis, and occasionally primary aberrant regeneration phenomena.¹⁸⁶ Pupillary abnormality is usually of the parasympathoparetic type (i.e., somewhat dilated and with a sluggish light reflex). CT or MRI of the sellar area is typical, if not pathognomonic (Fig. 23).

Aside from histopathologic confirmation, surgery generally affords no relief of diplopia; the effectiveness of fractionated or stereotactic radiation therapy is moot.¹⁹⁰

In the Thomas and Yoss¹⁶⁶ series of 102 patients with parasellar syndrome, nasopharyngeal carcinoma was the most common cause, accounting for approximately 1 in every 5 patients. Also, according to Godtfredsen and Lederman,¹⁸² 20% of nasopharyngeal tumors present as a cavernous sinus syndrome and, conversely, 20% of cavernous sinus syndromes are due to malignant nasopharyngeal tumors. Although nasopharyngeal tumors may occur at any age, they most frequently do so in the seventh and eight decades and occur more frequently in males. Tumorous growth usually begins in the roof of the nasopharynx or in the lateral region about the ostium of the eustachian tube. Therefore, symptoms of tubal occlusion, including recurrent serous otitis, may be the initial sign of a nasopharyngeal tumor. Tumor extension commonly involves the basal foramina of the middle cranial fossa such that trigeminal involvement, especially maxillary division (e.g., pain or numbness in the cheek or side of the face), is common. According to Godtfredsen and Lederman,¹⁸² among patients with neuro-ophthalmic signs of nasopharyngeal tumors, the following frequencies of involvement are found: in 70%, neuralgias of the first and second trigeminal divisions; in 65%, ophthalmoplegia (most often affecting the abducens, then the oculomotor and trochlear nerves); in 17%, exophthalmos; in 12%, optic nerve defect; and in 16%, Horner syndrome. Although strictly ocular signs occurred alone in 25% of the patients, they were associated either with first- or second-division trigeminal defects or with varying lower cranial nerve palsies in 50% of the patients.

Because of the high rate of ophthalmologic signs and symptoms in nasopharyngeal tumors, and the large percentage of cavernous sinus syndromes due to such lesions, competent nasopharyngeal examination is mandatory in multiple ocular motor palsies or painful ophthalmoplegia. Since subtle submucosal extension of tumor occurs, “blind” nasopharyngeal biopsy may be positive in the absence of visible tumor mass, but CT and MRI studies of the paranasal sinuses often disclose evidence of soft tissue masses or bone erosion, in which case biopsy is performed at the indicated site.

Although associated with a more chronic variety of frontal and periocular headaches, sphenoidal sinus mucoceles (pyoceles) may also produce ophthalmoplegia. The review by Nugent et al¹⁹¹ indicates that approximately one in three patients with a sphenoidal mucocele evidences palsy of the oculomotor or abducens nerves. However, in the series by Valvassori and Putterman,¹⁹² no patient showed oculoparesis. One or both optic nerves are commonly involved, with a picture of chronically progressive visual loss and optic atrophy, but visual loss may be abrupt.¹⁹³ Occasionally, patients demonstrate chiasmal defects, usually with severe visual loss in one eye and a temporal hemianopic field defect in the other. It should be recalled that the sphenoidal sinus shares a common bony wall with the optic canal, tuberculum sellae, cavernous sinus, and superior orbital fissure (See Chapter 4, Fig. 5; Chapter 5, Fig. 32). With large expansion, exophthalmos may occur, as well as disc edema.¹⁹⁴

Patients harboring sphenoidal mucoceles may have a history of otolaryngologic disease, but many do not. The diagnosis rests on typical radiologic features best seen by CT scanning, and recovery of visual and ocular motor function is dependent on chronicity of symptoms.

Metastatic tumors to the cavernous sinus comprised 23% of the 102 parasellar lesions reviewed by Thomas and Yoss,¹⁶⁶ and 33% of all neoplastic disease. Other than the nasopharynx, common primary sites include lung, breast, prostate, and systemic lymphomas. In the series of 17 patients with cavernous sinus metastases reported by Post et al,¹⁹⁵ unilateral, rather severe periorbital pain was the initial symptom in 12; 9 patients, including most of those with pain, had decreased sensation in trigeminal distribution, the ophthalmic division alone or with the maxillary in six cases, with the mandibular division in two cases, and isolated maxillary division in one case; four patients also had ipsilateral optic nerve involvement. High-resolution, contrast CT scanning demonstrated an enhancing soft tissue mass that bulged the wall of the cavernous sinus laterally, and secondary bone invasion was often present (see also Kline et al¹⁹⁶). In 6 of 17 patients, the cavernous sinus syndrome was the initial presentation of occult malignancy, and it represented the first sign of metastases in 5 patients with known disease. Median survival was 4.5 months from onset of parasellar symptoms, but focal radiation therapy was useful in pain control.

Skin carcinoma, especially squamous cell, may spread centripetally from the face or neck via perineural routes to the orbital apex or superior fissure, and may present years after dermatologic excisions.¹⁹⁷ Patients may present with diplopia due to minimal ocular duction deficits with few orbital signs and can also have trigeminal hypoesthesia or pain, or facial neuropathies.¹⁹⁸ tenHove et al¹⁹⁹ documented nine such patients, noting that enhanced MRI of infraorbital and orbital nerves was helpful for confirmatory biopsy; in addition, radiation therapy may stabilize the diplopia in these patients, allowing for the possibility of strabismus surgery. Contiguous perineural and endoneural extension may also lead to meningeal carcinomatosis.²⁰⁰

Identification of specific pathologic entities causing the cavernous sinus syndrome is rarely possible by clinical criteria alone. The mode of onset, frequency of remissions, rate of progression, presence or absence of pain, pattern of neurologic deficit, and response to steroid therapy cannot reliably predict the precise nature of a cavernous sinus lesion. Nonetheless, it is often possible, on the basis of history, physical findings, radiography, and other clinical factors, at least to limit etiologic considerations and manage accordingly. Although it is true that ultimate diagnosis rests with biopsy, either transnasal or transcranial, in some instances even without histologic confirmation radiation therapy may be a better choice than craniotomy, especially if abnormal tissue is not encountered outside of the cavernous sinus. Surgery indeed may further jeopardize visual function or intensify general morbidity.

Although the nervous system is involved relatively infrequently in patients with systemic sarcoidosis, multiple cranial neuropathies, aseptic meningitis, hydrocephalus, disease of CNS parenchyma, peripheral neuropathies, and myopathies may all occur with neurosarcoidosis. Of cranial palsies, peripheral facial nerve weakness is most frequent,²⁰⁵ but the ocular motor nerves may also be involved as well as the optic nerves and chiasm (see Chapter 5). Of 50 cases of neurosarcoidosis, Oksamen²⁰⁶ found that the angiotensin-converting enzyme (ACE) level in the cerebrospinal fluid was elevated in 18 of 31 patients.

Ocular motor nerve palsies may be the initial presenting sign of CNS toxoplasmosis, a potentially treatable disorder. Toxoplasma gondii is an opportunistic, neurotropic organism that usually causes multifocal CNS lesions and frequently involves the thalamus and brain stem.²⁰⁷ We have observed several immunodeficient or immunosuppressed patients who presented with ptosis or diplopia due to toxoplasmosis involving the brain stem. Asymptomatic lesions are often found elsewhere in the brain. Other cranial nerve and brain stem functions may become progressively involved.

The acquired immunodeficiency syndrome (AIDS) provides the clinical substrate for cranial neuropathies secondary to infections and lymphomas (Table 8). Third and sixth nerve palsies may herald CNS infection with cryptococcosis and toxoplasmosis,²⁰⁷ as well as with large cell lymphoma.²⁰⁸ Other ocular motility disorders include conjugate gaze palsies and internuclear ophthalmoplegia.²⁰⁹

Another infectious agent, enterovirus 70, causes acute hemorrhagic conjunctivitis that, in a number of cases, is associated with dysfunction of any of the spinal cord and/or cranial motor nerves.^210,211 One series²¹¹ yielded the following results: 50% of the patients showed cranial nerve disturbances; sole involvement of the seventh or fifth cranial nerves was most common, and when multiple cranial nerves were involved, these same two nerves were again most frequently affected; prognosis was related to both severity and type of cranial nerve dysfunction; and patients with mild initial weakness and involvement of cranial nerves VII, IX, and X showed complete recovery, whereas patients with severe weakness or involvement of nerves III, IV, VI, and V did not show significant improvement.

The spirochete Borrelia burgdorferi produces Lyme disease, which may manifest a variety of acute, subacute, and chronic ocular and neurologic symptoms, including conjunctivitis, scleritis, uveitis, panophthalmitis, neuroretinitis, fluctuating meningoencephalitis, peripheral radiculopathies, and cranial nerve palsies.²¹² By far, the facial nerve is most commonly affected, but other cranial nerve involvement, including the third, sixth, or optic nerve, is relatively rare even in endemic areas. Elevated serum IgM or IgG antibody titers are variably present, but false-negative results are common. The Western blot is a helpful confirmatory test, but cases of seronegative neuroborreliosis are well documented in the literature. Lyme disease is also a common cause of false-positive FTA-absorbed tests. Polymerase chain reaction may provide a sensitive tool for organism detection to complement immunologic techniques. The circular cutaneous lesion of erythema chronicum migrans is pathognomonic, as is the characteristic tick bite, but these phenomena may be unnoticed by the patient. The optimal treatment regimen for Lyme disease has not been defined, but a course of ceftriaxone (2 g/day) or cefotaxime (6 g/day) for 3 to 4 weeks is commonly prescribed. Intravenous penicillin and oral doxycycline (200 mg/day) for 2 weeks have been used successfully to treat Lyme meningitis, but these results require confirmation.

MYASTHENIA

The diagnosis of myasthenia is at times simple and straightforward, and on other occasions frustrating and elusive. Despite the well-publicized ocular signs, myasthenia ranks high on the list of “missed diagnoses,” simply because many physicians are unaware of the variations in presentation, do not know how to examine for subtle signs, and often do not think of this possibility, at any rate. Any puzzling acquired ocular motility disturbance—with or without ptosis, but with clinically normal pupils—should raise the question of myasthenia.

Myasthenia may be characterized as follows: weakness without other signs of neurologic deficit (no reflex changes, sensory loss, or muscle atrophy); variability of muscle function within minutes, hours or weeks; remissions and exacerbations (sometimes triggered by infection, fever, or trauma); and tendency to affect extraocular, facial, and oropharyngeal muscles. In addition, there is usually reversal or improvement of muscle function with cholinergic drugs. The onset of myasthenia may occur at any age, but before age 40, the disease is more common in women. Neonatal forms are rarely encountered, and the clinical course in children and infants differs from adults, demonstrating a wider spectrum of myasthenic syndromes.²¹³ (See also Chapter 13.) The association with thymoma is well known (approximately 10% of myasthenia patients), and in such patients morbidity tends to be more severe and mortality rates are higher. In addition, dysthyroidism is found in approximately 5% of myasthenic patients, such that ocular signs may be admixed (e.g., exophthalmos and ptosis, paretic and restrictive motility defects). There is also a distinct relationship between collagen vascular disorders, thymoma, and myasthenia, and a familial incidence of myasthenia has been reported.

Myasthenia gravis is an autoimmune disorder characterized by a reduction of available postsynaptic acetylcholine receptors on the end plates of the neuromuscular junctions of skeletal muscle. Antibody-receptor interactions block neuromuscular transmission and subsequently destroy the receptor complex. The humoral immune response (e.g., polyclonal IgG produced by B lymphocytes) apparently plays a critical role in producing this disease. Antiacetylcholine receptor antibody is said to be present in 85% to 90% of patients with generalized myasthenia gravis (GMG) but less in patients with myasthenia “restricted” to ocular muscles (OMG).²¹⁴ Indeed, given the “embryonic” type of acetylcholine receptor in ocular muscles, there is evidence for considerable immunologic heterogeneity between GMG and OMG.²¹⁵ This phenomenon may partially account for cases of “sero-negative” OMG. Although actual antibody titers correlate poorly with the severity of the disease, Drachman et al²¹⁶ demonstrated that the antibodies do accelerate degradation of acetylcholine receptors and increase the extent of receptor blockade. In turn, increased receptor degradation and blockade correspond closely with clinical status, and thus confirm the relevance of antiacetylcholine receptor antibodies in the pathogenesis of myasthenia. Thus, the concept of a “safety margin” is important in the pathophysiology of myasthenia. Normally, both acetylcholine receptors and acetylcholine molecules at the neuromuscular junction are in significant excess. Any aberration that decreases the likelihood of molecular interaction between these two entities reduces this safety margin and produces clinical symptoms. The cause of the autoimmune attack on acetylcholine receptors is not known, but the thymus regularly shows prominent germinal centers (presumably the source of antibody-forming cells), if not actual tumoral growth. Epithelial (“myoid”) cells normally present in the thymus do indeed histologically resemble skeletal muscle, complete with acetylcholine receptors; these cells may become antigenic.

Ocular muscle involvement eventually occurs in 90% of all myasthenia and accounts for the initial complaint in approximately 75%.²¹⁷ In a study involving 1487 patients,²¹⁸ more than 50% presented with manifestations limited solely to extraocular muscles and levator palpebrae; of those patients with strictly ocular involvement during the first month after onset, 34% continued to have clinically “ocular” myasthenia over a four-decade follow-up period. That is, in 14% of this series, clinical manifestations were limited to the ocular muscles during the entire observation interval (mean, 17 years). Generalized myasthenia evolved in 68% of the initially “ocular” group, 78% of whom had clinical evidence within 12 months. Bever et al,²¹⁹ in a similar study, reported that 49% of “ocular” myasthenia remains “ocular,” and that 82% of those patients who later developed generalized myasthenia did so within 2 years.

Since muscle fatigability and remissions are the hallmarks of the disease, it is not surprising that ocular signs may vary, lasting from a period of hours to a course of weeks or months. Although some degree of ptosis is almost invariable, it may at first be unilateral and noted only as the day or the fatigue progresses, or the ptosis may “shift” from eye to eye. Clinically, ptosis may be made more apparent by repeated eyelid closure or during sustained upward gaze (Fig. 24). In cases of unilateral ptosis, the contralateral upper lid may be retracted, but will assume a normal position if the eye with ptosis is occluded or if the ptotic lid is lifted with a finger (“curtaining” sign or “enhanced ptosis”). This represents an example of Hering's law of equivalent innervation to the lid levators, the intact lid responding to increased innervation evoked by the effort to raise the ptotic lid. Cogan²²⁰ described a “lid twitch” sign that is elicited by having the patient rapidly redirect gaze from the downward to the primary position. The lid will be seen to twitch upward and then resettle to its original ptotic position. Occasionally, fine fluttering vibrations of the lash margins are observed in myasthenic lids. Although this is not a pathognomonic sign, Cogan's lid twitch is only rarely associated with other causes of ptosis.

Authoritative consensus dictates that pupillary and accommodative musculature is clinically uninvolved by myasthenia, sporadic reports and laboratory data to the contrary, notwithstanding.^217,221 If pupillary signs are present, another diagnosis must be entertained.

Extraocular muscle involvement does not follow any set pattern, although some have suggested that upward movements may be involved earliest. In our experience, medial rectus weakness is quite common, but essentially any ocular movement pattern may develop, such that isolated muscle palsies, or even total external ophthalmoplegia, may evolve. The motility pattern can mimic central gaze palsies or even internuclear ophthalmoplegia, complete with nystagmoid movements in the abducting eye (Fig. 25).²²² Myasthenic “nystagmus” has been otherwise documented.²²³ Eye movement recordings may be helpful in the diagnosis of myasthenia, which tends to demonstrate hypometric large saccades, hypermetric smaller saccades, and intrasaccadic fatigue (resolved with edrophonium).²²⁴ Intersaccadic fatigue may result in the appearance of a bimodal saccade or very rapid small saccades (“lightning eye movements”) terminating in an apparent, small “quiver.” These movements are quite characteristic and may be observed clinically. That is, supernormal saccadic velocities are the rule in myasthenia, even when significant ductional defects are present. Weakness of the orbicularis oculi is a very consistent sign in ocular myasthenia (Fig. 26) and serves as a further clue in diagnosis. Rarely does corneal exposure occur, but lower lid ectropion is occasionally seen. The “peek” sign results from orbicularis fatigue during eyelid closure, resulting in one or both eyes slightly opening spontaneously as the patient appears to peek at the examiner.²²⁵

Although it is true that the diagnosis of myasthenia is made on the basis of history and careful physical observations, one of the most helpful and dramatic (if positive) tests in medicine is the Tensilon test (edrophonium infusion). However, Tensilon testing is complicated by the problem of interpretation of response. When deficits in lid elevation or ocular motility are moderate or marked, evaluation of response to anticholinesterase drugs is usually a simple matter. However, when signs are minimal or inconstant, edrophonium or neostigmine (Prostigmin) response is more difficult to assess. The patient's interpretation of change in diplopia pattern may be made easier by placing a red filter before one eye, but this technique shares the inadequacies of all subjective examinations. In fact, patients have reported “improvement” after intravenous saline placebo. Such artificial reactions may indicate a functional disorder, or “neurasthenia.” Before edrophonium is administered, lid weakness may be accentuated by prolonged upward gaze, but extraocular muscles are rarely weakened by exercise, with uncommon exceptions such as fatigue of sustained lateral gaze.²²⁶ The orbicularis strength should also be noted before and after administration of edrophonium (see Fig. 26).

False-positive reactions occur with both neostigmine and edrophonium, but are fortunately infrequent. False-negative tests are not uncommon. This is in part due to the physician's often rough evaluation of subtle and inconstant oculoparesis and ptosis, dependency on the patient's subjective impressions, day-to-day variability of signs, and inadequate observations of “end points.” Paradoxical edrophonium responses are recognized, including producing paresis of previously nonparetic muscles in myasthenics. Retzlaff et al²²⁷ believe such paradoxical reactions to be present in half of myasthenics subjected to Tensilon testing, using red-green glasses for diplopia assessment.

In the chronic or “fixed” form, ocular myasthenia may be confused with chronic progressive external ophthalmoplegia (CPEO), because either entity can demonstrate symmetric total external ophthalmoplegia, ptosis, facial weakness, edrophonium resistance, and pharyngeal symptoms. A slow, progressive symmetric course, without fluctuations or remissions and little or no complaints of diplopia, speaks strongly in favor of CPEO, as does familial incidence. The “fixed” type of chronic ocular myasthenia may also show mechanical resistance to attempted forced duction testing.

For the most part, intravenous edrophonium has replaced neostigmine in diagnostic testing for myasthenia, although neostigmine is useful in children or in adults with poor intravenous access. The Tensilon test is performed in the following manner: (1) ptosis and motility defects are evaluated as objectively as possible; (2) 1 mL (10 mg) edrophonium is drawn into a tuberculin or other small syringe and, after venipuncture, 0.2 mL of test dose is injected, but the needle is left in the vein; (3) tearing and fasciculations in the lids are indicators of cholinergic effect; and (4) if lid or extraocular muscle function is not improved within 30 to 60 seconds, the remaining 0.8 mL is slowly injected over similar intervals until a positive test result is observed, systemic effects (e.g., lid myokymia, tearing) occur, or the entire vial is injected, and the lid positions and eye movements assessed again.²²⁸ We have had no problem with the use of intravenous edrophonium, even in children. The effect of edrophonium is short lived, and all evaluations must be completed within 5 minutes. Many myasthenics show improvement within 30 to 45 seconds after doses as low as 0.3 mL. Rarely is the entire vial necessary to provoke a response, and in fact, large doses of edrophonium may paradoxically cause worsening of ocular motility in myasthenia.

The Hess diplopia screen (red-green glasses and matching projector lights) combined with intravenous edrophonium was used to test 10 normal control subjects, 12 nonmyasthenic patients with acquired strabismus, and 10 patients with acquired strabismus caused by OMG. A positive response to the edrophonium-Hess screen test was defined as a 50% or greater reduction in the strabismic deviation at the fixation point associated with maximum deviation within 1 minute of edrophonium infusion. All myasthenic patients had a 50% or greater reduction in the initial deviation within 1 minute of edrophonium infusion. Myasthenic patients had a statistically significant reduction in the average deviation up to 150 seconds after edrophonium infusion. In contrast, with or without edrophonium infusion, control subjects had a purely horizontal fluctuation in binocular alignment of less than or equal to 2° for the entire 4-minute period after edrophonium infusion. None of the 12 nonmyasthenic patients tested positive to the edrophonium-Hess screen test. These results suggest that clearly defined endpoint criteria make the edrophonium-Hess screen test a sensitive and specific quantitative study.²²⁹

Siatkowski et al²³⁰ performed Tensilon tests on 30 normal subjects and 14 patients with nonmyasthenic strabismus. There were no clinically significant changes in muscle balance after Tensilon injection in any of the subjects, although the normal subjects had a slight increase in their near exophorias (mean, 2 prism diopters). The strabismic patients tended to have a slight change in their vertical deviation (mean change, 1.7 prism diopters; maximum change, <5 prism diopters) which was neither clinically nor statistically significant. The mean dose of edrophonium required for systemic response was 7.1 mg.

Just as the Tensilon test may on occasion be positive when the Prostigmin test is negative, the Prostigmin test may be positive when the Tensilon test is negative. Miller et al²³¹ suggested that neostigmine be used in patients whose signs are minimal, particularly in those with diplopia but no ptosis. Arguably, the longer duration of neostigmine's effect allows more time for quantitative measurements of ocular motility. Such patients are usually pretreated with intramuscular atropine (approximately 0.6 mg) before receiving intramuscular injection of neostigmine (approximately 1.5 mg). Ocular motility is reassessed 30 to 45 minutes thereafter.

It should be emphasized that neurasthenia may masquerade as myasthenia, especially where the chronically fatigued or tired patient shows no real eye muscle involvement, the so-called findings being limited to variable limb weakness. A placebo injection of, for example, physiologic saline that produces increased muscle strength and/or rapid alleviation of fatigue will quickly provide a useful diagnostic distinction. A small pediatric scalp-vein needle permits alternate connection of syringes first with saline and then with edrophonium.

Diagnostic procedures that complement Tensilon and Prostigmin testing, particularly in generalized myasthenia, include (1) electromyography (EMG) of muscle action potentials evoked by repetitive supramaximal nerve stimulation (approximately 3 to 5 Hz), and for the presence of the jitter phenomenon on single muscle fiber studies; and (2) antiacetylcholine receptor antibody titer (see above). In OMG, testing of the orbicularis muscles may be helpful. The relative importance of several methods—stimulated single fiber EMG (stimulated SFEMG), repetitive nerve stimulation test (RNS) of orbicularis oculi muscle, and infrared reflection oculography (IROG)—was investigated.²³² Based on the results of the three neurophysiologic tests, the patients can be divided into three groups:

  Group 1: Those with an abnormal stimulated SFEMG, abnormal RNS, and/or abnormal IROG
  Group 2: Those with only a slightly abnormal stimulated SFEMG
  Group 3: Those with normal results in all three tests

The clinical diagnosis of OMG was made in all 11 patients in the first group; in 6 of 7 patients (86%) in the second group; and in 1 of 14 patients (7%) in the third group. This study emphasizes that the orbicularis oculi muscle is a suitable muscle for stimulated SFEMG in patients with suspected OMG. A seemingly simple “sleep test” was proposed,²³³ based on the phenomenon of myasthenic symptoms and signs improving after rest: patients are kept in a quiet room in a restful state for 30 minutes, and levator and extraocular muscle function is assessed before and after rest. In this series, the sleep test was positive in cases of known OMG.

A diagnosis or firm suspicion of myasthenia on the part of the ophthalmologist is an indication for thorough examination by a neurologist. Thin-section, contrast-enhanced CT scan or MRI of the mediastinum should be performed to search for occult thymoma, but in a significant number of patients with only hyperplastic or normal thymus glands,²³⁴ CT scan may suggest thymoma. Ideally, tests to determine thyroid function and the presence of collagen vascular disease should be performed.

The pharmacologic treatment of myasthenia, ocular or otherwise, is beyond the purlieu of even the interested ophthalmologist and is strictly the domain of an experienced neurologist, who would be more familiar with the response of myasthenics to medications, with the minor and major complications of the primary disorder, and with the difficulties of dose variations and medication schedules. The ophthalmologist should collaborate by reevaluating ocular motility and using press-on prisms and lid crutches when indicated. Large, variable, or incomitant deviations are best treated with an opaque lens. Ptosis surgery is dangerous because defective ocular motility can lead to problems of corneal exposure.

Therapy for myasthenia at present is somewhat individualized,²³⁵ but is based on one of the following options: (1) increasing the amount of acetylcholine available with cholinesterase inhibitors such as pyridostigmine (Mestinon); or (2) blunting the autoimmune response with corticosteroids, especially for the often-resistant ocular symptoms, or less frequently with immunosuppressive agents (e.g., azathioprine, cyclosporine), plasmapheresis, and/or thymectomy. Gamma-globulin therapy and plasmapheresis are rarely, if ever, indicated for purely ocular myasthenia. Other pharmacologic agents include ambenonium, a biquaternary compound that binds irreversibly to acetylcholinesterase, with a duration of approximately 8 hours.

Thymectomy is rarely used in OMG but often used in GMG. Remission postoperatively is well documented, although the benefit of surgery may be delayed from 1 to 3 years. For OMG, we have found that a combination of pyridostigmine bromide and oral corticosteroid provides salutary results, but some authors have reported improvement with the use of steroids alone.²³⁶

MYASTHENIA-LIKE SYNDROMES

The Eaton-Lambert syndrome is a paraneoplastic disorder of the neuromuscular junction that produces proximal limb weakness and fatigability resembling myasthenia in some aspects. In contrast to true myasthenia, ocular, facial, and oropharyngeal musculature is preferentially spared, a temporary increase in muscle power is seen after brief exercise, and deep tendon reflexes are diminished or absent.²³⁷ EMG diagnosis entails demonstrating a characteristic incremental response to repetitive nerve stimulation, which is precisely the opposite of myasthenia. Although patients with this disorder are sensitive to small doses of curare, as in true myasthenia the weakness is due to a presynaptic mechanism that causes impaired release of acetylcholine²³⁸ at both nicotinic and muscarinic nerve terminals. Specifically, antibodies to voltage-gated calcium channels in motor and autonomic nerve terminals disrupt calcium influx and reduce acetylcholine release. Approximately 70% of patients with Eaton-Lambert syndrome harbor malignant neoplasms, usually small-cell bronchogenic carcinoma; other instances are associated with autoimmune disorders, such as Sjögren's syndrome or discoid lupus,²³⁹ but in some cases no other primary disease can be discovered.

Ocular involvement is distinctly rare and, if present (particularly if there is isolated ocular involvement), practically excludes the diagnosis of Eaton-Lambert syndrome. Patients have been reported with ptosis and/or ocular motility disorders,²⁴⁰ as well as with documented abnormal eye movement recordings.²⁴¹ Breen et al²⁴² reported transient improvement of ptosis after sustained upgaze as a clinically useful sign in distinguishing Eaton-Lambert syndrome from myasthenia gravis. Grisold et al²⁴³ provided a general review of paraneoplastic neurologic syndromes in which detection of autoantibodies directed against central and peripheral nervous system structures has suggested an autoimmune etiology. The therapeutic results of 258 patients with paraneoplastic neurologic disease (e.g., paraneoplastic encephalomyelitis, sensory neuronopathy, cerebellar degeneration, motor neuron disease, stiff-man syndrome) were summarized. The results showed that in some entities, such as Lambert-Eaton syndrome, successful treatment can be expected. In other syndromes, such as subacute sensory neuronopathy or paraneoplastic cerebellar degeneration, therapeutic success varies from 5% to 10%.

Some pharmacologic agents may induce a clinical picture closely mimicking myasthenia. For example, D-penicillamine, given for rheumatoid arthritis, can produce isolated ocular signs and symptoms or generalized muscle involvement, and affected patients have elevated antiacetylcholine receptor antibodies, along with the same HLA antigens seen in true myasthenia.²⁴⁴ A number of antibiotics, including the polypeptides (Colistin, polymyxin B) and aminoglycosides (neomycin, streptomycin, kanamycin, azithromycin) can also induce weakness resembling myasthenia gravis.²⁴⁵ Diplopia, accommodative insufficiency, and bulbar muscle weakness may be encountered. The antineoplastic agents vincristine and vinblastine have special neurotoxic propensity, including ocular signs such as ptosis, external ophthalmoplegia, isolated muscle paresis, facial palsy, and lagophthalmos.²⁴⁶

Numerous other pharmacologic agents can decrease transmission at the neuromuscular junction,²⁴⁷ such as neuromuscular blockers, anticholinesterase agents, antiarrhythmics (procainamide and quinidine), anticonvulsants (phenytoin), β-blockers (propranolol, timolol), corticosteroids, cisplatin, lithium, and magnesium. Obviously, great care must be taken when patients with myasthenia or other disorders of neuromuscular transmission are exposed to or treated with these agents. Corticosteroids, for example, are commonly used to treat myasthenia and may exacerbate muscle weakness, in some instances to the point where respiratory support is necessary.

Toxins elaborated by scorpions, ticks, wasps, spiders, and bacteria (Clostridium botulinum, Clostridium tetani) also affect the neuromuscular junction. Botulinum toxin acts presynaptically to prevent release of acetylcholine and also destroys nerve endings, which require several months for regeneration. Ophthalmologic findings in botulism include ptosis, ophthalmoparesis, and dilated, poorly reactive pupils.^248,249 Of course, botulinum toxin is commonly used therapeutically to produce isolated transient paresis of the extraocular muscles and of the facial and neck muscles in treating strabismus, blepharospasm, hemifacial spasm (including Meige's syndrome) and torticollis.

THYROID-RELATED MYOPATHY (GRAVES DISEASE)

Restricted eye movement caused by pathologic changes in extraocular muscles commonly, but not exclusively, associated with dysthyroidism is an extraordinarily frequent cause of diplopia. Encountered in all age groups (but rarely occurring in those less than 20 years old), thyroid-related restrictive myopathy (TRM) is the most common cause of spontaneous double vision in middle age and early senescence. Like myasthenia, TRM ranks high on the list of frequently missed diagnoses; patients are constantly subjected to inappropriate, invasive, and expensive radiodiagnostic studies. The ophthalmologist and neurologist should learn well the subtle ocular signs that usually accompany TRM and should know how to perform the single most important office maneuver, the forced duction test, to establish the presence of mechanical resistance (Chapter 3, Fig. 6). Comments here are limited to those aspects of TRM pertinent to neuro-ophthalmology: that is, those findings that permit a clinical diagnosis and obviate further uncomfortable and costly studies.

In subtle cases of TRM, the striking clinical signs of congestive proptosis are absent, but spontaneous lid retraction (stare) or lag on downward gaze is observable (see Chapter 3, Fig. 11; Chapter 14, Fig. 4). These lid signs may be elicited by having the patient perform pursuit eye movements while fixating some object moved vertically at a moderately fast speed. As the eyes turn downward, one or both lids are noted to lag (or “hang up”). A peculiar “jelly roll” edema is often evident in the upper or lower lids, but at times is difficult to distinguish from the redundancy of lid tissue that accompanies aging.

Careful inspection of the globe itself may reveal the conjunctival vessels overlying the anterior aspect of the horizontal recti muscles to be dilated and tortuous. The hypertrophied extraocular muscles themselves are occasionally visible (Fig. 27).

The single most common ocular motility abnormality encountered in TRM is unilateral “elevator palsy” (Fig. 28), or a hypodeviation that increases on upward gaze. While mimicking a superior rectus palsy, the actual problem is fibrotic shortening of the inferior rectus, which restricts upward rotations. That the globe is tethered by a taut muscle is established by the palpable resistance to mechanical elevation (i.e., a positive forced duction test). If both inferior recti are involved, the patient shows an upward gaze palsy somewhat mimicking midbrain syndromes (Fig. 29). Similar fibrotic contraction of the medial rectus produces an abduction deficit that mimics a sixth nerve palsy, but the globe resists outward rotation when the insertion of the medical rectus is grasped. Downward gaze is limited when restrictive fibrosis of the superior rectus occurs. Isolated lateral rectus involvement, with abduction deficits, is uncommon, but all gaze functions may be reduced. In addition to the myopathy itself, impaired orbital venous outflow may play a role in the exophthalmos and strabismus of this disorder.²⁵⁰

Commonly, torsional movements of the globe are observed on attempted horizontal or vertical versions (see Fig. 29A and B). For example, on attempted right gaze, the right eye abducts incompletely and extorts slightly as it reaches the position of maximum abduction. This excyclotorsion is seen especially in the company of elevation deficits (tight inferior rectus).

In the early stages of the disease, an affected muscle may in rare cases appear paretic rather than restricted. Hermann²⁵¹ reported on two patients with diplopia with negative forced ductions, but with saccadic velocities consistent with inferior rectus paresis. We also have observed a patient with obvious Graves disease who presented with an inferior rectus paresis, including a positive three-step test and negative forced ductions; echography revealed a greatly enlarged inferior rectus muscle. Several months later the hypertropia converted to a hypotropia, as a typical restrictive pattern evolved. Such paresis is distinctly unusual, and may represent thyroid “myositis” as a precursor to muscle fibrosis. However, mechanical restriction by the involved muscle with positive forced duction testing is the rule.

An additional clue to the restrictive nature of TRM is the finding of elevation of intraocular pressure on attempted upward gaze.²⁵² This phenomenon, attributed to a fibrotic and taut inferior rectus muscle, may aid in establishing the cause of otherwise puzzling spontaneously acquired diplopia.

The diagnosis of TRM is not so difficult a task on clinical grounds, if the physician bears in mind the characteristic lid and orbital congestive signs, the typical patterns of motility disturbance, and the use of the forced duction test. Increase in extraocular muscle bulk, the hallmark of Graves orbitopathy, may be assessed by standardized A-scan ultrasonography,²⁵³ CT scanning, or MRI (Fig. 30). Usually multiple muscles in both orbits are enlarged, but asymmetry may be striking. To affirm the diagnosis in terms of biochemical tests of thyroid function is another problem altogether. Ocular manifestations may antedate laboratory or clinical evidence of dysthyroidism, but many patients present with ophthalmologic complications occurring months to years after surgery or radioactive iodine therapy for hyperthyroid states. At the time of ocular diagnosis, many of these patients are euthyroid by all parameters of multiple laboratory tests of thyroid function. However, hypothyroidism with elevated thyrotropin (thyroid-stimulating hormone, TSH) levels after radioactive iodine treatment appears to be an important adverse risk factor for development or exacerbation of ophthalmopathy.²⁵⁴ In addition to a history and physical examination, laboratory procedures to determine triiodothyronine (T₃), thyroxine (T₄), TSH, and T₃ resin uptake have assumed a fundamental role. T₄ and T3 are the major circulating hormones produced by the thyroid. By increasing the sensitivity of analysis, radioimmunoassay (RIA) techniques have dramatically simplified thyroid hormone assessment. Furthermore, T3 (RIA) and T₄ (RIA) levels are not influenced by inorganic iodine contamination from outside sources. Hence, the administration of iodinated radiologic contrast dye does not confound the evaluation of thyroid function when RIA methods are employed. Both the T₄ (RIA) and the previously widely used T₄ measurement by the Murphy-Pattee competitive protein-binding assay require simultaneous T₃ resin uptake determination. The T₃ resin uptake analyzes the unbound thyroxine-binding globulin. Numerous conditions (e.g., pregnancy, hepatitis, recent surgery, renal failure) and pharmacologic agents (e.g., estrogens, corticosteroids, phenytoin) may alter thyroxine-binding globulin affinity; therefore a computed value, the free T₄ index, is often used to estimate the amount of free thyroid hormone available to the tissues. The free T₄ index is calculated from the serum T₄ concentration and the T₃ resin uptake.

Although T₃ thyrotoxicosis is well recognized by internists and endocrinologists as a distinct clinical entity, ophthalmologists must be aware that T₄ determination alone does not completely evaluate peripheral blood thyroid hormone status. In addition, T₃ is often elevated out of proportion to T₄ in Graves disease. Long-acting thyroid stimulation determinations, although still available, have no currently recognized value in diagnosis or patient care.

Since approximately two thirds of patients with euthyroid Graves disease demonstrate an autonomously functioning pituitary-thyroid axis, this homeostatic system must be evaluated. An autonomous pituitary-thyroid axis indicates that the thyroid gland has escaped the normal feedback, regulatory control of circulating TSH; it is thus known as the autonomous thyroid gland. For many years, the Werner suppression test was employed to assess any “escape” of the thyroid from normal TSH control. This test involved the administration of oral T₃ (Cytomel) for 7 days with prior and follow-up determination of radioactive iodine uptake detected over the thyroid gland. With disruption of the pituitary-thyroid balance, the administration of oral T3 fails to suppress radioactive iodine uptake below 50% of the initial level, thereby indicating autonomous thyroid activity (provided that the initial uptake is at least 15%).

The intravenous thyrotropin-releasing hormone (TRH) test has now virtually supplanted the more cumbersome, time-consuming, and costly Werner suppression test. TRH is the hypothalamic regulatory factor controlling the release of TSH from the anterior pituitary gland. Normally, intravenous administration of TRH causes a four- to five-fold peak rise in blood TSH level within 20 to 30 minutes after injection. The TSH response to TRH is fairly constant, except in patients with Cushing's syndrome from either endogenous or exogenous excess corticosteroids. In addition, patients with an autonomous pituitary-thyroid axis will fail to show the expected increase in TSH response. A blunted or absent pituitary TSH response to TRH injection signifies a positive test, as found in approximately 50% of patients with Graves ophthalmopathy considered “euthyroid” by conventional testing.²⁵⁵ A normal TRH test is therefore seen in the remaining 50% of these patients and designates them truly euthyroid by currently available laboratory criteria.

Autoimmune abnormalities, such as thyroid-stimulating antibodies and thyroid-displacing activity, may be used in conjunction with the TRH test to detect occult thyroid disease. The collaboration of a competent endocrinologist is of obvious advantage. In addition, elevated serum IgE²⁵⁶ and anti-eye-muscle antibodies²⁵⁷ have been reported in patients with thyroid-related myopathy.

For the internist, a medical approach to therapy should be tempered by knowledge that thyroid-related orbitopathy is more or less a self-limited disease, and that emphasis should be placed on the prevention of serious ocular complications. It seems reasonable that rendering hyperthyroid patients euthyroid, and preventing them from becoming hypothyroid, is advantageous. If the euthyroid state is preferable, then no specific medical manipulation of euthyroid ophthalmopathic patients is indicated.²⁵⁵

Treatment of optic neuropathy in Graves disease is considered in Chapter 5. The strabismus in acute and subacute orbitopathy has been demonstrated to improve with both corticosteroid and radiation therapy,^258–260 but definitive surgical treatment should be postponed until deviations have been stable for a minimum of 6 months. Because of the incomitance of the strabismus, prisms are often inadequate to control patients' symptoms, necessitating extraocular muscle surgery. As a general rule, muscle resections should not be employed in this disease, because such procedures do not address the underlying mechanism of the restrictive strabismus and may, in fact, worsen it. Long-term results of rectus muscle recessions employing the adjustable suture technique are quite favorable,²⁶¹ and adjustable suspensions of the lower eyelid retractors may be employed concurrently to minimize lower eyelid retraction after inferior rectus surgery.²⁶² The surgeon should attempt initially to undercorrect the deviation, since late overcorrections are common in Graves' ophthalmopathy.²⁶³ Botulinum toxin has a limited role, if any, in Graves' ophthalmopathy, but may be used in those rare patients with extraocular muscle paresis in order to minimize or delay contracture of the antagonist muscle.

PROGRESSIVE (CHRONIC) EXTERNAL OPHTHALMOPLEGIA

There is considerable controversy regarding the precise nosologic classification of the “muscular dystrophies,” including the chronic external ophthalmoplegias (i.e., those not involving the internal ocular muscles of the pupil). Although they were once traditionally considered primary myopathies, later contributions have challenged this etiologic concept and have argued strongly in favor of another: primary neurogenic disorders or abnormal proliferation of mitochondria are believed to cause “ragged-red fibers” (so called because of their dark red color on modified Gomori trichrome stain), which are a hallmark of the severe biochemical defects in oxidative phosphorylation characteristic of many mitochondrial encephalomyopathies.²⁶⁴ Recent literature has focused on the importance of diffuse, systemic mitochondrial abnormalities (Table 10). In patients with progressive external ophthalmoplegia (PEO) or CPEO, light microscopic examination of extraocular muscle, orbicularis oculi, and at times other skeletal muscle reveals ragged-red muscle fibers admixed within a population of relatively normal muscle fibers. On electron microscopic examination, these same ragged-red fibers demonstrate strikingly abnormal mitochondria. Ragged-red fibers may be found in other diseases, and small numbers are indeed seen in the orbicularis and extraocular muscles of normal persons, but not in their limb muscles. Also, mitochondria are morphologically abnormal in skeletal muscle biopsies from PEO patients with or without ragged-red fibers.²⁶⁵ In the Kearns-Sayre variant, such abnormal mitochondria have also been observed in liver cells, sweat glands, and granular and Purkinje cells of the cerebellum.²⁶⁶ All recent studies have suggested that mitochondrial dysfunction plays an essential role in producing the multisystem involvement in many PEO patients. Mitochondrial dysfunction is associated with a variety of genetic defects due to nucleotide mutations.^264,267,268 Muscle mitochondrial DNA (mtDNA) deletions may be detected, localized, and quantitated by Southern blot analysis of transfer RNA (tRNA) genes in the mtDNA (+ RNA leucine, glutamine, isoleucine, and formylmethionine).²⁶⁹ Such techniques confirm the high frequency of mtDNA deletions or point mutations in PEO. At the onset of the disease, no clinical, morphologic, or molecular features can predict whether PEO will remain isolated or become part of a more severe multisystem disease. However, patients with mtDNA deletions are characterized by more severe ophthalmoplegia of earlier onset. Muscle alterations are roughly parallel in severity to the proportion of deleted mtDNA molecules in muscle. There are sporadic cases of patients with multitissue disease and mtDNA deletions; their clinical presentation usually closely resembles Kearns-Sayre syndrome.

Clinically, PEO is characterized by insidiously progressive, symmetric immobility of the eyes, which are fixed to oculocephalic or caloric stimulation. There is no pain and the pupils are spared, but the lids typically are ptotic and the orbicularis oculi weak (Figs. 31 and 32). Unlike Graves' ophthalmopathy, there is no lid retraction, proptosis, or congestive conjunctival signs. In longstanding PEO, however, fibrotic changes in extraocular muscles may produce mechanical resistance and a positive forced duction test. Chronic or “fixed” ocular myasthenia may be confused with PEO, because both disorders tend to demonstrate the following: symmetric total or subtotal external ophthalmoplegia; ptosis; normal pupils; orbicularis oculi, facial, and bulbar weakness; and resistance to Tensilon or other cholinergic agents. A slowly progressive symmetric ophthalmoplegia, without fluctuations or remissions, speaks strongly in favor of PEO (see below, hereditary form). Otherwise, electrophysiologic testing and muscle biopsy may be required to distinguish between chronic myasthenia and PEO.

Although not always an easy task, it is usually possible clinically to distinguish ophthalmoplegia due to CNS lesions from the PEO syndromes. Patients with PEO, however, do not demonstrate an increase in ocular motility when the doll's head maneuver is employed. On the other hand, cerebral gaze palsies are acute, usually asymmetric, and show retention of reflex eye movements, including oculocephalic deviations. Pontine gaze palsies are usually asymmetric and accompanied by other neurologic deficits, such as hemiparesis, hyperreflexia, and other ipsilateral cranial nerve palsies. Supranuclear gaze palsies that otherwise may simulate PEO (e.g., progressive supranuclear bulbar palsy, parkinsonism) are discussed in the next section.

Depending on the associated signs and symptoms, PEO may be classified into several subgroups (see Table 9). Accompanying the Kearns-Sayre form of PEO, a mild to moderate “salt and pepper” disturbance of peripheral retinal pigment epithelium has been described (Fig. 32B), especially in adolescents.²⁷⁰ Unlike retinitis pigmentosa, as a rule there is neither optic atrophy, arteriolar attenuation, nor visual disturbance to any real degree. Visual fields are grossly full, and electroretinography may be surprisingly normal. The major manifestations of Kearns-Sayre syndrome are as follows: childhood onset of PEO without family history; retinal pigmentary degeneration; cardiac conduction defects, often leading to complete heart block and Stokes-Adams attacks; ragged-red muscle fibers on skeletal muscle biopsy; elevated cerebrospinal fluid protein; and marked vacuolization (status spongiosus) of the cerebrum and brain stem.

A number of other findings are frequently, but not invariably, associated with this syndrome. Whether or not the Kearns-Sayre symptom complex represents an atypical (“slow”) viral, toxic, or multisystem genetic mitochondrial disturbance is currently unknown. Rowland²⁷¹ reviewed a number of reports of familial occurrence and found that “among the 70 cases, there has been only one family in which more than one person had the entire syndrome.” Administration of coenzyme Q-10, a component of the mitochondrial electron transport system, has been observed to normalize serum pyruvate and lactate levels and improve both atrioventricular block and ocular movements in a patient with Kearns-Sayre syndrome.²⁷²

Oculopharyngeal dystrophy of Victor is a rather benign hereditary condition, usually autosomal dominant, which has an onset in the fifth and sixth decades and involves the bulbar musculature. Temporalis wasting may be striking (see Fig. 31). Pathologically, ragged-red fibers with abnormal mitochondria are not described in this condition. Rather, there is marked reduction in the number of muscle fibers, and those fibers that remain show significant degenerative changes and characteristic nuclear inclusions.²⁷³ A large number of French Canadians are affected with this variety of PEO, which is traceable to a common ancestor from a Quebec isolate. Other variations, which may occur either sporadically or in an heredofamilial form, include involvement of muscles of the neck and upper extremities. Autopsy of one such case showed no pathologic changes in either the peripheral or the central nervous system.²⁷⁴ Some patients have ptosis and pharyngeal symptoms with relative sparing of ocular motility, and we have seen one case of profound ophthalmoplegia and pharyngeal involvement, but without ptosis.

Ionescu et al²⁷⁵ described the association between inherited ophthalmoplegia and intestinal pseudo-obstruction due to decreased motility of the stomach and small bowel. Ptosis and ophthalmoplegia begin in childhood, and gastrointestinal symptoms appear in adolescence; there is progressively worsening malnutrition, and death occurs before age 30 regardless of medical treatment. Abnormal synthesis of contractile proteins in muscle cells was demonstrated in the one case studied.

Mitochondrial myopathy, encephalopathy with lactic acidosis, and strokelike episodes (MELAS) syndrome is one of the mitochondrial encephalomyopathies that has distinct clinical features, including strokelike episodes with migrainous headache, nausea, vomiting, encephalopathy, and lactic acidosis.²⁷⁶ For example: A 27-year-old woman presented with a history of partial seizure, strokelike episodes including hemiparesis, hemianopia and hemihypesthesia, sensorineural hearing loss, migrainelike headache, and lactic acidosis. A brain CT scan showed encephalomalacia in the right parieto-occipital area and hypodensity in the left temporoparieto-occipital area with cortical atrophy. Muscle biopsy revealed ragged-red fibers and paracrystalline inclusions in the mitochondria. Genetic study revealed an A to G point mutation at nucleotide position (np) 3243 of mtDNA. External ophthalmoplegia and ptosis were also found during two exaggerated episodes in this patient. Therefore, the overlapping syndrome of CPEO in the MELAS syndrome was considered. This patient was also found to have a carnitine deficiency, and she responded to steroid therapy. Muscle biopsy revealed excessive lipid-droplet deposits. It was concluded that a carnitine deficiency may occur in MELAS syndrome with the A to G point mutation at np 3243, and it was recommended that patients with MELAS syndrome and carnitine deficiency be started on steroid or carnitine supplement therapy.²⁷⁶

Hereditary abetalipoproteinemia (Bassen-Kornzweig syndrome) refers to the association of PEO, pigmentary retinopathy, ataxia, and intestinal fat malabsorption. The laboratory assessment of patients with potential mitochondrial disease is extensive, as outlined by Johns²⁶⁴ (Table 11).

Regarding therapy, there is no pharmacologic relief for the weak muscles, including systemic or locally injected corticosteroids; in fact, in Kearns-Sayre syndrome systemic corticosteroids may precipitate hyperglycemic acidotic coma and death.²⁷⁷ If exotropia or diplopia develop, standard extraocular muscle surgery may be performed. However, these patients rarely complain of diplopia, perhaps in part because of slow onset of the disease, symmetry of the ophthalmoplegia, and comitancy of the strabismus. Surgical repair of ptotic lids should be approached with caution because, in the presence of poor ocular motility (specifically minimal upward movement), patients may experience severe complications of corneal exposure after lid-lifting procedures. Lid crutches are an excellent alternative (see Fig. 31C). In patients with an early onset, cardiac evaluation is mandatory to rule out complete heart block. A cardiac pacemaker is often indicated and may be lifesaving, although sudden neurologic deterioration and death can occur in Kearns-Sayre patients despite a functioning cardiac pacemaker.²⁷⁸

The ophthalmoplegia in progressive supranuclear palsy first affects volitional vertical gaze, especially downward. That the lesion is at first supranuclear can be demonstrated by full vertical deviations with oculocephalic (doll's head) maneuvers (Fig. 33). Pursuit movements may be preserved, such that optokinetic testing “draws” the eyes tonically in the direction of stimulus movement. Eventually, horizontal gaze is involved, with both saccadic and pursuit palsies. Although oculocephalic deviations may be demonstrable even late in the disease, marked neck dystonia makes doll's head maneuvers difficult to assess. Cold calorics show slow tonic deviation. Finally, all eye movements, including reflex movements, may be lost.

Therapy in these patients is generally directed at education and instruction regarding appropriate head movements; however, the use of idazoxan has proved useful in some patients.²⁸² Interestingly, although progressive supranuclear palsy is considered a supranuclear disorder, mitochondrial adenosine triphosphate production in the extraocular muscles has also been shown to be defective in these patients.²⁸³

Progressive supranuclear palsy is distinguished from Parkinson's disease by the pattern of ophthalmoplegia, lack of tremor, presence of pyramidal tract signs, dementia, and death, which usually ensues within 10 years. MRI is also helpful in distinguishing these two entities. In progressive supranuclear palsy, definitive atrophy of the midbrain and the region around the third ventricle is seen in more than 50% of cases. In Parkinson's disease, alterations in the pars compacta of the substantial nigra may be encountered.²⁸⁴ Levodopa does not alter eye movement but may alleviate rigidity.²⁸⁰ Since ocular symptomatology is marked, the ophthalmologist should be aware that defective vertical gaze movement may explain these patients' difficulty seeing objects in the inferior visual field. Bifocals are unsuitable, but single-vision reading glasses are indicated.

Patients with Parkinson's disease demonstrate a relative deficiency in spontaneous eye movements, which in association with infrequent blinking, produce a rather typical parkinsonian stare. As with progressive supranuclear palsy patients, blepharospasm and apraxia of lid opening may be seen. Upward gaze is more commonly initially involved and, along with convergence, may be weak or absent, even more so than those deficits associated with aging alone. Rapid volitional eye movements are fragmented into multiple saccades, and slow pursuit is accomplished similarly by a series of small amplitude saccades (“cogwheel” eye movements). Ophthalmoplegia in Parkinson's disease may well mimic progressive supranuclear palsy.²⁸⁵

Knox et al²⁸⁶ reviewed Whipple's disease, a rare cause of supranuclear ophthalmoplegia, dementia, and facial myoclonia, but not necessarily gastrointestinal symptoms of diarrhea. Pathological confirmation is provided by jejunal biopsy for periodic acid-Schiff-positive, foam-filled macrophages containing microorganisms.

A number of spontaneous and heredodegenerative CNS disorders characterized chiefly by ataxia tend to produce uncompensated small-angle heterotropias, with momentary diplopia, or frank ophthalmoplegia. These disorders include Friedreich's ataxia, cerebellar and spinocerebellar degenerations, familial or sporadic olivopontocerebellar atrophies, multisystem atrophy, and spastic or myoclonic ataxias.²⁸⁷

Burian and Burns²⁹⁰ examined 25 myotonic patients and catalogued the ocular changes, including macular and peripheral retinal pigment epithelial dystrophy (Table 12). Thompson et al²⁹¹ documented sluggishly reacting, miotic pupils, which also dilated poorly with mydriatics, in myotonic patients. Some patients with myotonic dystrophy have neovascular tufts on the iris that leak on fluorescein angiography and may bleed spontaneously. Short, depigmented ciliary processes have been described and may contribute to the low intraocular pressure seen in these patients.²⁹² Pryse-Phillips et al²⁹³ examined 133 members of an affected family and found a number of subjects with incomplete manifestations of the disease. Twenty-seven of the subjects lacked clinical or EMG evidence of myotonia; the most common signs in this group were upper facial weakness, brachial hyporeflexia, ocular hypotension, and lens changes.

TABLE 12. Ocular Signs of Myotonic Dystrophy

  Lids: ptosis, myotonic lag, blepharitis
  Extraocular movements: symmetric external ophthalmoplegia, pursuit decomposition (?cerebral), Bell's and convergence myotonia, intermittent horizontal tropias
  Orbicularis: weakness, myotonic closure
  Cornea: keratitis sicca (diminished tears, infrequent blink)
  Orbit: enophthalmos
  Pupils: miotic, sluggish to light and near
  Intraocular pressure: hypotonia (average 10 mmHg)
  Lens: subcapsular polychromasia, “snowballs,” posterior cortex star figure, posterior subcapsular plaques
  Retina: macular and peripheral pigmentary degeneration, diminished electroretinogram, elevated dark-adapt threshold
  Fields: usually normal; generalized constriction

Electro-oculography of horizontal saccades and smooth-pursuit eye movements studied in 26 patients with myotonic dystrophy showed a significant decrease of the maximum velocity of the visually guided saccades in 83% of the patients.²⁹⁴ Smooth-pursuit eye movements were not significantly different from age-matched controls. Visual evoked potential latencies (P100) were significantly prolonged compared with controls in 64% of the patients. The saccadic latency of the visually guided saccades was correlated with the prolonged visual evoked potential latencies, indicating that lesions in the primary visual pathways probably contribute to the oculomotor dysfunction. The isolated decrease of the maximum velocity of the saccades in combination with EMG findings favors a peripheral (dystrophic) pathophysiologic mechanism. Additionally, neuronal loss in the medullary reticular formation is also documented.²⁹⁵

Upward gaze is typically affected, with preservation of downward movement (Fig. 35). The vertical palsy is supranuclear, and doll's head maneuver or Bell's phenomenon should elevate the eyes; however, eventually all upward gaze mechanisms fail. Skew deviation may be present, accounting for vertical diplopia. Attempts at upward saccades produce variable degrees of retraction-convergence nystagmus, in bursts or sustained. Retraction of the globe is especially evoked by downward rotation of optokinetic targets (saccadic phase upward). Accommodative spasms also occur on attempted upward gaze, and these episodes of momentary myopia may presage other signs and symptoms. Ultimately, accommodative paresis ensues, and pupils become mid-dilated and show light-near dissociation³⁰² (see Fig. 35). There may be spasms or paralysis of convergence and “pseudoabducens palsy”: that is, slower movement of the abducting eye than the adducting eye during horizontal saccades can also be observed.

Pinealomas are the most common lesion producing the “Parinaud-plus” syndrome (Fig. 36). Mass lesions involving the periaqueductal gray matter may arise in the posterior third ventricle, quadrigeminal plate (tectum), supracollicular subarachnoid space, or falco-tentorium. As the aqueduct becomes obstructed, internal hydrocephalus develops, and headache and papilledema appear. In addition to neoplasms, vascular occlusions, trauma, extra-axial and intra-axial arteriovenous malformations, demyelination, giant aneurysms of the posterior fossa, infections, trauma, stereotactic surgery for pain, and hydrocephalus from various causes have all been associated with the dorsal midbrain syndrome. Paralysis of upgaze can be an early sign of malfunctioning of a shunt placed to treat hydrocephalus, and it is reversible with repair or replacement of the shunt. Also, a reversible dorsal midbrain syndrome has been observed after jejunoileal bypass for obesity.³⁰³ CNS toxoplasmosis in AIDS patients has now become an important cause of Parinaud syndrome as well.³⁰⁴ A single case of Parinaud syndrome has been described in association with Leber's hereditary optic neuropathy.³⁰⁵

Vertical supranuclear ophthalmoplegia has been associated with metabolic disorders, including certain lipid storage diseases such as Niemann-Pick type C,^306,307 which may present in adults as dementia and ataxia.³⁰⁸ The Niemann-Pick variant is characterized by sea-blue histiocytes in the bone marrow and visceromegaly. Ocular motor abnormalities include loss of voluntary vertical saccades, especially downward; loss of the fast phase of optokinetic nystagmus; defective convergence; and substitute “head-thrusting.” Pathologically, lipid storage has been demonstrated in numerous ocular tissues, but ophthalmologic changes are observed only in later life, when the optic nerves appear pale and the perimacular areas show gray discoloration.³⁰⁹ Final clinicopathologic correlation is lacking, but clinical features suggest diffuse involvement of cortical gray matter, basal ganglia, cerebellum, and upper midbrain, where corticobulbar ocular motor fibers may be preferentially involved in the subthalamic and pretectal regions.

Other forms of ophthalmoplegia are present in Wilson's disease,³¹⁰ kernicterus,³¹¹ and barbiturate overdose.³¹²

Postoperative strabismus is not peculiar to cataract surgery alone, and it is well known to occur after scleral buckling procedures, as well as after implantation of aqueous drainage devices in glaucoma.^318,319 In these cases, a restrictive strabismus results from the presence of foreign objects in Tenon's space and around the extraocular muscles.

Patients with strabismus after ocular surgery now constitute an increasing proportion of adults with diplopia. Many smaller deviations resolve spontaneously, or become comitant with time, lending themselves to prism therapy. Most cases, however, eventually require strabismus surgery and demonstrate excellent results with conventional techniques and the use of adjustable sutures.³¹⁷

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