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Show Journal of Neuro- Ophthalmolagy 20( 2): 73- 84, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Ocular Motility Review for 1997- 1998: Parti Eric R. Eggenberger, DO, and David I. Kaufman, DO Each year brings new scientific knowledge that builds on itself in a geometric fashion. Ocular motility basic and clinical neu-rosciences continue to advance with this accelerating pace. The years 1997 through 1998 brought new knowledge to the motility world. This review focuses on the clinical advances within this realm, presented in supranuclear to myopathic organization. Part II of this review will appear in the September 2000 ( 20: 3) issue. Key Words: Abducens- Myasthenia gravis- Ocular motility- Oculomotor- Trochlear. SUPRANUCLEAR The supranuclear structures governing eye movements are often overlooked in clinical practice; however, several diseases specifically target these regions and many common pathophysiologies produce dysfunction of these mechanisms. Perhaps the most common supranuclear efferent pathology is skew deviation. Skew deviation is a tonic vertical misalignment of the eyes related to supranuclear inputs to the ocular motor nuclei, and it results from several common pathophysiologies, such as stroke. The fact that skew may result from peripheral vestibular lesions was emphasized by Riordan- Eva et al. ( 1) in a report detailing 18 patients who underwent vestibular nerve surgery. Among this cohort, five ( 28%) patients developed skew postoperatively, with the hypotropia ip-silateral to the surgery. Skew deviation was of small magnitude (< 6 prism diopters) and incomitant in all patients. Three patients noted diplopia; however, this resolved spontaneously within 1 day to 6 months. In contrast to the relatively infrequent occurrence of skew postoperatively, ten of 11 ( 91%) patients demonstrated significant changes in the magnitude of the subjective visual vertical deviating toward the operated side by 5 to 28 degrees. Patients with skew deviation demonstrated the largest subjective visual vertical changes, and the authors speculated that a spectrum of responses occurred after vestibular surgery, with skew as the most extreme. There are no well- documented reports of seizure-induced ocular misalignment. Nystagmus is the most Manuscript received December 24, 1999; accepted February 1, 2000. From the Center for Clinical Neuroscience and Ophthalmology, Michigan State University, East Lansing, Michigan. Address correspondence and reprint requests to Eric R. Eggenberger, DO, Michigan State University, A- 217 Clinical Center, 138 Service Road, East Lansing, MI 48824. common efferent accompaniment to seizure, and this event is rarely the sole manifestation of epilepsy. The case of a 43- year- old man with partial seizure- induced skew, manifest as right- beating nystagmus with left hypotropia, was reported by Galimberti et al. ( 2). The hy-pertropia appeared comitant vertically and horizontally, and no torsion was noted, as judged by scleral vessels. Left posterior epileptic discharges, possibly within the vestibular cortex, were present during the ictus during which the patient reported oscillopsia and diplopia. The clinical case of a 60- year- old man with a right-sided midbrain lesion was presented by Ohashi et al. ( 3). The lesion manifested as complete vertical gaze palsy, ocular tilt reaction with skew ( 10- prism diopter right hypertropia), left head tilt, and clockwise torsion OU. Magnetic resonance imaging ( MRI) of the lesion revealed a small recent hemorrhage dorsomedial to the red nucleus within the region of the interstitial nucleus of Cajal. Unilateral midbrain lesions are frequently reported to produce upgaze palsy by affecting the posterior commissure, but downgaze palsy in such lesions is rare. The direction of the ocular tilt reaction in this case corresponded to experimental interstitial of Cajal lesion data. Although the effects of vestibular dysfunction involving the semicircular canals, including nystagmus and vertigo, are relatively easy to discern, effects of otolith dysfunction are much more difficult to demonstrate. Otolith dysfunction manifests with skew, ocular tilt, and deviation of the subjective visual vertical. Although semicircular canal dysfunction is relatively easily investigated with tests of the vestibular ocular reflex ( VOR) and nystagmus recording, otolith effects are much more difficult to measure, requiring rotations or movement outside the yaw plane. Averbuch- Heller et al. ( 4) investigated the response to static and dynamic head roll in four patients with skew deviation, four patients with spasmodic torticollis, two patients with unilateral vestibular nerve section, and ten normal control patients. The protocol involved ear- to- shoulder rotation ( head rotation in roll) with search coil measurements of resultant torsional eye movements ( ocular counter roll). Sinusoidal roll gain was abnormal in three of the four patients with skew ( more evident with roll away from the side of the brainstem lesion), three of the four with torticollis, and both of the patients with the vestibular nerve section ( more evident with roll toward the lesioned ear). The fact 73 E. R. EGGENBERGER AND D. I. KAUFMAN that skew deviation produces a measurable defect in ocular counter roll is not surprising. The authors speculated that these defects endure because of the limited influence of vision on torsional eye movements. Torsional eye movement abnormalities and otolith defects will likely remain outside the routine investigation of patients with vestibular defects until a more complete understanding of such defects and easier methods of investigation are realized. Bentley et al. ( 5) investigated three patients with me-sodiencephalic lesions. In contrast to the recognized pattern of skew and nystagmus, in which a slow phase is the initiating event, these three patients demonstrated episodic nystagmus with fast- phase initiation. Slow- phase eye movements characterized cessation of the episodic nystagmus. The authors speculated that the fast- phase initiation of nystagmus indicates burst cell activation within the rostral interstitial nucleus of the medial longitudinal fasciculus ( MLF) and stands in contrast to the more common pathophysiology of vestibular asymmetry. Although postencephalitic parkinsonism ( PEP) is not often seen, it remains of neuro- ophthalmologic interest because of its association with oculogyric crisis, ocular palsies, and convergence insufficiency, as well as continued rare occurrences. Postencephalitic parkinsonism was the most common form of parkinsonism in the 1920s and 1930s, following the influenza pandemic of 1919. In the short term, ophthalmoplegia, somnolence, fever, headache, and confusion were common; the parkinsonian syndrome took its onset months or years later ( average, 27 years; median, 5 years). Postencephalitic parkinsonism shares some characteristics with the relatively more common progressive supranuclear palsy ( PSP), such as progressive extrapyramidal and behavioral and cognitive symptoms; however, the characteristic vertical supranuclear palsy of PSP had not been reported in PEP. Wennig et al. ( 6) reported six patients with PEP who exhibited delayed- onset oculomotor abnormalities: four patients had vertical supranuclear palsy, and two had eyelid apraxia. These patients originally contracted encephalitis between 1919 and 1939 and exhibited extrapyramidal symptoms 5 to 44 years later. Pathologic examination confirmed the clinical diagnosis and revealed involvement of several brainstem structures potentially related to the ocular motility disturbance, such as the nucleus centralis pontis oralis, rostral interstitial nucleus of the MLF, nucleus raphe interpositus, dorsal tegmental nucleus, interstitial nucleus of Cajal, and the nucleus of the posterior commissure. Although the disease remains primarily of historical interest, rare cases or variants of PEP will likely continue to be seen in large neuro-ophthalmologic practices. Ping- pong gaze ( PPG) is a rare ocular motor alteration characterized by spontaneously alternating conjugate horizontal eye movements in coma. Ping- pong gaze typically indicates bilateral cerebral hemisphere impairment, and previous reports inclusive of electrographic studies have documented a smooth eye movement waveform without saccadic characteristics. Johkura et al. ( 7) reported three cases of PPG, with electroculographic recordings demonstrating saccadic cogwheeling eye movements. All three patients survived in a persistent vegetative state after initial insults of trauma, status epilepticus, and cardiopulmonary arrest. One patient demonstrated a transition from smooth- appearing to saccadic PPG in association with clinical improvement. The authors suggested that saccadic PPG is a variant of classic PPG, which seemed to be associated with a higher level of coma and less extensive hemispheric damage. CRANIAL NERVE III The most common cause of acute pupil- involved oculomotor nerve palsies is aneurysmal compression. Although this syndrome most commonly results from posterior communicating artery aneurysms, a clinically indistinguishable scenario may result from basilar bifurcation aneurysms. Basilar tip aneurysms are particularly difficult to approach surgically, and endovascular procedures have begun to emerge as first- line treatment options. Raymond et al. ( 8) presented data on 30 patients with basilar bifurcation aneurysms treated with Guglielmi detachable coils. Subarachnoid hemorrhage prompted treatment in 23 of the patients, and seven technical complications occurred in this cohort, including one death during treatment and one patient with residual diplopia. The morbidity and mortality rates seen with this endovascular series following subarachnoid hemorrhage compared favorably with surgically treated series. Immediate angiography revealed complete aneurysmal obliteration in 42%, whereas 6- month angiography demonstrated 30% complete obliteration. It is clear that endovascular therapy is associated with less permanent results than surgical treatment. No rebleeding occurred in the mean follow- up period of 15.5 months. Further study will be required to understand the long- term efficacy and safety of endovascular aneurysmal procedures. Posterior communicating artery aneurysms are the most feared cause of third nerve palsies. Horiuchi et al. ( 9) reported a case of a fenestrated third nerve related to an internal carotid artery ( ICA) posterior communicating artery aneurysm. The patient presented with a partial, pupil- involved third nerve palsy and was found to have an aneurysm projecting through a fenestrated oculomotor nerve. The lateral portion of the fenestrated nerve was sacrificed, and postoperatively the patient was left with a complete third nerve palsy. The pupil remains a key component in the evaluation of third nerve palsies to assist in separation of " medical" versus " surgical" pathophysiologies. " The rule of the pupil" states that pupil involvement speaks for compressive lesions, whereas microvascular etiologies typically spare the pupil. Jacobson ( 10) studied the validity of this clinical rule in a prospective series of 26 patients with diabetes- associated oculomotor palsy using a pupil ruler. Internal ophthalmoparesis was observed in ten ( 38%) of these patients, with anisocoria less than 1 mm in most and no patient with a fully dilated, unreactive pupil or anisocoria greater than 2.5 mm. The author emphasized J Neuro- Ophthalmol, Vol. 20, No. 2, 2000 OCULAR MOTILITY REVIEW 1997- 1998 75 the characteristics of minimal anisocoria and incomplete internal ophthalmoparesis as potentially helpful signs in distinguishing microvascular pupil involvement from compressive oculomotor pupil involvement. Trobe's editorial ( 11) in connection with this study highlighted the clinical dilemma of deciding which patients to treat with contrast angiography, magnetic resonance angiography, or no imaging. He points out that age, worsening palsy over days, pain, and vascular risk factors are present with sufficient overlap between the microvascular and aneurysmal groups so as to render them insufficient in deciding a course of action. Pupil involvement remains helpful within the previously noted parameters. Management of oculomotor nerve palsies with pupillary involvement will remain on a case- by- case basis, taking into account the aforementioned factors, and with the pupil yielding an impression as to the likelihood of ischemia versus the " unlikelihood" of aneurysm ( 11). Aberrant regeneration of the third nerve is an important diagnostic sign. The most common form of oculomotor aberrant regeneration involves lid retraction in down gaze ( pseudo- Graefe sign). Although this phenomena may follow any lesion that disrupts the integrity of the outer nerve sleeve, it most commonly occurs due to compressive lesions. When aberrant regeneration occurs without an identified preceding third nerve palsy, it is referred to as primary aberrant regeneration and is most often associated with slow- growing lesions such as cavernous sinus meningioma or aneurysm. Landau ( 12) presented a case of primary aberrant regeneration of the oculomotor nerve associated with a pituitary adenoma. There was also a clinical discussion by Lepore ( 13). Pathophysiologic mechanisms, including misdirection of sprouting axons, ephaptic transmission, and central synaptic reorganization, were reviewed. Symptomatic therapy for the diplopia that accompanies oculomotor palsies is particularly challenging. Fa-had and Helveston ( 14) described a patient with congenital pupil- involved oculomotor palsy who preferred to fix with the paretic left eye. A bifocal was fashioned with the reading segment rotated 90 degrees counterclockwise to compensate for loss of accommodation and ophthalmoparesis with limited horizontal ductions OS. Consideration could be given to such novel solutions when faced with the visual rehabilitation challenges of complete third nerve palsy. The third nerve follows a well- described path from its origin within the mesencephalic nucleus through the cerebral peduncle, subarachnoid space, cavernous sinus, and orbit. Localization of lesions remains a crucial task of the neuro- ophthalmologist and is primarily aided by associated signs and symptoms. Perhaps Weber syndrome ( ipsilateral oculomotor palsy with contralateral hemiparesis) is the most common midbrain syndrome to involve the third nerve, with localization to the third nerve fascicle within the cerebral peduncle. The less common Benedikt syndrome, characterized by unilateral oculomotor palsy and contralateral tremor, localizes to the third nerve fascicle within the red nucleus and substantia nigra. Borras et al. ( 15) described a case of Benedikt syndrome after a stereotactic procedure for aspiration of third ventricular colloid cyst. The procedure was complicated by small ventromedial mesencephalic hemorrhage with immediate notation of partial pupillary involved oculomotor palsy. Contralateral tremor appeared 3 weeks postoperatively and was unresponsive to anticholinergic and levodopa treatment. This case highlights the delayed occurrence of tremor after midbrain lesions and illustrates a rare stereotactic complication. Oishi and Mocizuki ( 16) reported a case of a midbrain infarction causing ipsilateral oculomotor palsy and contralateral monocular downbeat nystagmus. The patient acutely demonstrated a complete right third nerve palsy with bilateral ptosis, impaired adduction and supraduc-tion of the left eye, and monocular downbeat nystagmus OS. Magnetic resonance imaging revealed a right midbrain and thalamic infarction. The authors speculated that a lesion involving the paramedian thalamopeduncu-lar region could produce both ipsilateral third nerve palsy with bilateral downbeat nystagmus; however, the ipsilateral third nerve palsy prohibits ipsilateral nystagmus manifestation. Microvascular, or diabetic, oculomotor neuropathy accounts for the majority of third nerve palsies encountered in general practice. Diabetic neuropathy in general was reviewed by Said ( 17). The prevalence approximates 30%, with increased risk conferred by hypertension, longer duration of diabetes, and poor glycemic control. Included in the paper was a review of diabetic third nerve palsies with reference to the existing pathologic studies documenting intracavernous localization with central fascicular- demyelinating predilection. The pathophysiology of cranial mononeuropathy may relate to watershed ischemia between anterior and posterior cerebral circulations, whereas peripheral neuropathy appears to result from a combination of ischemia and metabolic factors. Miller et al. ( 18) explored the anatomic relationship between the oculomotor nerve complex and the MLF with a 3- T MRI histopathologic strategy on cadaver specimens. The MLF could be identified as low signal intensity ( TR 1000/ TE 30) passing ventromedially between the red nuclei joining and wrapping around the oculomotor nucleus from a ventral approach. The oculomotor nucleus appeared as paired 1- mm ovoid intermediate- signal regions immediately ventral to the periaqueductal grey. These MRI characteristics are unlikely to be realized with most patients in a standard 1.5- T MRI scan. However, larger magnetic- strength MRI brings the promise of anatomic MRI resolution sufficient to assist in neuro- ophthalmology research and challenging clinical cases. The organization of the oculomotor nucleus has been well studied. The innervation of the levator palpebrae superioris was studied in the cynomolgus monkey by Vander Werf et al. ( 19). These researchers found approximately 30% labeling in the unpaired central caudal nucleus, with 2% of neurons doubly labeled from both left and right levator muscles without lateralization. Af- J Neuro- Ophthalmol, Vol. 20, No. 2, 2000 76 E. R. EGGENBERGER AND D. I. KAUFMAN ferent innervation was restricted to the ophthalmic branch of the gasserian ganglion, with the suggestion of bilateral innervation. The study demonstrated a functionally and anatomically single representation of the extraocular muscles in the oculomotor nucleus of the monkey and confirmed observations from the seminal denervation studies of Warwick ( 20). Rarely, acute thrombosis of the carotid artery produces unilateral ocular motor nerve palsies or visual loss with contralateral hemispheric signs. Balcer et al. ( 21) reported the rare case of a patient with a painful right pupil- involved third nerve palsy. Angiography, performed to eliminate aneurysmal compression, revealed high- grade stenosis of the right internal and external carotid artery with extensive intraluminal thrombus. Intravenous heparin was initiated, and endarterectomy was performed 12 hours later. Reexamination 1 hour postoperatively revealed complete resolution of the oculomotor nerve palsy, including anisocoria. The authors reviewed the microvascular supply of the oculomotor nerve, including the basilar- posterior artery branches, inferior cavernous sinus artery branches, and recurrent ophthalmic artery branches. They speculated that a low flow situation with resultant ischemia accounted for their patient's symptoms and rapid recovery. Sanchez Dalmau ( 22) discussed the evaluation and differential diagnosis of slowly progressive third nerve palsy. The case involved a 7- year- old boy with a partial third nerve palsy progressing over months. The importance of a properly performed, enhanced MRI with attention to the clinically guided anatomy was emphasized ( i. e., was the clinically relevant anatomy imaged with sufficient quality and correct interpretation?). Repeated imaging in this case revealed a small cystic lesion of the involved third nerve after its emergence from the brainstem. The differential diagnosis for slowly progressive third nerve palsies primarily focuses on space- occupying lesions, most commonly benign lesions such as meningiomas or neurinomas ( as was suspected in the presented case). Among the more unusual reported causes of oculomotor dysfunction were cases of third nerve palsy related to sphenoid sinus mucocele, Lyme disease, and chronic sensory ataxic neuropathy. Sethi et al. ( 23) reported two patients with oculomotor palsy, one with pain and pupillary sparing and the other painless pupillary- involved, related to sphenoid sinus mucocele. Both patients demonstrated improvement after surgery. The single case of a 12- year- old girl with recurrent oculomotor palsy and headache was presented by Savas et al. ( 24). Elevated serum and cerebrospinal fluid ( CSF) immunoglobulin ( IgG) levels for Borrelia were noted. An MRI scan revealed a 4- mm low- intensity mass with enhancement at the peduncular exit zone of the oculomotor nerve. Although the authors attributed their findings to chronic recurrent borreliosis, the possibility of a benign oculomotor nerve growth, such as neurilemomas, cannot be eliminated ( 22). Umehara et al. ( 22A) reported the case of a 40- year- old man initially presenting with diplopia. He subsequently developed gait ataxia and extremity numbness. Ophthalmoparesis was present OU with 2.5- and 3.5- mm light- fixed pupils. General examination demonstrated absent muscle stretch reflexes, absent position sense in all extremities, and elevated CSF protein ( 275 mg/ dL) with otherwise normal formula. Serum testing was notable for elevated IgM anti- GQlb antibody. Magnetic resonance imaging revealed nonenhancing enlargement of the oculomotor nerves bilaterally. Double filtration plasmapheresis transiently improved the ataxia and ophthalmoparesis. Miller Fisher syndrome ( MFS) is often associated with IgG anti- GQlb antibody, and the authors speculated that their patient's IgM anti- GQlb antibody may account for the ophthalmoparesis and oculomotor hypertrophy. In 1885, Edinger reported a pair of nuclei dorsal and ventral to the oculomotor nuclei with unknown function. In 1887, Westphal subsequently reported brainstem findings in a man dying from tertiary syphilis with pupillary sparing corresponding to relative sparing of a " medial and lateral" cell group that he postulated controlled pupillary constriction, thus giving rise to the Edinger- Westphal nucleus of the third nerve. Transynaptic labeling with [ 3H] proline was undertaken in the macaque monkey by Kourouyan and Horton ( 25) to study the exact location and characterize pretectal relay nuclei. The primary retinal projection to the pretectal region terminated in the ipsilateral and contralateral olivary nuclei; however, scattered patches of extraolivary pretectal label were observed with variation between sides and animals. Transsynaptic labeling revealed a 230 p, m x 610- p, m region on either side of midbrain within the periaqueductal gray just dorsolateral to the somatic portions of the oculomotor nucleus. The labeled region contain neurons that were smaller than those of neighboring somatic oculomotor subnuclei. The study serves as another example of how Horton and colleagues continue to refine our knowledge of microneuroanatomy as it relates to the visual system. Diplopia associated with oculomotor palsies is particularly challenging to treat. The multidirectional nature and muscle involvement render prisms and strabismus surgery untenable in many such patients. Ing ( 26) advocated the use of monovision as an option in select patients with binocular diplopia and presbyopia. He reported the use of monovision spectacles or contact lenses in patients with presbyopia and diplopia with chronic intractable small angle misalignment. The distance correction was typically given to the dominant eye. The author advocated the possible use of this system for ocular myasthenia, torsional diplopia, and bifocal intolerance. This option is worth considering in select patients meeting the aforementioned criteria. CRANIAL NERVE IV Trochlear nerve paresis is a common and often disabling source of diplopia. The phenomenon of the masked bilateral superior oblique palsy is well known to strabismus surgeons and consists of the appearance of an J Neuro- Ophthalmol, Vol. 20, No. 2. 2000 OCULAR MOTILITY REVIEW 1997- 1998 77 apparent contralateral superior oblique palsy after surgery for apparent unilateral superior oblique palsy. The mechanisms for this phenomenon remain to be elucidated, and theories include subtle bilateral trochlear neuropathies with manifestation of the less severe palsy postoperatively or simple overcorrection of the unilateral palsy. It has been suggested that attention to signs of potential bilateral trochlear nerve palsy could alert the surgeon to the possibility of " unmasking" the contralateral side postoperatively. These signs include a reversal of the hypertropia in any field of oblique gaze, extorsion of > 10 degrees, " V" shift > 20 diopters, chin down rather than head tilt position, bilateral fundus extorsion, a small hypertropia in primary position with a large hypertropia in ipsilateral head tilt, and a reversal of hypertropia with head tilt to the contralateral side ( 27). Ellis et al. ( 28) retrospectively studied 108 patients with a preoperative diagnosis of unilateral trochlear nerve palsy. Thirty ( 27.7%) of the patients demonstrated apparent contralateral superior oblique palsy postoperatively, and this cohort was compared with the remainder of the subjects. There was no difference in preoperative age, etiology, hyperdeviation in any position, V pattern, or extorsion between the groups. These authors concluded that surgical overcorrection could produce the clinical findings of apparent contralateral superior oblique palsy postoperatively. More aggressive skull- based surgical approaches have produced a corresponding increase in morbidity in the form of cranial neuropathies. Transection of cranial nerves was previously thought irreparable; however, more recent experimental and clinical evidence has shown the contrary. Van Overbeeke et al. ( 29) reported the case of an intraoperative transection of the trochlear nerve with subsequent repair. The patient underwent cavernous sinus meningioma resection 3 months after presenting with partial ipsilateral fourth nerve paresis. The tumor completely encased the trochlear nerve intraopera-tively, which was transected. An interposing nerve graft constructed from the sural nerve was secured to the trochlear nerve terminals using 10- 0 nylon suture and fibrin glue. Postoperatively, she noted increased vertical diplopia; however, at a 6- month follow- up examination, improved fourth nerve function was noted. Examination 3.5 years postoperatively inclusive of Hess screen was entirely normal and without misalignment. The authors point out the challenges involved in intracranial nerve repair, which carries significant challenges compared with peripheral nerve repair given the former's smaller caliber, lack of epineural layer, and minimal supporting connective tissue. The sixth and fourth nerves are prime candidates for such repairs because the single target muscle alleviates the concern for aberrant regeneration. We will likely see these and similar procedures with increasing regularity given the increasingly aggressive surgical intervention along the skull base. Although intracranial schwannomas occur in association with neurofibromatosis and a predilection for sensory nerves, occasionally these benign tumors are observed on motor nerves in isolation. Santoreneos et al. ( 30) presented a case of an isolated trochlear nerve schwannoma without neurofibromatosis and reviewed the literature on the existing 17 cases. A 35- year- old woman presented with an 8- week history of evolving left hemiparesis, bilateral bulbar paresis, and uncharacteristic emotional lability. A Tl- weighted MRI scan revealed a large uniformly enhancing mass within the prepontine and interpeduncular cistern, felt to be consistent with meningioma. Preoperatively, the extraocular movements were reportedly full, without diplopia. Intraoperatively, the fourth nerve could not be identified. The mass was histologically consistent with a schwannoma. Postoperatively, deficits included partial right sixth and left third nerve palsies with complete fourth nerve palsy. The fourth nerve palsy persisted; the other ocular motor deficits resolved by the 18- month follow- up examination. Less than 40 cases of ocular motor schwannoma have been reported. Interestingly, unlike the more common sensory nerve schwannomas, the motor- based tumors occur outside the transitional zone between glial and Schwann cells. Typically, these tumors enhance intensely, but often inhomogeneously, which may serve as a radiographic point against the possibility of meningioma. Central neurocytoma is a rare tumor of neuronal origin, primarily occurring in the supratentorial ventricular system of young adults. The case of a 18- year- old man presenting with a right trochlear palsy referable to a 2- cm mass in the rostral pons was presented by Soontornni-yomkij and Schelper ( 31). At surgery, a neurocytoma was discovered. This case is a rare example of this tumor occurring in the infratentorial region. Cephalic tetanus is a rare form of localized tetanus, characterized by facial paresis, trismus, dysphagia, or blepharospasm. The rare case of bilateral trochlear nerve palsies with downbeat nystagmus referable to cephalic tetanus was reported by Orwitz et al. ( 32). The patient, a 79- year- old man, developed facial dysesthesia, followed within weeks by dysphagia and trismus. He subsequently developed bilateral ptosis and vertical diplopia. Examination was consistent with bilateral fourth nerve paresis with a V pattern esotropia and 10 degrees relative cyclo-tropia and downbeat nystagmus. Tetanus immunoglobulin and tetanus toxoid were administered, and trismus, diplopia, and nystagmus resolved over 6 weeks, whereas ptosis resolved at 4 months. Cephalic tetanus is usually a manifestation of an infection in the pericrania] structures, although the exact source frequently eludes detection. Tetanospasmin, the neurotoxin produced by Clostridium tetani, has complex actions including inhibitory effect on presynaptic inhibitory neurons ( reached via transsynaptic transportation) as well as possible presynaptic blockade or direct nuclear effects explaining the combination of clinical findings. These effects may be present for several weeks. Tetanus remains a rare disease; however, this case illustrates the potential neuro- ophthalmic consequences. The rare case of a 54- year- old man with bilateral J Neuro- Ophihalmol, Vol. 20, No. 2, 2000 78 E. R. EGGENBERGER AND D. 1. KAUFMAN trochlear nerve palsy related to a large quadrigeminal plate arachnoid cyst was reported by Ohtsuka et al. ( 33). The patient presented with torsional diplopia and mild truncal ataxia. Arachnoid cysts occur most commonly in the middle or posterior fossa, and infratentorial arachnoid cysts have produced ophthalmoparesis. These cysts may enlarge spontaneously or via bleeding from cyst wall vessels. Treatment of the patient was not discussed. The rectus muscles pass through small fibromuscular connective tissue pulleys located just posterior to the equator in primary position. An MRI study to investigate pulley displacement in the face of superior oblique palsy was reported by Clark et al. ( 34). These investigators performed coronal MRI on 7 subjects with unilateral superior oblique palsy and on 18 normal volunteers. Magnetic resonance imaging was able to demonstrate reduced cross- sectional area and absent contractile changes with vertical gaze, consistent with superior oblique paresis in the patients. A statistically significant 1.1- mm superior displacement of the medial rectus fibromuscular pulley alone was associated with superior oblique palsy. This displacement was felt to be related to the superior rectus atrophy and of doubtful clinical significance. CRANIAL NERVE VI Brainstem tumors present a difficult surgical challenge. Fourth ventricular tumors with floor invasion, such as ependymoma, medulloblastoma, or astrocytoma, are particularly difficult to resect without additional morbidity. Although neurophysiologic monitoring is possible, the techniques are not widely available. Grabb et al. ( 35) described an electromyographic ( EMG) monitoring technique to assist surgical resections within the fourth ventricle. EMG monitoring was performed on the lateral rectus and facial muscles in 17 children with tumor compression or infiltration of the fourth ventricular floor. Increased EMG activity within these muscles was taken to indicate cranial nerve stimulation within the region of the nucleus or axons and helped guide the resection. Nine new neuropathies ( four abducens, five facial) occurred in six children postoperatively. Intraoperative lateral rectus activity did not predict postoperative abducens palsy, nor did lack of lateral rectus activity assure preserved function. Both intraoperative lateral rectus activity and intraoperative facial muscle EMG activity were associated with facial palsy; however, this activity was not an absolute predictor of postoperative palsy. Facial palsy occurred in only one case without EMG activity. Although these numbers are small, the authors felt that the technique may have provided important information to the surgeon, thus helping to avoid facial palsies. Increasingly aggressive skull- based surgical procedures in the pursuit of more complete tumor resection are associated with increased morbidity in the form of cranial neuropathy ( 29). Successful repair of transected or injured ocular motor nerves has rarely been reported. Sawamura et al. ( 36) reported the case of a 56- year- old woman presenting with palsies of cranial nerves VII, VIII, and IX/ X and truncal ataxia referable to a large petroclival meningioma. During resection, the abducens nerve was completely transected adjacent to the Dorello canal. The petrosphenoidal ligament was cut to allow opposition of the nerve segments with 10- 0 suture. At 9 months postoperatively, the patient no longer reported diplopia in any position of gaze, and normal ocular alignment was observed. The authors discussed the viability of attempted nerve transection repair with the use of fibrin glue. These techniques will likely see increasing use. Dolichoectactic arteries are well known to cause cranial neuropathy. Basilar or vertebral artery ectasia not infrequently produces ocular motor deficits. Most such cranial neuropathies are monophasic; however, Blumen-thal et al. ( 37) reported the rare case of seven recurrent abducens nerve palsies ( 2- 5 weeks in duration) attributed to dolichoectasia and lateral protrusion of the cavernous internal carotid artery. The patient was an otherwise healthy 59- year- old man who experienced these episodes over 4 years. The authors discussed the differential diagnosis of recurrent abducens nerve palsy, including demyelination, ischemia, rare skull- based tumors, and postviral or vaccine in children. Pseudotumor cerebri ( PTC) is characterized by elevated intracranial pressure and normal neuroimaging and CSF contents. Papilledema is usually, but not universally, present in PTC. Sixth nerve palsy is the only focal sign commonly observed in PTC, present in approximately 15% of patients. Krishna et al. ( 38) reported a case of a 17- year- old woman presenting with headache and abducens neuropathy OS referable to PTC without papilledema. Lumbar puncture revealed opening pressure 440 mm H20. With acetazolamide treatment, motility returned to normal at the 2- month follow- up examination. Possible mechanisms for PTC without papilledema were discussed, including lack of communication between the subarachnoid space in the intracranial vault and the orbital portion of the optic nerve or intermittent increases in intracranial pressure. This article serves to reemphasize the possibility of FTC- related symptoms in the absence of papilledema. Intracranial hypotension may result from dural tears, iatrogenic and accidental CSF shunts, or after craniotomy. Spontaneous intracranial hypotension is a rare cause of headache, and both intracranial hypotension and hypertension may produce abducens nerve palsy. The case of a 50- year- old woman with headache and abducens nerve palsy resulting from spontaneous intracranial hypotension was discussed in the case records of the Massachusetts General Hospital ( 39). Cerebrospinal fluid analysis in this case revealed 14 white blood count ( 67% lymphocytes), protein 71 mg/ dL, and glucose 62 mg/ dL. An MRI revealed smooth enhancement of the pachy-meninges without leptoemeningeal enhancement. The importance of dural versus leptomeningeal enhancement was emphasized. The dura ( composed of the vascular outer layer of periosteum and the inner lining of the subdural space) is distinct histologically and pathophysi- J Neuro- Ophthalmol, Vol. 20, No. 2, 2000 OCULAR MOTILITY REVIEW 1997- 1998 70 ologically from the leptomeninges ( arachnoid and pia mater). Several potential pathophysiologies for dural enhancement were discussed, including neoplastic ( dural metastasis), infection, inflammatory disease, or after subdural hemorrhage. In most cases, infectious meningitis presented as leptomeningeal enhancement, whereas meningeal carcinomatosis results in dural enhancement. Typically, spontaneous intracranial hypotension presents as postural headache with intracranial pressure < 60 mm H20. A search for the CSF leak should follow the suspicion of the diagnosis, with radionucleotide cisterno-gram. Treatment strategies include bedrest, acetaminophen with caffeine, or blood patch targeting the site of the leak if one is identified. Lumbar epidural saline infusion or steroids may also be effective ( 39). Mokri et al. ( 40) reported their experience with 26 cases of intracranial hypotension, termed the syndrome of orthostatic headache and diffuse pachymeningeal gadolinium enhancement. All patients had postural headache, usually pulsating in quality. Nausea was present in ten patients, and diplopia was the next most common symptom, observed in seven patients. Diplopia was related to unilateral ( five) or bilateral ( two) abducens neuropathy. Overdraining CSF shunts accounted for intracranial hypotension in six patients, and CSF leak was present in 11 cases ( one cribriform plate, one cervico-thoracic, two cervical, five thoracic, two lumbar locations). Lumbar punctures were performed in 24 patients, with CSF pressures < 40 mm H20 in 11 patients, 41- 90 mm H20 in six patients, and variable in seven patients ( ranging from atmospheric to normal). Variable, primarily lymphocytic pleocytosis > 5 cells/ mm3 was noted in 15 patients, with a maximum of 222 cells/ mm3 in a single spinal tap. The CSF was blood tinged in four patients, and variable red blood counts ( 2- 36 cells/ mm3) were present in 22 patients with grossly clear CSF. Elevations of CSF protein were noted in all but one patient and were > 70 mg/ dL in 19, > 200 mg/ dL in seven, and > 500 mg/ dL in four patients. The CSF glucose was normal in all patients except three with diabetes who demonstrated elevated CSF glucose. Magnetic resonance imaging meningeal enhancement was noted in all patients, with a linear, noninterrupted, smooth- non- nodular and thickened appearance. Subdural collections were present in 69%, bilateral in most, with 2 to 7 mm thickness. Evidence of brain and brainstem descent was present in 62%. Treatment was directed at pathophysiology, with all overshunting patients responding to corrective surgical procedures. Four of five patients undergoing epidural blood patches with identified level of CSF leak responded with improvement. Overall, 15 patients had complete clinical and MRI resolution. Biopsy was performed in ten patients, and the dura appeared grossly normal in all. Histologically, a thin zone of fibroblasts and thin- walled vessels without inflammation or hemorrhage was present on the subdural surface of the dura. These findings were felt to be consistent with decreased CSF volume and pressure without evidence of a primary meningeal process. The authors advocated addressing the primary cause if identified ( overshunting) or considering epidural blood patch, especially if the site of the CSF leak can be identified with computed tomography myelography or radioisotope cisternography. Neuromas arising from the cranial nerves are uncommon, with the exception of the acoustic and trigeminal nerves. The rare case of a 54- year- old woman presenting with headache and trigeminal and abducens nerve palsy was presented by Okada et al. ( 41). The clinical findings were related to a large heterogenous prepontine mass. Resection produced improvement in headache and facial hypesthesia; however, no mention of postoperative ocular motility was made. Notation was made of a cystic component of the tumor. The possibility of total resection with nerve graft was considered in additional comments. Eosinophilic granuloma accounts for the majority of Langerhans cell histiocytosis. The calvarium, mandible, rib, and pelvis are favored bony locations, whereas the skull base is relatively rare. The case of a 4.5- year- old boy presenting with complete abducens nerve palsy referable to clival- based eosinophilic granuloma was reported by Brisman and colleagues ( 42). The patient was treated with stereotactic radiosurgery, and resolution of signs and symptoms was observed at 1- month follow- up. A review of intracranial skull- based eosinophilic granuloma was presented. Although there are no large treatment series, biopsy confirmation followed by excision or stereotactic radiotherapy was advocated for clival eosinophilic granuloma. Congenital facial nerve palsies may be associated with other cranial neuropathies. Perhaps the best known is Mobius syndrome, composed of bifacial palsy with absent horizontal gaze. Carr et al. ( 43) reported the findings in 29 children ( five boys, 24 girls) with congenital facial neuropathy and reviewed an additional 186 cases from the literature. Among their 29 cases, all the boys had isolated facial nerve palsy without associated features. Among the 24 girls, half were isolated, whereas in the other half, abducens neuropathy was the most common associated feature. Six patients had bilateral abducens nerve palsy consistent with Mobius syndrome. Three of the six patients with Mobius syndrome had right hypoglossal palsy, one had bilateral oculomotor palsy, and one had bilateral trochlear palsy. The literature review detailed a group with 85% bilateral facial palsy and 60% male gender. The most common associated neuropathy was abducens nerve palsy ( 68%), followed by glossopharyngeal ( 28%), hypoglossal ( 26%), and oculomotor ( 20%). The report emphasized the heterogenicity of congenital facial nerve palsies and concluded that the accessory nerve was the least likely nerve to be involved, rendering it a reliable donor for reanimation. Sphenoid sinus mucoceles, inspissated mucus with an epithelial lining, are uncommon. Although headache appears to be the primary symptom, visually related symptoms, including visual loss or diplopia, are not uncommon. Muneer and Jones ( 44) reported three cases of sphenoid mucocele presenting with unilateral abducens J Neuro- Ophthalmol, Vol. 20. No. 2, 2000 80 E. R. EGGENBERGER AND D. I. KAUFMAN neuropathy. Symptoms resolved after sinus surgery in all cases. Direct compression of the abducens nerve within the cavernous sinus of superior orbital fissure was the postulated mechanism. MULTIPLE OCULAR MOTOR NERVE PALSIES Imaging is an indispensable tool for the neuro-ophthalmologist. Although orbital computed tomography provides quick and dependable resolution of orbital structures, the MRI advantages of greater soft tissue resolution, multiplanar capability, and nonionizing radiation often make it the study of choice for orbital disease. Ettl et al. ( 45) reported the imaging capabilities of MRI in demonstration of normal orbital structures in seven volunteers using a 1- T Siemens unit ( Munich, Germany). Detailed images were reported, demonstrating the arterial structures ( central retinal, posterior ciliary, lacrimal, ethmoidal supratrochlear supraorbital, and dorsal nasal arteries), veins ( superior ophthalmic, lacrimal, medial, and inferior ophthalmic veins), and branches of the ocular motor and abducens nerves, as well as the frontal nasociliary, lacrimal, and infraorbital nerves. The authors emphasized the flow void concept of moving blood and the natural high signal contrast of the orbital fat. Improving imaging time and technology will enhance the orbital resolution of MRI even further in the future. Miller Fisher syndrome, characterized by ophthalmo-paresis, ataxia, and areflexia, is thought to be a variant of Guillain- Barre syndrome. The differential diagnosis includes Wernicke encephalopathy, cerebral infarction, botulism, multiple sclerosis, myasthenia gravis, encephalitis, or neoplasm. Immunoglobulin G anti- GQlb antibody has demonstrated a strong association with the oph-thalmoparesis in MFS. Anti- GQlb shares molecular characteristics with the lipopolysaccharide of Campylobacter jejuni isolated from stools of patients with MFS. A series of four patients with MFS were reported by Ohtsuka et al. ( 46). All patients demonstrated anti- GQlb antibody and C. jejuni stool isolates. Diplopia occurred 8 to 14 days after diarrhea in this cohort. All of the three patients undergoing C. jejuni serotyping demonstrated Penner serotype 2. The authors concluded that C. jejuni enteritis, especially serotype 2, is likely related to MFS associated with anti- GQlb antibodies. A case of a 36- year- old man with neurosyphilis masquerading as MFS was presented by Stepper et al. ( 47). The patient developed ataxia, areflexia, abduction paresis OS, and right arm weakness. The CSF demonstrated 43 mononuclear cells with protein 2.4 g/ L. Treatment with IVIg was associated with slight improvement, including resolution of the diplopia; however, 15 months later, the patient reported increasing imbalance, especially in darkness, and recurrent diplopia. Examination revealed lateral and vertical gaze dysfunction, bilateral ptosis, skew deviation, near- light pupillary dissociation, and areflexia with decreased vibratory sense and positive Romberg sign. Treponema pallidum hemagglutination ( serum) and venereal disease research lab ( serum and CSF) were positive, as were frozen samples from the J Neuro- Ophthalmol, Vol. 20, No. 2, 2000 original presentation. MRI of the spine demonstrated T2- hyperintensities within the posterior columns consistent with tabes dorsalis. Intravenous penicillin produced stabilization of symptoms; however, persistent ataxia and other features were disabling. The authors emphasized red flags at presentation mitigating for an alternate diagnosis, including absence of complete ophthalmoplegia and prominent CSF pleocytosis. Neurosyphilis remains " the great imitator," and MFS remains a diagnosis of exclusion. Mucormycosis is an often fatal fungal infection, usually occurring in the setting of immunocompromised status or diabetes. The organism has a predilection for sinus, orbit, brain, and vascular involvement. Treatment may be challenging even when the diagnosis is made early. Langford and colleagues ( 48) reported their experience with a novel therapeutic approach to rhino- orbital mucormycosis. A 43- year- old woman presented with right eye and facial pain in diabetic ketoacidosis. Examination demonstrated proptosis OD with facial swelling, decreased trigeminal ( VI) sensation, and acuity 20/ 20 OD. A right subtotal maxillotomy was performed, with debridement of necrotic tissue demonstrating mucor hy-phae. The procedure was guided by frozen section analysis until clear, hyphae- free margins were obtained. Amphotericin B- soaked gauze was packed in the cavity, and reoperation 4 days later revealed no evidence of mucor. Amphotericin B was given intravenously for 6 weeks, and at the 34- month follow- up examination, no recurrence was observed, and acuity remained 20/ 20 OU without diplopia. These extraordinary results produced without exenteration will require replication before becoming standard therapy, but they hold promise for effective and well- tolerated therapy. Non- Hodgkin lymphoma may present a diagnostic challenge. Approximately 5% of these cases present with lymphomatous meningitis, often with neuro- ophthalmic consequences. Finelli and Lesser ( 49) reported the unusual presentation of a 54- year- old woman with progressive ptosis and diplopia. Examination revealed acuity 20/ 20 OU with complete bilateral ptosis and complete ophthalmoparesis except for retained intorsion OU. The right pupil was 2 mm and minimally reactive, and the left pupil was 4 mm and nonreactive. There was no disc edema, and the remainder of the neurologic examination was unremarkable. Magnetic resonance imaging and computed tomography scans of the head were normal without meningeal enhancement, although the patient had been treated with prednisone for a presumed diagnosis of myasthenia before hospital consultation. The CSF demonstrated 100 white blood count with protein 198 mg/ dL, and cytology was positive for B- cell non- Hodgkin lymphoma. Computed tomography- guided biopsy of a mediastinal mass was consistent with high-grade Burkitts- like lymphoma, and the patient died 10 weeks after diagnosis, despite intrathecal methotrexate and CHOP ( cyclophosphamide, adriamycin, vincristine, and prednisone). The authors emphasized the differential diagnosis of bilateral ptosis and ophthalmoparesis, in- OCULAR MOTILITY REVIEW 1997- 1998 81 eluding infarct, neoplasm, nutritional deficiency, MFS, cavernous sinus syndromes, meningitis, tetanus, granulomatous disease, botulism, neuromuscular junction dysfunction, and myopathy. Although the mediastinal mass, ptosis, and ophthalmoparesis could masquerade as myasthenia, the pupil involvement eliminated this consideration. Increased intracranial pressure is well known to produce nonlocalizing abducens neuropathy. Pseudotumor cerebri, a syndrome characterized by increased intracranial pressure, may be associated with abducens nerve palsies; however, on rare occasion other patterns of misalignment have been described, including oculomotor palsy or skew deviation. Friedman et al. ( 50) reported nine patients with PTC associated with misalignment other than abducens neuropathy. Findings included complete ophthalmoparesis, internuclear ophthalmoplegia, vertical gaze palsies, and ptosis. All eye movement abnormalities resolved once intracranial pressure was controlled. Cerebral venous occlusion was present in four of the patients. The authors emphasized the need for rigorous investigation of patients with PTC associated with nonabducens nerve paresis patterns of misalignment to eliminate the possibility of cerebral vein thrombosis. The report of two women with hyperemesis gravidarum presenting with confusion, imbalance, and diplopia emphasized the importance of considering the possibility of Wernicke encephalopathy. ( Wernicke's original report in 1881 concerned three patients dying with the well- known clinical triad.) Both patients presented with seizures after prolonged hyperemesis, and despite therapy within days of presentation both patients were left with residual deficits, including memory impairment or nystagmus and imbalance. The authors speculated that intravenous hyperalimentation, constituting a carbohydrate load, precipitated the acute thiamine deficiency. The report of Rees et al. ( 51) serves to remind us of the morbidity associated with delay in diagnosis of this potentially fatal condition. The diagnosis of Wernicke encephalopathy remains clinical; however, it is well known that the full triad of ophthalmoparesis, encephalopathy, and ataxia need not be present in all cases. Caine et al. ( 52) reported the results of a new set of screening criteria for Wernicke encephalopathy, determined by review of clinical histories of 28 patients with neurologic and neuropsychologic assessment as well as neuropathologic diagnosis of Wernicke encephalopathy. The criteria included two of the four features: 1) dietary deficiencies; 2) oculomotor abnormalities; 3) cerebellar dysfunction; and 4) either an altered mental state or mild memory impairment. The new criteria were then applied to a cohort of 106 alcoholic subjects obtained from necropsy samples. Using these criteria, the diagnosis of Wernicke encephalopathy, either alone or with amnesia ( Wernicke- Korsakoff syndrome), or hepatic encephalopathy improved from 22% to 85%. Wernicke encephalopathy was unrecognized only when coexistent hepatic encephalopathy was present; however, Wernicke encephalopathy neuropathology was found in a significant number of patients with hepatic encephalopathy. The study suggests that the criteria of Wernicke encephalopathy should be modified and that a lower threshold for treatment should be applied, especially in the face of alcoholic hepatic encephalopathy. In practice, thiamine should be administered to any patient presenting with any two of the'clinical criteria or with dietary deficiency. Treatment of skull- based neoplasms has expanded dramatically in the past 20 years. Treatment options have expanded and now include the more routine use of stereotactic radiosurgery. Parameters and tolerance of conventional radiation therapy differ from radiosurgery. Despite the increased use of radiosurgery, the long- term side effects are not fully understood. Leber et al. ( 53) reported the dose- response tolerance of the visual pathways and cranial nerves after radiosurgery ( gamma knife) in 50 patients with benign skull- based neoplasms. The mean follow- up was 40 months, and tumor control was achieved in 98%. Of the 210 ocular motor cranial nerves within the field of radiation, no evidence of radiation- induced deterioration was observed. These nerves received a much higher dose of radiation ( mean, 14.2 Gy) than the visual pathways. Among the 28 ocular motor nerves with a tumor- related deficit, 21% recovered " markedly or even completely." Among the 66 visual pathway sites exposed to radiosurgery, no patient receiving less than 10 Gy experienced optic neuropathy. Among patients receiving 10- 14.9 Gy, the actuarial incidence of optic neuropathy was 26.7%, and with following doses of greater than 15 Gy, the incidence was 77.8%. Previously impaired vision improved in 25.8% and was unchanged in 51.5%. The authors concluded that the visual pathways have a much higher sensitivity to radiosurgery than other cranial nerves, and doses of greater than 10 Gy are probably best avoided. The incidence of radiation- induced visual pathway destruction needs to be taken into careful consideration before recommendation of radiosurgery. Balloon occlusion tests can be included in the preoperative evaluation of patients with skull- based lesions to determine their tolerance of carotid occlusion. Two patients ( from 129 total balloon occlusion tests) suffering cavernous sinus syndromes after balloon occlusion tests were reported by Lopes et al. ( 54). Both patients developed transient dysfunction of cranial nerves II through VI after cervical ICA occlusion. The authors speculated that the involved cavernous sinus nerves were likely supplied by the meningohypophyseal trunk and the inferior cavernous sinus arteries of the ICA, emphasizing the importance of patent external- to- internal carotid artery communication in the successful completion of balloon occlusion testing. NEUROMUSCULAR JUNCTION Myasthenia gravis ( MG) remains the prototypical neuromuscular junction disease. Myasthenia gravis is of particular importance to neuro- ophthalmologists because of the high rate of ocular involvement in these patients and J Neuro- Ophthalmol, Vol. 20, No. 2, 2000 82 E. R. EGGENBERGER AND D. I. KAUFMAN the potential difficulty with the diagnosis of ocular MG. A report of 100 patients with MG was reported by Beek-man and colleagues ( 55). The diagnosis was delayed in many patients ( more than 2 years in 26%). Ocular MG was present in 14%; 29% of this subgroup had positive acetylcholine receptor antibodies compared with 94% antibody- positive rate for the generalized MG subgroup. Thymectomy was performed in 56% ( 12 with thymoma), and 51% were treated with immunosuppressive drugs. After mean follow- up of 9.6 years, remission was present in 43% ( including 15% pharmacologic remission, while 36% remained dependent on immunosuppressive therapy). Tensilon testing exhibited relatively high sensitivity ( 94%- 100% for generalized disease and 69%- 91% for ocular disease in the literature). Repetitive nerve stimulation was positive in 71% of generalized and 42% of ocular cases. Prednisone therapy was associated with a 65% side effect rate, similar to previous reports. Overall, thymectomized patients younger than 50 years of age had the best clinical outcomes. The series was comparable in most respects with the available studies in the literature. This paper serves to further our understanding of MG and contains useful guideline information for our patients ( 56- 58). The relationship between MG and the thymus is complex and incompletely understood. MG appears to be primarily an antibody- driven disease, but the full immune- related pathophysiology remains an enigma. The relationship of thymic cells to MG was studied by Yoshikawa and Lennon ( 59). These investigators tested thymus cells from 119 patients with MG, 109 of which were seropositive for acetylcholine receptor antibody. Among this cohort of 109 seropositive patients, 75% demonstrated thymus cell secretion. Thymocytes from patients treated with corticosteroids produced significantly less antibody than untreated patients. Among five immunocompetent patients with generalized MG and seronegative acetylcholine- binding antibody status, two demonstrated thymocyte antibody secretion in vitro. This finding implies thymus secretion of acetylcholine receptor antibody in 40% of " seronegative" MG patients. Antibody production from both thymus and nonthymic sources was documented in one patient. The authors concluded that the thymus is the principal, but not exclusive, source of immunocytes reacting with muscle antigens. This study furthers our knowledge of the complex relationship between the thymus and MG and opens new questions for future research. Myasthenia gravis may present with a myriad of symptoms depending on the muscles involved. The diagnosis may be quite challenging. The advent of acetylcholine receptor antibody assay was critical not only in the diagnosis but in furthering our understanding of the pathophysiology. A reprint of the classic 1976 article documenting the usefulness and prevalence of antibodies in MG was reprinted in Neurology. Commentary by Dr. Lindstrom provided a degree of background to this publication, including the usefulness of fish electric organs as acetylcholine receptor source, and snake venom as binding marker. The article's reported rate of antibody detection ( 98%) has changed only minimally in the subsequent 20 years, and the concept that ocular MG's association with lower rate of antibody formation than generalized MG patients remains true. Clearly, further work into the pathophysiology of MG will likely refine the diagnostic laboratory assays, and ideally more specific tests will come into use providing greater diagnostic yield, However, the 1976 Neurology article retains its value quite well over time. It is also noteworthy that even in the 1970s the turnaround time for publication was significant, with this landmark article received for publication in October 1975 and not appearing in print until November 1976 ( 60,61). The treatment of MG varies with disease severity, coexistent medical conditions, and the managing clinician. Massey ( 62) reviewed treatment options of MG, noting lack of standardized measure of disease severity and absence of rigorous prospective trials. Additionally, the reported 22% remission rate in untreated patients confounds reported therapeutic effects in uncontrolled series. Cholinesterase inhibitors are useful initial therapy but rarely suffice alone. An adjunctive role, often with per- meal timing is often useful. Thymectomy has received " general agreement" as a valuable treatment in patients younger than 60 years of age with generalized disease and with the suspicion of thymoma. More than 50% of thymectomized patients experience sustained improvement. Corticosteroids were the first immunosuppressive used in MG, and remain a mainstay of therapy. High- dose daily prednisone ( 60 to 80 mg) results in predictable improvement, but the side effects are well known and include the potential exacerbation within 1 to 2 weeks of steroid initiation. The low- dose prednisone option was discussed; however, the difficulty of predicting when any steroid- related exacerbation may occur and differentiating this from disease worsening was noted. It appears that this regimen is associated with fewer side effects and has been useful in our hands. Azathioprine remains the primary nonsteroid immunosuppressive agent. In 2 to 3 mg/ kg/ d dosage, improvement begins after 2 to 8 months but may not be maximal for 1 to 2 years. Monitoring of blood counts and liver function is necessary; increasing mean cell volume by 10 units from baseline values serves as a reasonable therapeutic marker. Side effects include flulike symptoms in 15% to 20%, and this marks intolerance of the medication in this population. Cyclosporin and cyclophosphamide were discussed, but potential side effects are significant. Plasmapheresis and IVIg were discussed as potential short-term ( 6- 8 weeks) options. The specific difficulties of MG and pregnancy were discussed, noting that one third of women with MG will worsen during this time. Magnesium sulfate in this population is best avoided, and pharmacologic options are limited. Cholinesterase inhibitors have been used in pregnancy; however, corticosteroids have been infrequently associated with mild fetal defects and azathioprine is potentially teratogenic. Pheresis may be used, but there is concern that this may J Neuro- Ophthalmol, Vol. 20, No. 2. 2000 OCULAR MOTILITY REVIEW 1997- 1998 83 remove critical hormones for pregnancy maintenance. The safety of IVIg has not been established in pregnancy. This article serves as a good overview of therapy, although, similar to most articles primarily pertaining to generalized MG, tends to downplay the morbidity of purely ocular MG. In neuro- ophthalmology practice, most patients with diplopia are eager for therapy, and acetylcholinesterase inhibitors generally are insufficient for this symptom. As previously discussed, only a paucity of data exist regarding IVIg use in MG. Dalakas ( 63) reviewed the collective experience of IVIg as MG therapy. The reported studies concerning IVIg for mis indication have generally been small and uncontrolled. The studies have not answered crucial questions, such as when to use IVIg, how long to maintain therapy, if the medication is useful in crisis or in place of pheresis, or if IVIg provides steroid- sparing effect. A review of available studies dating to 1986 revealed that most patients responded to IVIg ( up to 78%), and the response occurred after 3 to 10 days and persisted for a mean of 45 days ( range, 30- 120 days). Most studies used 2 g/ kg over a 5- day period ( 0.4 g/ kg/ d x 5 days). No consistent change in acetylcholine receptor antibody was uniformly noted in the studies. The mechanism of action of IVIg remains enigmatic but appears complex, with several potential actions. Idio-typic- anti- idiotypic interaction may play a key role. This refers to antibody directed against Fab segments of other antibodies. These dimer antibody complexes may have a regulatory role in the immune system, and free IVIg monomer segments may bind patient antibody to directly limit the amount of pathologic antibody in serum. IVIg also affects the complement system, decreasing the amount of C3b and C4b available to interact with acetylcholine receptor antibody. 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