Ординатура / Офтальмология / Английские материалы / The Neurology of Eye Movements_Leigh, Zee_2006

370 The Diagnosis of Disorders of Eye Movements

normal but vision is impaired, then the process is probably in the orbit. The ocular motor deficit may be complete if disease occurs in either the cavernous sinus or orbit, but with a more anterior location, the pupil and muscles supplied by the inferior division of the oculomotor nerve tend to be spared.639 Tumors (particularly meningioma, pituitary adenoma, and nasopharyngeal carcinoma) are common causes of combined ophthalmoparesis. Meningioma and pituitary adenoma are slow growing, but hemorrhage into a pituitary adenoma, as already discussed, produces the distinctive clinical syndrome of pituitary apoplexy. Combined ocular motor palsies may also be due to nerve infarction in the cavernous sinus.356

CAROTID-CAVERNOUS FISTULA

This abnormal communication between the carotid arterial system and the cavernous sinus is of two types: direct and dural. Direct fistulae are caused by tears in the intracavernous portion of the internal carotid artery arising from severe head trauma or from rupture of a preexisting aneurysm. These are high-flow fistulae, characterized by sudden onset of pulsatile

proptosis, bruit, and impaired vision; they lie anteriorly in the cavernous sinus and drain forward into the orbit.372 Dural fis-

tulae are due to rupture of thin-walled meningeal branches of the internal or ex-

ternal carotid arteries within the cavernous sinus; such rupture may occur spontaneously, especially in elderly, hypertensive patients, and following minor head trauma or straining. These low-flow fistulae present more subtly, with subjective bruit, mild proptosis, chemosis, conjunctival redness, and glaucoma; they lie posteriorly in the cavernous sinus and tend to drain posteriorly to the inferior petrosal sinus rather than into the superior ophthalmic vein. Sometimes they are evident on MRA.642a Occasionally, the presentation is one of painful ophthalmoplegia without chemosis or exophthalmos.7'245'336 Thrombosis of the superior ophthalmic vein may produce temporary

worsening followed by spontaneous remission.559

Diplopia is common with both direct and dural fistulae; abduction weakness is frequent and all eye movements may be affected. It is thought that while all three ocular motor nerves may be affected, a more common cause of the restricted ocular motility is hypoxic, congested extraocular muscles.367 Embolization is an effective treatment for many patients with carotid-cavernous fistula.313-347'372'420 Some dural shunts spontaneously resolve.

TOLOSA-HUNT SYNDROMEAND

PAINFUL OPHTHALMOPLEGIA

Almost any process causing ophthalmoplegia can be painful, with the possible exceptions of myasthenia gravis and chronic progressive external ophthalmoplegia.22 The physician should always be concerned about infections and tumors. However, there are patients who present with painful, combined ophthalmoplegia due to a granulomatous inflammatory process that affects the cavernous sinus, extending forward to the superior orbital fissure and orbital apex. Called the Tolosa-Hunt syndrome, this is usually a disease of middle or later life that may spontaneously remit and relapse. The presenting complaints are steady, retro-orbital pain and diplopia. The third, fourth, or sixth nerves or a combination of ocular motor nerves may be affected. Visual impairment occurs in some patients.265'631 There is some overlap with orbital pseudotumor. Sensation supplied by the ophthalmic and maxillary trigeminal divisions may be impaired. The pupil may be constricted if the sympathetic innervation is involved or dilated if parasympathetic innervation is affected. Pathologic examination has shown a lowgrade, noncaseating, granulomatous, inflammatory response in the cavernous sinus encroaching on the carotid artery and nerves of passage.87'212

Diagnosis is by imaging, which demonstrates soft-tissue infiltration in the cavernous sinus, sometimes with extension into the orbital apex, but without erosion of bone.216 The infiltrate is either hypointense on Tl-weighted images and isointense on T2-weighted images, or hyperintense on Tl-weighted and interme-

diate-weighted images.216 Angiography may show narrowing of the carotid siphon, occlusion of the superior orbital vein, and nonvisualization of the cavernous sinus.

It has been suggested that the TolosaHunt syndrome is a variant of a larger syndrome of recurrent multiple cranial neuropathies.35'283-648 There is also an association with other forms of vasculitis, such as lupus or Wegener's granulomatosis.128'427 Patients with the Tolosa-Hunt syndrome usually respond promptly to

MRIs to monitor such patients are advisable 216,350,452,626,705

The differential diagnosis of TolosaHunt syndrome includes the entities described in Table 9-9. Orbital myositis may

usually be distinguished by swelling and erythema of the eyes.80'426'581'603 The com-

bination of painful palsies of the ocular motor nerves associated with Horner's syndrome is called Raeder's paratrigeminal syndrome2'2'2- and often reflects coexistent involvement of the oculosympathetic fibers in the cavernous sinus, usually due to mass lesions. Ophthalmoplegic migraine is reported to affect each of the ocular motor nerves and sometimes is difficult to distinguish from Tolosa-Hunt syndrome.126-614

HEAD TRAUMA AND

OPHTHALMOPLEGIA

Multiple ocular motor nerve palsies occurring with trauma are usually due to severe head injury, with fractures of the orbital, sphenoid, or petrous temporal bones.

Blowout fracture of the orbit may be confused with ocular motor palsies. It is caused by a blunt impact to the globe or infraorbital rim that fractures the orbital floor.315'555'689 Prolapse of the inferior rectus muscle through the bony defect mechanically restricts upward gaze. There may also be enophthalmos, and injury to the globe may seriously disturb vision and pupillary reactions. Diagnosis is suggested by a history of painful vertical diplopia following

Diagnosis of Diplopia and Strabismus 371

trauma and is confirmed by resistance to forced duction of the eye, and by CT, which shows herniation of soft tissue through the fracture.399

NEUROPATHIES CAUSING OPHTHALMOPLEGIA

Guillain-Barre Syndrome

The oculomotor, abducens, and trochlear nerves may be involved, in varying degree, by this disorder. Manifestations range from minor changes in saccadic trajectory to complete external and internal ophthalmoplegia.173 Occasionally, the extraocular muscles are involved first;57 sometimes ptosis is the only sign.524 The eye movement abnormalities may resemble those of myasthenia gravis (seebelow). Prior infection with Campylobacter jejuni can be demonstrated in some patients with Guillain-Barre syndrome. Such patients may show raised antibodies against GM1 ganglioside, an issue that has relevance to those cases in which there is selective involvement of the eyes (see below).

Miller Fisher Syndrome

Miller Fisher syndrome comprises ophthalmoplegia (external and sometimes internal), areflexia, and ataxia of the limbs or gait.181 It is probably a variant of Guil- lain-Barre syndrome.51'456 The degree of ophthalmoparesis varies, but certain patterns might suggest involvement of the central nervous system.10'407 For example, the ophthalmoplegia may resemble a horizontal or vertical gaze palsy or internuclear ophthalmoplegia. Ptosis is often absent even in the presence of significant ophthalmoparesis. Bell's phenomenon may also be preserved even when vertical eye movements are otherwise absent. Rebound nystagmus, impairment of smooth pursuit, optokinetic nystagmus, and suppression (cancellation) of the vestibuloocular reflex point to cerebellar dysfunction.712 As with myasthenia gravis, some of these findings might be due the effects of central adaptation to peripheral weakness. Other findings, however, such as the confusion that some patients suffer, the disso-

elated involvement of the levator palpebrae superioris and superior rectus, and the MRI findings in some cases, point

to central involvement—an encephalitic component.56'525'623a'712 Fisher himself was

impressed by the symmetry of the ocular motor deficit and by ataxia unaccompanied by sensory loss, and "reluctantly interpreted" the clinical signs "as manifestations of an unusual and unique disturbance of peripheral neurons."181

Immunological evidence has clarified the relationship of Miller Fisher syndrome to Guillain-Barre syndrome and involvement of the central nervous system. First, anti-GQlb antibodies have been detected in over 90% of patients with Miller Fisher syndrome.101 Antibodies against the ganglioside GQlb have also been detected in those patients with Guillain-Barre syndrome who have involvement of their eye movements, and also in patients with the Bickerstaff's brain stem encephalitis.9 The latter is characterized by ophthalmoplegia and ataxia, but also by pyramidal and sensory tract findings and cerebrospinal fluid pleocytosis.708 Consistent with this immunopathologic hypothesis,plasmapheresis is reported to improve both Bickerstaff's encephalitis and Miller Fisher syndrome.456'706 Neuropathologic examination of two patients with Miller Fisher syndrome showed a normal central nervous system.134'490 Autopsy of a patient who had Bickerstaff's encephalitis in association with Guillain-Barre syndrome and anti-GQlb antibodies showed a normal brain stem but demyelination of the ocular motor and spinal nerves.709 Other studies have shown staining of the molecular layer of the cerebellum by anti-GQlb antibodies, which is evidence for a central origin of the ataxia—and probably some of the eye movement disorders—in Miller Fisher syndrome.333

Thus, evidence suggests that anti-GQlb antibodies play a key role in producing the disturbance of eye movements in Miller Fisher syndrome, Guillain-Barre syndrome, and Bickerstaff's encephalitis.456 As in Guillain-Barre syndrome, C.jejuni may be the responsible trigger, since anti-GQlb antibodies bind to surface epi-

topes on this organism.272 Patients presenting with unexplained ophthalmoparesis may benefit from testing for anti-GQlb antibodies.707

Recurrent Neuropathies

Causing Ophthalmoplegia

Certain patients with chronic relapsing neuropathies may have involvement of the extraocular muscles. Ocular palsies may pre-

cede the development of the neuropathy by weeks.154-184 Motor symptoms may be

slight291 and some patients appear to have "relapsing Fisher's syndrome."544'662 In the future, immunological studies are likely to clarify these entities. Rarely, recurrent ocular motor palsies may be part of a familial disorder that is characterized principally by recurrent Bell's palsy.11

OCULAR NEUROMYOTONIA

This rare disorder is characterized by episodes of diplopia that are usually precipitated by holding the eyes in eccentric gaze, often sustained adduction.171'187'455'701 In most cases, these episodes of diplopia are caused by involuntary, sometimes painful, contraction of one or more muscles innervated by one oculomotor nerve. One patient with bilateral oculomotor nerve involvement has been described,432 and another with involvement of the lateral rectus muscle.36 Most reported patients have undergone radiation therapy to the parasellar region, but idiopathic cases have also been reported.187

One reported patient showed ocular neuromyotonia in the muscles supplied by his right oculomotor nerve.187 There was no diplopia or misalignment of the visual axes in primary gaze. Following sustained left gaze, he developed horizontal diplopia and an esotropia (see VIDEO: "Ocular Neuromyotonia"), but following sustained right gaze, no diplopia or deviation occurred. Following sustained down gaze, he developed diplopia and left hypertropia, and following sustained up gaze, he developed diplopia and a right hypertropia. The metrics of his saccades indi-

cated a defect of both relaxation and maximal contraction of affected muscles.

The mechanism responsible for ocular neuromyotonia is unknown. Both ephaptic neural transmission and changes in the pattern of neuronal transmission following denervation have been suggested,187 because spontaneous activity has been observed in the ocular electromyograph of affected patients.481'519 Axonal hyperexcitability due to dysfunction of potassium channels has also been implicated by analogy with systemic neuromyotonia.171'457

The episodic nature of the diplopia often suggests myasthenia gravis, but anticholinergic medicines are ineffective. Carbamazepine, however, is often effective treatment. Other differential diagnoses are superior oblique myokymia, thyroid ophthalmopathy, cyclic oculomotor palsy, and rippling muscle disease.334 The specific relationship of the onset symptoms following sustained attempts to hold eccentric gaze points to the diagnosis, and this should be specifically looked for during the examination of patients with evanescent, unexplained diplopia.

DISORDERS OF THE NEUROMUSCULAR JUNCTION

Several diseases affecting the neuromuscular junction at either presynaptic or postsynaptic sites may cause abnormalities of eye movements. Cholinergic crisis in myasthenia and acute poisoning with organophosphate anticholinesterases (insecticides) can also cause ophthalmoparesis and ptosis as part of a picture of generalized weakness.392

Botulism

The neurotoxin of Clostridium botulinum blocks release of acetylcholine from nerve terminals. Botulism may be caused by ingested toxin in contaminated food, intestinal production of toxin in infants, wound

infection, and in subcutaneous heroin abuse.246'247'393'513'635 In any of these forms,

ferential diagnosis includes brain stem stroke, drug intoxications (see Table 10-21 in Chap. 10), Wernicke's encephalopathy, pituitary apoplexy, myasthenia gravis, and

These saccades were followed by backward drifts that gave the appearance of quivering movements similar to those encountered in myasthenia gravis (see VIDEO: "Myasthenia gravis").247 This finding might reflect a greater sensitivity of the orbital, singly innervated muscle fibers to botulinum toxin.595 These fibers are continuously active and appear to be important for holding the eye steady after a saccade has ended.502 Another patient who was studied 6 days after mild systemic botulism showed slow horizontal and vertical saccades with centripetal postsaccadic drift (Fig. 9-19) (see VIDEO: "Eye movements in botulism").606 Edrophonium (Tensilon) may produce some improvement of saccadic velocity and increased range of movement.25

Alan B. Scott introduced botulinum A toxin as therapy for strabismus.550 It is a helpful adjunct in the management of childhood strabismus403'599 and some cases of paralytic strabismus.6'359 Botulinum A toxin has also been used to reduce or abolish acquired nystagmus by injecting it either into selected extraocular muscles or

into the retrobulbar space (see Fig. 10-17 in Chap. 10).364'634 Botulinum toxin is an

effective treatment for facial spasms and blepharospasm;288 occasionally, transient diplopia may occur after such therapy.696

The Lambert-Eaton

Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome (LEMS) is due to impaired release of acetylcholine secondary to an autoimmune disorder af-

Figure 9-19. Slow saccades due to botulism (see VIDEO: "Eye movements in botulism"). Eye movements of a 39-year-old man with botulism. Measurements of his horizontal eye movements made on day 6 of his illness show slow saccades. Note also that abducting saccades are slower than adducting saccades, causing a transient convergence at the end of each horizontal gaze shift. The top two traces are position plots and the bottom two traces are corresponding velocity plots for the right eye (OD)and left eye(OS). (Courtesy Dr. John S. Stahl)

fecting voltage-gated calcium channels.219 The LEMS is usually associated with carcinoma, which may be occult. Typicalsymptoms are weakness and fatigability of the proximal limb muscles, along with autonomic dysfunction. Symptoms or signs of extraocular involvement, if present, are usually mild, although ophthalmoparesis occasionally occurs.531 Nevertheless, measurements of saccades are likely to demonstrate characteristic hypometria with closely spaced saccades.118'135 Some patients also show slow saccades. The characteristic facilitation of muscle power with repeated efforts can sometimes be observed as hypometria gives way to hypermetria during

Myasthenia Gravis

CLINICAL FEATURES OF MYASTHENIA GRAVIS

Myasthenia gravis is a disease of nicotinic acetylcholine receptors that is characterized by fatigable muscle weakness.456 It commonly affects the extraocular muscles. Half of all patients present with ocular symptoms and more than 90% eventually develop eye movement abnormalities.588 Of those patients who present with ocular symptoms, half persist with purely ocular myasthenia. Of those who generalize, most do so within 2 years of the onset of the disease. Younger patients tend to have a more benign course, though relapses may occur.45 A congenital or familial myasthenic syndrome usually has a benign course, with onset in childhood, and often involves the extraocular muscles.160 Rarely, ocular myasthenia occurs as a reversible complication of penicillamine therapy.294

Muscle fatigue is the hallmark of myasthenia gravis and may affect the lids, eye movements, or both. Lid abnormalities include progressive and often asymmetric ptosis, brought out by attempting sustained upward gaze. If there is a small, asymmetric ptosis, instruct the patient to fix upon an object with the eye showing less ptosis and observe the ptotic eye behind a cover; over the course of a minute, worsening of the ptosis may become evident. Ptosis in myasthenia may be improved by applying an ice pack over the closed eye for 2 minutes.561 Transient eyelid retraction occurs during refixations from down to straight ahead, called Cogan's eyelid twitch sign.108 This sign is not pathognomonic, however, and may occur with brain stem or oculomotor disorders.428 Attempted eyelid closure may be impaired. Ptosis is often relieved after a

short nap ("sleep test" for ocular myasthenia).462

The more common abnormalities of myasthenia are summarized in Table

9-10. Myasthenia gravis characteristically causes intermittent diplopia due to variable extraocular muscle weakness. Such weakness is often asymmetric and may mimic third, fourth, or sixth nerve palsy, gaze paresis, internuclear ophthalmoplegia, one-and-a-half syndrome (see Ocular Motor Syndromes Caused by Disease of the Pons in Chap. 10) or strabismus. The pseudo-internuclear ophthalmoplegia of myasthenia gravis is sometimes associated with depression or downshoot of the adducting eye.278 Fatigue, during sustained attempts to hold lateral or upward gaze, is manifest as centripetal drift or increasing fatigue nystagmus (Fig. 9-20A), which may be followed by rebound nystagmus.

Perhaps the earliest and most sensitive signs of extraocular involvement are abnormalities of saccades and quick phases of nystagmus. Examples are shown in Figure 9-20. Large saccades may be hypometric and small saccades may be hypermetric. For large saccades, the eye may start off rapidly but slow in midflight and creep up to the desired eye position. A characteristic quiver movement consists of an initial, small saccadic movement followed by a rapid drift backward (Fig. 9-20B). The relationship between the peak velocity and amplitude of saccades

(the main-sequence relationship) is more vari-

Table 9-10. OcularManifestations of

Myasthenia Gravis

Ptosis

Peekaboo sign: prolonged eyelid closure leading to eye opening

Lid twitch108

Gaze-evoked centripetal drift478 or nystagmus180

Diplopia: due to single or multiple extraocular muscle weaknesses, which may simulate oculomotor, trochlear,533 abducens, or combined

palsies; internuclear ophthalmoplegia;211'493 gaze palsy; one-and-a-half syndrome130'602

Saccades: hypometria of large saccades, hypermetria of small saccades, quiver

movements, and "hyperfast" SaC-

^^es110>173'471>548'549'587>593>699'702

After edrophonium: saccadic hypermetria, macrosaccadic oscillations

able than that of normal subjects.42 During prolonged optokinetic nystagmus, quick phases may become slow. Injection of edrophonium (Tensilon) often reverses extraocular muscle weakness and causes saccades to become hypermetric. Sometimes the patient is not able to hold steady fixation because of repetitive hypermetric saccades that overshoot the target in both directions—macrosaccadic oscillations (see VIDEO: "Myasthenia gravis"). The duration of saccades is decreased41 and the velocity of larger saccades may be increased.40

PATHOPHYSIOLOGYOF OCULAR MOTOR FINDINGS IN MYASTHENIA GRAVIS

Two separate factors account for the various ocular motor findings in myasthenia gravis: failure of neuromuscular transmission and central adaptive mechanisms.

Failure of Neuromuscular

Transmission

During repetitive activation of motor nerves, the amount of acetylcholine released at the nerve terminals declines to a plateau value that depends upon the firing frequency. In myasthenia, neuromuscular transmission is tenuous, since the number of functioning postsynaptic acetylcholine receptors is reduced. A small decrease in the amount of released neurotransmitter reduces the probability that an endplate potential will be generated and so predisposes to failure of neuromuscular transmission. Factors that may predispose the extraocular muscles to frequent involvement in myasthenia gravis include their higher discharge rates, chemicaldifferences in the nature of the receptors, and the lack of action potentials in the tonic fibers.284'286'290 Though failure of neuromuscular transmission affects both global and orbital extraocular muscle fibers, the more constant activity of the latter makes them more susceptible to fatigue.

The fundamental process in myasthenia gravis is an autoimmune response against the acetylcholine receptor.284'588

Thus, over 80% of patients with generalized myasthenia and about 65% with the pure ocular form have anti-acetyl- choline-receptor antibodies in their sera. It has been suggested that antibodies spe-

cifically directed against the fetal form of the acetylcholinereceptor, which may be found at synapses on extraocular but not skeletal muscles, may be an important factor that predisposes the extraocular

muscles to involvement by myasthe- nia 286,289,290 However, myasthenia also af-

fects the levator of the lids, which does not have synaptic fetal acetylcholine receptors.287 This fact and the report that a patient with antibodies directed against fetal acetylcholine receptors did not manifest ocular myasthenia (even though her baby developed transplacental, neonatal myas-

thenia) indicate the complexity of the issue.456'661

Saccades that start off at high velocities but slow in midflight and creep up to the target (Fig. 9-20B) probably reflect intrasaccadic fatigue; muscle fibers are unable to sustain the vigorous muscular contraction required for the duration of the saccadic pulse of innervation. The saccadic step of innervation then carries the eye slowly to its final position. The peak velocity of such saccades may be normal but the duration is prolonged. Early in the disease, subtle changes in the waveform of saccades, best detected in velocity traces, may be noted with a characteristic deceleration that varies from saccade to saccade. Normal subjects only show these changes for large saccades.5

Later in the disease, patients with little residual ocular motility may seem to make superfast saccades within their limited range of motion. The peak velocity of these movements is often greater than would be expected for the size of the saccade.471 Though central adaptive changes may be partly responsible (see below), this cannot be the whole explanation; adaptive increases in saccadic innervation that occur in other types of muscle palsies do not produce superfast saccades.476 A more likely explanation is that the global (predominantly fast-twitch) fibers of the agonist muscle, which are relatively inactive and rested during fixation, can start the saccade with a normal pulse of activity. So tenuous is neuromuscular transmission, however, that fatigue develops rapidly, aborting the pulse. Since the orbital (predominantly tonic) fibers may also become fatigued during the saccade, the eye stops and may even begin to drift backward. When the tonic fibers are completely fatigued, the step is absent. Then the mechanical forces of the orbit pull the eye

rapidly back toward the central position, causing a glissade. The combination of the aborted saccade and oppositely directed glissade constitutes the quiver movement (Fig. 9-20B). The presence of such rapid movements in patients with restricted ocular motility should always suggest myasthenia; such movements are absent in patients who have slow or restricted movements due to disease of the central nervous system. Occasionally, a quiver-like movement may be followed by a slow continuation of the saccade; presumably the fatigued pulse is followed, after a brief period of electrical silence, by either a renewed step from tonic fibers or another corrective saccadic pulse.

The ability to hold the eye steady after a saccade may be affected by postsaccadic fatigue. Depending upon whether the pulse or step is more affected, the resulting pulse-step mismatch causes onward or backward postsaccadic drift. Often sustained eccentric gaze will bring out nystagmus (Fig. 9-20A), with slow-phase waveforms that follow a linear or negative exponential time course. This has been called fatigue nystagmus and muscle-paretic nystagmus549 and probably occurs when the orbital fibers are fatigued. This nystagmus differs from gaze-evoked nystagmus due to cerebellar disease, which often diminishes with sustained effort. The global fibers are relatively spared, since they only discharge vigorously during saccades or quick phases. Occasionally, when nystagmus develops with sustained eccentric gaze, the amplitude (as well as the velocity) is more marked in the abducting eye. This dissociated nystagmus mimics internuclear ophthalmoplegia.602

Adaptation and the Effects of Edrophonium in Myasthenia Gravis

Not all features of myasthenic eye movements can be ascribed to neuromuscular block. As discussed in Chap. 3, the brain monitors the accuracy of saccades and makes adaptive changes of innervation to optimize ocular motor performance (see Chap. 3). When myasthenia causes paretic saccades, central adaptation is stimulated if the patient habitually views with the

paretic eye. These mechanisms can be applied to the pulse-step pattern of innervation that normally produces fast, accurate saccades. Large saccades often fall short of the target; they are hypometric. Smaller saccades, however, made around the central position, are often orthometric or even overshoot the target. Why should saccades become hypermetric in myasthenia gravis? The answer is apparent from the observation of the effects of edrophonium (Tensilon). During the edrophonium test, saccade size increases. Many saccades become too large, and occasionally an extreme degree of hypermetria produces continuous, to-and-fro saccadic movements about the target known as macrosaccadic oscillations (Fig. 9-20C) (see VIDEO: "Myasthenia gravis"). Saccade hypermetria occurs because the central nervous system has adaptively increased the size of the saccadic pulse in an attempt to overcome the myasthenic weakness. The central changes are revealed by edrophonium, which transiently removes the peripheral neuromuscular blockade, exposing the increased saccadic innervation. If the brain had been standing idly by, edrophonium would merely have caused refixations to become orthometric.

EYE MOVEMENTS AND THE DIAGNOSIS OF MYASTHENIA GRAVIS

When ocular motility is minimally affected, careful study of eye movements— preferably measurements of saccades— before and during the edrophonium (Tensilon) test or the neostigmine test may be particularly useful. Before edrophonium, an early finding is variability of saccadic trajectory and main-sequence relationships.42 Edrophonium is best given in small (0.2 mg) increments to avoid missing a positive response owing to cholinergic excess. Neostigmine (0.5 mg, given intramuscularly with atropine, 0.5 mg) is also useful, because it allows more time to make both clinical observations and quantitative measurements. We examine and record at 15to 20-minute intervals for about 45 minutes to look for a positive re-

sponse, which includes changes in saccadic accuracy and especially the production of hypermetria. Such effects are probably diagnostic of myasthenia gravis. The duration of saccades, especially larger movements, tends to shorten.40 The velocity, especially of larger saccades, tends to increase.40 In contrast, normal subjects or patients with ocular motor palsies show increased duration and slowing of saccades after edrophonium.40'41 These changes in normal subjects and in patients with nonmyasthenic strabismus illustrate the dangers in not measuring the nature of the changes produced by edrophonium. Furthermore, some nonmyasthenic ocular deviations get worse after edrophonium if one muscle is more susceptible to the effects of the drug than the others. In particular, subjective tests such as the red glass, Maddox rod, or Lancaster redgreen test must be interpreted cautiously, as they may give misleading results. Only the direct observation of a weak muscle becoming stronger after edrophonium is reliable evidence of myasthenia.125 Even then, the diagnosis depends on the full clinical picture; false-positive test results have been reported with central structural lesions, and myasthenia can coexist with intracranial lesions.150'428 If the Tensilon test is negative, the longer-acting agent neostigmine (given with atropine) may help make the diagnosis. Neostigmine has the advantage of giving the examiner more time to detect a change in ocular alignment or saccade metrics but has the disadvantage that its rate of absorption after intramuscular injection varies.

In patients with purely ocular manifestations, single-fiber EMG of the superior rectus and levator muscles may contribute to the diagnosis by showing jitter.521 Sin- gle-fiber studies of the facial muscles are useful, too, but may not differentiate mitochondrial myopathy or oculopharyngeal dystrophy from myasthenia.644

Late in the course of myasthenia gravis, all ocular motility may become restricted and the patient may be refractory to edrophonium or neostigmine testing. Imaging studies show atrophied extraocular muscles.470 If a clear history is unavailable, dif-

ferentiation from the syndrome of chronic progressive external ophthalmoplegia may be difficult.

TREATMENT OF

OCULAR MYASTHENIA

Anticholinesterase drugs such as pyridostigmine are less effective for the treatment of diplopia and ptosis than for other symptoms.169 Because of the variability of ocular deviations, prisms are not usually helpful and surgery is only considered if there is troublesome diplopia in patients who are otherwise in remission.467 Treatment with a short course of prednisone and long-term azathioprine is reported to reduce the risk and severity of generalized symptoms and to promote remission of the disease.589 Thymectomy, prompted by abnormal appearances on chest CT, is reported to provide no advantage over medical treatment for ocular symptoms.589 Simple measures such as dark glasses to reduce the discomfort of diplopia, prisms to correct for stable ocular deviations, and "lid-crutches" for ptosis are often appreciated by selected patients.588

CHRONIC PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA AND RESTRICTIVE OPHTHALMOPATHIES

Progressive limitation of ocular motility, accompanied by ptosis but usually without diplopia, occurs in many disease states (Table 9-11). Such chronic progressive external ophthalmoplegia (CPEO) usually spares the pupils but involves the orbicularis oculi. Saccades in CPEO are slow throughout their movements, unlike those in myasthenia, in which initial saccadicvelocity is often normal. Imaging of the orbit with MR may show small extraocular muscles.92

The peculiar histological features of the extraocular muscles and their unusual responses to disease have complicated attempts to identify separate disease entities (see section on Structure and Function of

Table 9-11. Differential Diagnosis of

Chronic Progressive Ophthalmoplegia

Oculopharyngeal dystrophy

Mitochondrial cytopathies: Kearns-Sayre syndrome, CPEO* (sporadic), CPEO (dominant), MELASt

Myotubular myopathy

Stephens syndrome (CPEO, ataxia, peripheral neuropathy)

Myotonic dystrophy

Bassen-Kornzweig syndrome (abetalipoproteinemia)

Refsum's disease

Endocrine ophthalmoparesis (ophthalmic Graves disease)

Congenital extraocular fibrosis or adherence syndromes

Orbital pseudotumor Myasthenia gravis

Limited ocular motility owing to brain stem disease (e.g., Mobius syndrome, spinal muscular atrophy, progressive supranuclear palsy)

*CPEO = chronic progressive external ophthalmoplegia.

i^MELAS = mitochondrial encephalopathy, lactic acidosis, and stroke.

Extraocular Muscle). Because of this difficulty in reliably discerning distinct nosologic entities, the term ophthalmoplegia plus has been used to describe CPEO accompanied by a variety of other findings.156 However, modern genetic techniques have defined distinct defects of nuclear or mitochondrial DNA in some of these disorders.346

Involvement of theExtraocular Muscles in MuscularDystrophies

DUCHENNE'S DYSTROPHY

Duchenne's and Becker's dystrophies, which are due to allelic abnormalities of genetic expression of the protein dystrophin, lead to severe weakness of the limbs and trunk but, remarkably, spare the extraocular muscles. Thus, for example, patients with advanced disease have normal-velocity