Journal of Neuro-Ophthalmology, September 1998, Volume 18, Issue 3

Ocular Motility Review 1996

Journal of Ncmv- Oplulwlmology 18( 3): 211- 226, 1998. © 1998 Lippincotl Williams & Wilkins, Philadelphia Ocular Motility Review 1996 Eric R. Eggenberger, D. o., and David I. Kaufman, D. O. 1996 was an exciting year for ocular motility. Many interesting cases and advances in scientific understand­ing were reported in virtually all areas of motility. Sev­eral of these topics comprise this review. This article has been organized by location from supranuclear to myo­pathic etiologies. SUPRANUCLEAR Progressive Supranuclear Palsy ( Steele- Richardson- OIszewski Syndrome) Progressive supranuclear palsy ( PSP), also known as the Steele- Richardson- Olszewski syndrome, is a well-known cause of supranuclear, primarily vertical gaze dysfunction accompanied by extrapyramidal symptoms and cognitive dysfunction. Litvan and colleagues as­sessed the accuracy of clinical criteria for the diagnosis of PSP as proposed in four previous publications. These authors studied the validity and interrater reliability of six neurologists applying diagnostic criteria to autopsy-proven cases including 24 cases of PSP compared with 29 cases of Lewy body disease, 10 cases of cortico- basal ganglionic degeneration, 7 cases of postencephalitic par­kinsonism, 16 cases of multiple system atrophy, 7 cases of Pick's disease, and 12 cases of other parkinsonian or dementing illness. None of the criteria had both high sensitivity and high predictive value, prompting the use of a regression analysis to identify diagnostically rel­evant data. This analysis showed that vertical supra­nuclear palsy with downgaze abnormalities and postural instability with unexplained falls were the most useful features in predicting the diagnosis. A progressive dis­ease course including these features constituted the man­datory inclusion criteria, whereas mandatory exclusion criteria included a history of encephalitis, hallucinations, cerebellar signs, noniatrogenic dysautonomia, unilateral dystonia, alien hand syndrome, early cortical dementia, or focal lesions on examination or imaging. Using data Manuscript received December 1997; accepted May 1998. From the Cenler for Clinical Ncnroscience and Ophthalmology, Ocular Motility Laboratory, Michigan State University, East Lansing, Michigan, U. S. A. Address all correspondence to: Eric R. Eggenberger, D. O., Michigan State University, A- 217 Clinical Center, 138 Service Road, East Lan­sing, MI 48824. from the patient's first visit, these criteria outperformed previously published guidelines, with a mean sensitivity of 57% and positive predictive value of 85%. When ap­plied to data from the patient's last visit to clinic, the criteria showed a sensitivity of 66% and positive predic­tive value of 76% ( 1). The clinical research criteria for PSP diagnosis were also the subject of an international workshop sponsored by the National Institute of Neurological Disorders and Stroke ( NINDS) and Society for PSP, Inc. The partici­pants formulated criteria based on review of the literature and then validated the criteria using a clinical data set from autopsy- confirmed cases of PSP. Diagnostic cer­tainty was expressed as possible, probable, and definite PSP. The possible PSP category requires the presence of a gradually progressive disorder with onset at or later than age 40, either vertical supranuclear palsy or both slowing of vertical saccades and prominent postural in­stability with falls in the first year of onset, and no evi­dence of other diseases that could explain the clinical features. The probable PSP category requires vertical su­pranuclear palsy, prominent postural instability, and falls in the first year of onset, as well as other features of possible PSP ( symmetric proximal greater than distal akinesia or rigidity; abnormal neck posture, especially retrocollis; poor or absent response of parkinsonism to levodopa therapy; early dysphagia and dysarthria; or early cognitive impairment with at least two of the fol­lowing: apathy, abstract thought impairment, decreased verbal fluency, imitation behavior, or frontal release signs). Definite PSP requires a history of probable or possible PSP and histopathologic evidence typical of the disease. Diseases that may be confused clinically with PSP and distinguishing features are discussed, including cortico- basal ganglionic degeneration ( alien hand syn­drome, cortical sensory deficits, limb apraxia, and asym­metric bradykinesia), Parkinson's disease ( tremor-dominant disease and levodopa response), Lewy body dementia ( hallucinations, cortical dementia with apha­sia), multiple system atrophy ( prominent cerebellar symptoms or autonomic dysfunction), Whipple's disease ( ocular- masticatory myorhythmia and polymerase chain confirmation), and Creutzfeldt- Jakob disease ( duration less than 1 year with myoclonus and electroencephalo­gram ( EEG) abnormalities). The proposed criteria for possible PSP are highly sensitive, whereas the criteria for probable PSP are highly specific, rendering each useful for 711 212 E. R. EGGENBERGER AND D. I. KAUFMAN different analysis and studies. Although efforts at im­proving the clinical accuracy of PSP diagnosis are help­ful, an effective and objective diagnostic test would aid immeasurably in the evaluation of patients with sus­pected PSP ( 2). The cause of PSP remains unknown and few epide­miologic studies are available to investigate associations. Anecdotal reports have implicated genetic and environ­mental factors in the pathogenesis of PSP. Golbe et al. performed a questionnaire survey including 75 patients with PSP and control subjects matched with regard to hydrocarbon, pesticide, and herbicide exposure, urban or rural living, occupation, trauma, education level, mater­nal age, and family history of neurologic diseases. Pa­tients with PSP were less likely to have completed 12 years of education; this coincides with the education-related risk associated with Alzheimer's disease. The re­sults contradict an earlier study by the same group that in retrospect appears to have been related to the earlier study's ascertainment bias. The authors speculate that education level may be a proxy for the risk factors as­sociated with a more direct cause such as early- life nu­trition, or occupational or residency exposure ( 3). The role of heredity in the pathophysiology of PSP remains elusive. There have been several anecdotal re­ports of multiple family members with PSP in the litera­ture; however, several larger series have not noted this association. In one case- control questionnaire, a trend toward relatives with parkinsonism was reported. Tetrud ct al. reported the occurrence of autopsy- proven PSP in a brother- sister pair. Both developed parkinsonism in the eighth decade and subsequently exhibited typical fea­tures of PSP over the next 5 years. Their mother and possibly maternal grandfather had a parkinsonian syn­drome, whereas essential tremor was noted in their father and two of the brother's three children. The probands exhibited typical pathologic features of PSP upon au­topsy. Although the absence to date of a large kindred with PSP precludes molecular linkage studies, the au­thors suggest that pairs such as those described in their report could be pooled for analysis ( 4). The neuropsychiatric aspects of PSP as discerned by ( he Neuropsychiatric Inventory ( NPI) administered to 22 patients with PSP and patients with Alzheimer's disease and control subjects were discussed by Litvan et al. The NPI focuses on 10 behaviors: delusions, hallucinations, agitation, dysphoria, anxiety, euphoria, apathy, disinhi-bition, irritability, and abnormal motor behavior. The presence of high apathy and low agitation plus anxiety scale scores correctly identified patients with PSP 85% of the time. The presence of these subtypes of cognitive dysfunction may aid in the diagnosis of PSP ( 5). Treatment for PSP is challenging at best; only a few patients respond to dopaminergic or anticholinergic drugs, and responses are often short- lived and weak. Electroconvulsive therapy alters several neurotransmit­ters, resulting in both increased postsynaptic dopamine receptor sensitivity and enhanced tyrosine hydroxylase activity which favors dopamine effect. The effects of electroconvulsive thereapy on five patients with PSP were reported by Barclay et al. Although no permanent side effects were reported, transient side effects occurred in all patients and included confusion, dysarthria, dysph­agia, and dystonia. Two patients showed no change, but two other patients experienced mild improvement and one enjoyed dramatic improvement in motor function. The authors concluded that electroconvulsive therapy may ameliorate motor symptoms in some | atoemts with PSP;] however, long hospitalizations and significant side effects such as confusion limited its usefulness ( 6). The presence of the e4 allele of the apoprotein E gene ( ApoE) is a significant risk factor for the development of Alzheimer's disease and is overrepresented in Lewy body disease, but not in Parkinson's disease or alcoholic dementia. To discern the potential relationship between the ApoE genotype and PSP, Anouti and colleagues stud­ied 52 patients with PSP and 52 age- matched control subjects. The distribution of ApoE allele frequencies and genotype demonstrated no difference between the PSP and control groups. The authors concluded that ApoE genotype is not a risk factor for PSP; currently, the ApoE genotype is only conclusively associated with dementia of the Alzheimer's type at present ( 7). The cortical pathology of PSP was examined in 10 cases by Verny et al. The distribution and ultrastructure of neurofibrillary tangles in PSP is distinct from those found in Alzheimer's disease, with the former demon­strating more subcortical involvement with 15- nm- to 20- nm- wide single tubules compared with the latter cor-tically based paired helicoidal filaments. In this series, examination of PSP cases showed the uniform presence of tau- positive cortical lesions, found in highest concen­tration in the precentral and angular gyrus primarily af­fecting the deep cortical layers. Small and large neurons were involved in the process of tau protein deposition. These characteristics are in contrast to the neurofibrillary tangles ( NFT) pattern observed in Alzheimer's disease. Neurofibrillary tangles concentration analysis appeared to implicate the pedunculopontine nucleus in the spread of these lesions. Further advancement in our understand­ing of this and other neurodegenerative processes awaits additional investigations ( 8). Skew Deviation Skew deviation is perhaps the most common supra­nuclear motility problem encountered in practice. Alter­nating skew on lateral gaze with uncrossed bilateral hy~ pertropia was compared with oblique muscle overaction in a report by Hamed et al. These authors noted Guy ton and Weingarten's hypothesis that oblique muscle over-action and underaction and A- and V- pattern strabismus results from loss of torsional oculomotor control second­ary to loss of fusion ( 9). Seven consecutive patients with posterior fossa tumors and alternating skew deviation were examined to discern whether loss of fusion played a role in their ocular misalignment. Five of the seven patients were orthophoric and demonstrated 40 seconds of arc stereopsis; none of these five patients exhibited ocular torsion per fundus photographs. The authors con- ./ Neiiw- Ophthulnml, Vol. 18, No. .?, I9W OCULAR MOTILITY REVIEW 213 eluded that alternating skew on lateral gaze is neurologi-cally mediated, similar to the situation in adults with acquired alternating skew, and defective fusion plays no role ( 10). Although skew deviation is well known in brainstem lesions, it is infrequently reported after peripheral ves­tibular injuries. Vibert and colleagues reported a series of 13 patients who had unilateral vestibular neurectomy and labyrinthectomy, and 5 patients with sudden unilateral vestibular or cochlear- vestibular deficits with skew de­viation. Five of the patients demonstrated hypertropia contralateral to the affected ear, whereas one patient ex­hibited an ipsilateral hypertropia. Cyclodeviation with rotation of the superior portion of the eye toward the affected ear was reported and associated with ipsilateral head tilt comprising the ocular tilt reaction. Skew devia­tion resolved within a few days, whereas conjugate cy-clotorsion persisted for weeks to months. This report reemphasized the occurrence of skew deviation after acute peripheral vestibular lesions, either surgical or non­surgical in origin, and stressed the associated cyclode­viation and recovery patterns ( 11). Supranuclear Vertical Gaze The case of a 76- year- old man with a tegmental mes­encephalic infarction and absent vertical gaze was re­ported by Beversdorf et al. The patient had several brief periods of unresponsiveness during the first days of hos­pitalization; postulated to result from an ischemic mechanism involving the thalamomesencephalic reticu­lar formation ( 12). A case of Niemann- Pick type C reported by Shulman et al. ( 13) prompted a letter by Patterson and Pentchev ( 13a) that emphasized the importance of eye movements in the evaluation of suspected neurodegenerative dis­eases. Both groups of authors acknowledge that vertical supranuclear palsy is not a pathognomonic sign of Ni­emann- Pick type C; however, Patterson and Pentchev stated that they had never encountered a case of Nieman­n- Pick type C with neurologic symptoms that lacked the sign. In addition, they emphasized the importance of ex­amining saccades and pursuits movements in the evalu­ation of such patients. NUCLEAR AND INFRANUCLEAR Oculomotor Anatomy An anatomic study of the vascular supply of the ocu­lomotor nerve was published by Cahill et al. The oculo­motor nerve was divided into proximal, middle, and dis­tal ( intracavcrnous) portions. Thalamoperforating arter­ies supplied the proximal segment of the nerve in all 11 specimens, whereas supplemental blood supply to this portion was present in 6 specimens. The middle portion of the oculomotor nerve did not appear to receive nutri­ent arterioles from adjacent arteries ( i. e., posterior com­municating artery), and the vascular supply of this seg­ment presumably arises from intraneural arterioles pass­ing from the proximal and distal ends of the nerve. The distal portion of the oculomotor nerve received its blood supply from the inferior cavernous sinus artery in all specimens, whereas seven nerves also received a supple­mental supply from the tentorial artery arising from the hypophyseal trunk. This study emphasized the relatively constant pattern of blood supply to the oculomotor nerve. The middle segment of the nerve is of particular interest, because it only appears to be nourished by intraneuronal arteries arising proximally and distally to this segment. A close relationship exists between the distal ( cavernous sinus) oculomotor vascular supply and blood supply lo the pituitary gland ( 14). Oculomotor Dysfunction: Etiology A study detailing the etiology of ocular motor cranial neuropathies from a primary ophthalmology depart­ment's perspective was reported by Tiffin et al. This study included 165 cases evaluated over a 9- year period, comprising!' 28 oculomotor palsies ( 17%), 35 trochlear palsies ( 21%), and 93 abducens neuropathies ( 57%). This series was unique because it included a paucity of sinister pathophysiologies, with only one aneurysm ac­counting for an ocular motor deficit ( resulting in a sixth nerve palsy) discovered in this series of 93 cases, com­pared with a 4% to 11% rate quoted in previous series, and only one neoplasm discovered presenting as a sixth nerve palsy, compared with a 6% to 24% rate per pre­vious series. This retrospective series was generated from patients undergoing orthoptic measurements, and, accordingly, likely underestimated the number of serious and hospitalized patients. In addition, only three patients underwent magnetic resonance imaging ( MR1) scanning. This series may be of some use to the comprehensive ophthalmologist, but it is unlikely to significantly alter neuro- ophthalmologic investigation into cranial nerve palsies ( 15,16,17,18,19,20). The oculomotor nerve is occasionally injured in trauma, although typically, these patients are associated with more severe closed head injuries including loss of consciousness or skull fracture. According to autopsy findings, traumatic oculomotor nerve palsies appear to result from nerve damage lo the proximal extramedullary nerve trunk, superior orbital fissure, and exit site from the midbrain. The case of a 39- ycar- old woman with a traumatic oculomotor nerve palsy and MRI correlate of the site of injury was reported by Balcer et al. Gradient-echo T2- weighted MRI demonstrated an abnormal signal consistent with hemorrhage at the midbrain exit of the oculomotor nerve, providing a radiographic correlate for Heinze's autopsy series ( 21,22). The third nerve is frequently involved in aneurysm of the posterior communicating artery. Although the timing of ruptured aneurysm repair depends on the clinical sta­tus of the patient and remains somewhat controversial, the effect of this timing on third- nerve function was as­sessed by Leivo et al. These authors reviewed the litera­ture of cases with surgical timing details and included their own extensive experience with posterior communi­cating aneurysms. A total of 28 patients with appropriate data were studied. The results showed a more favorable outcome regarding third- nerve function for those patients operated on early than for those who were operated on ./ Ncnro- Ophlhiilmol. Vol. IX, No. .(, 1998 214 E. R. EGGENBERGER AND D. I. KAUFMAN late: 8 of 9 patients operated on within 3 days completely recovered third- nerve function, compared with only 4 of 13 patients operated on surgery after more than 6 days ( 23). Although glioblastoma multiforme is the most com­mon malignant glial tumor of adults, it is typically lo­cated in the cerebral hemispheres. Rarely, glioblastoma multiforme has been reported to occur primarily within the leptomeninges, cerebellum, brainstem, spinal cord, or optic nerves and tracts. The case of a 70- year- old woman presenting with an incomplete third- nerve palsy due to a primary glioblastoma of the oculomotor nerve was re­ported by Reifenberger et al. The initial neuroimaging showed a 12- mm extraaxial enhancing mass following the route of the third nerve's exit from the midbrain without obvious signs of penetration into the brainstem. Partial resection was performed, and, at surgery, the tu­mor appeared to infiltrate the surface of the brainstem. The tumor was presumed to have arisen from glial cells within the proximal nerve or in the adjacent meninges. The patient died 6 weeks postoperatively during radia­tion therapy due to a suspected pulmonary embolus. Pri­mary tumors of the oculomotor nerve are rare, usually due to Schwannomas, although primary eosinophilic granuloma with oculomotor nerve involvement has been reported ( 24). Ezra and Plant reported a patient presenting with par­oxysmal superior rectus and levator palpebrae spasm. This 34- year- old man developed 3- to 4- second episodes characterized by a right hypertropia and right lid retrac­tion. An MRI and cerebrospinal fluid ( CSF) were con­sistent with multiple sclerosis ( MS), including a high signal lesion in the midbrain in the region of the third-nerve fascicle. The spells resolved with carbamazepine treatment. Although other paroxysmal symptoms in MS such as Lhermitte's symptom, tonic motor spasm, and trigeminal neuralgia are well described, this appears to be the first report of a paroxysmal event in MS involving the extraocular muscles. The authors considered mecha­nisms suggested for other paroxysmal spontaneous dis­charges in peripheral nerves as possible mechanisms, such as ectopic potentials in demyelinated axons refer­able to impaired ion buffering with increased extracellu­lar potassium ( 25). Late- onset aberrant regeneration of the oculomotor nerve, manifest as impaired abduction, was reported after basilar artery aneurysm clipping. Electromyogram ( EMG) showed failure of medial rectus relaxation on attempted abduction. The authors emphasized the poten­tial relationship between basilar artery aneurysms and aberrant regeneration- associated abduction deficit ( 26). Lumbar puncture in patients with aneurysmal oculo­motor palsies often indicates evidence of subarachnoid hemorrhage. Two patients with aneurysmal oculomotor palsies showing pleocytosis ranging from 41 to 148 lym­phocytes, unaccompanied by xanthochromia, were re­ported by Keane. The author emphasized that a modest CSF lymphocytic pleocytosis does not eliminate the pos­sibility of aneurysmal origin of oculomotor palsies ( 27). Although acute bilateral oculomotor palsies are most often due to anteriorly located pathology such as sellar/ cavernous sinus region, polyneuropathy, or neuromuscu­lar junction lesions, an unusual case of bilateral third-nerve palsies due to midbrain hemorrhage was reported by Worthington and Halmagyi. The patient exhibited complete ophthalmoplegia acutely; abduction returned later. The transient horizontal abducting paresis was pos­sibly related to interruption of descending saccadic and pursuit pathways. The authors emphasized the rarity of this case in contrast to more common explanations for similar findings including pituitary apoplexy, cavernous sinus thrombosis, Fisher's syndrome, or botulism ( 28). Arroya and Horton reported a case of chronic inflam­matory demyelinating polyradiculopathy associated with a painful, pupil- involved third- nerve palsy. Although ophthalmoplegia and sensory symptoms have been well described, their patient was unique in requiring angiog­raphy to rule out an aneurysmal etiology. Other causes for a painful oculomotor palsy cannot be excluded in this patient; however, it would appear that chronic inflam­matory demyelinating polyradiculopathy in the appropri­ate clinical setting may produce this finding ( 29- 31). Systemic vasculitides are well associated with neuro-ophthalmologic symptomatology, with giant cell arteritis being the most familiar to eye physicians. A case of Churg- Strauss syndrome with neuro- ophthalmic findings reemphasizes the spectrum of potential involvement with systemic vasculitis. Churg- Strauss syndrome ( allergic granulomatous angiitis) is a systemic necrotizing vascu­litis. The disease is characterized by asthma, recurrent lung infiltrates, peripheral neuropathy, paranasal sinus abnormalities, eosinophilia, and extravascular eosino­phils. A patient presenting with monocular visual loss due to anterior ischemic optic neuropathy and branch retinal artery occlusion was described. A diagnosis of Churg- Strauss syndrome was made based on a myocar­dial biopsy performed for a dilated cardiomyopathy. The patient's course was later notable for the development of a trochlear nerve palsy and documentation of bilateral Elschnig spots. Afferent signs associated with Churg- Strauss syndrome include retinal or optic nerve ischemia. It is interesting to note that the only efferent reports in Churg- Strauss syndrome are two earlier cases of troch­lear nerve palsy ( 32). Oculomotor Palsy Treatment Corrective muscle surgery for oculomotor palsies is difficult due to the varied misalignment pattern. Maruo et al. reported their surgical results in 138 patients with oculomotor palsies, including 35 patients with follow- up of at least 4 years. These authors found equal results with superior rectus transposition in cases of complete oculo­motor palsy and medial rectus resection in cases of in­complete oculomotor palsy; recession of the lateral rec­tus greatly enhanced the effectiveness of the procedure, regardless of which method was used. Excellent results ( within 7 degrees of deviation) were achieved in 83% of incomplete oculomotor palsies but only in 61% of com­plete oculomotor palsies. No significant benefit was J Neum- Oplillialiliol. Vol. / « , No. J. 1998 OCULAR MOTILITY REVIEW 215 achieved by using combined oblique transposition and medial rectus resection ( 33). Trochlear Nerve The trochlear nerve is unique in several respects, in­cluding its crossed and long course and dorsal exit from the brainstem. A long and important segment of the trochlear nerve runs in the cerebellomesencephalic and ambient cisterns, and the nerve has important rela­tionships with the superior cerebellar artery. A detailed anatomic and neurovascular study of the cisternal seg­ment of the trochlear nerve was reported by Markinovic et al. These authors studied the trochlear nerves in 15 brainstem preparations. The trochlear nerve emerged as a single trunk ( 33%), a trunk with accessory root­lets ( 13.3%), or as 2 to 3 roots with ( 26.7%) or with­out accessory roots ( 26.7%). The nerves appeared in close relationship or in contact with the superior cerebel­lar artery. The cisternal segment of the trochlear artery was supplied by vessels from the medial superior cer­ebellar artery stem, and the longest segment of the nerve was usually nourished by a single long artery that most often arose from the vermian artery ( 26.7%) or collicular artery ( 26.7%). These vessels were also found in the oculomotor and abducens nerves. There was no anasto­mosis involving the trochlear nerve's nutrient arteries ( 34). Wong and Sharpe reported the case of a 15- year- old male with a history of recurrent fourth- nerve palsy asso­ciated with migraine headaches. These episodes occurred many times over several years and persisted for hours to days, with several attacks lasting for 3 to 4 months. Acute treatment with ergotamine and sumatriptan, as well as prophylactic therapy with propranolol, were not effective in preventing spells. Although ophthalmoplegic migraine most commonly affects the oculomotor nerve and less frequently involves the abducens nerve, the au­thors emphasized that recurrent trochlear nerve palsies may be related to migraine ( 35). Abducens Nerve The early course of ischemic abducens nerve palsies was the subject of a report by Jacobson. Thirty- five pa­tients with ischemic abducens nerve palsies were exam­ined within the first week of onset. Only 2 of the 35 patients initially presented with complete deficit of the abducens nerve, whereas 54% of the remaining 33 pa­tients demonstrated progression of their abduction defi­cit. Most of the patients progressed within the first 2 to 3 weeks after the onset of their diplopia. This report fol­lowed Jacobson's earlier report ( 36a) regarding a similar course frequently exhibited by patients with ischemic oculomotor palsies and highlights this common charac­teristic in the initial course of ischemic ocular motor nerve palsies ( 36). Progressive multifocal leukoencephalopathy, second­ary to the JC virus ( papovavirus family), is commonly related to acquired immunodeficiency syndrome ( AIDS). Although perhaps progressive multifocal leukoencepha­lopathy is better known for postchiasmal visual field de­fects, a review of 10 patients with progressive multifocal leukoencephalopathy by Ormerod et al. also emphasized the efferent aspects of the disease. Three of these patients had abducens nerve palsies, whereas the other seven had postchiasmal field defects. Of note, none of the patients with abducens nerve palsies had visual field defects. Ataxia, dementia, and long tract signs were also com­mon. The authors emphasized that progressive retrochi-astnal visual field defects or cranial nerve palsies ( espe­cially abducens nerve palsies), should alert the clinician to the possibility of progressive multifocal leukoen­cephalopathy in patients at risk for immunocompromised status ( 37). The abducens nucleus contains motoneurons with ax­ons destined for the ipsilateral lateral rectus muscle and internuclcar neurons with axons destined for the contra­lateral medial rectus subnucleus via the medial longitu­dinal fasciculus; accordingly, nuclear lesions produce gaze palsies. A patient with a small, MRI- demonstrable lesion affecting the region of the right abducens nucleus was reported by Miiri et al. In addition to gaze palsy, the patient exhibited contralateral gaze- evoked nystagmus with impairment of smooth pursuit and vestibular ocular reflex in the contralateral hemifield. The authors postu­lated that the contralateral gaze- evoked nystagmus re­sulted from damage to the nucleus propositus hypoglossi or fibers destined for the medial vestibular nucleus, both of which are involved in gaze holding ( 38). The classic article by Duane regarding the syndrome that now bears his name was reviewed in Archives of Ophthalmology and is of historical interest ( 39). Duane syndrome consists of abducens nucleus agenesis and in­nervation of the lateral rectus via branches of the oculo­motor nerves. Three patients with an apparent variant of Duane syndrome were the subject of a report by Wein-acht and colleagues. The three patients demonstrated V ™ pattern incomitance, abduction deficit, and retraction of the globe on upgaze. Electromyogram in one patient showed lateral rectus firing during vertical gaze. Al­though a sporadic teratogenic effect in the second tri­mester has been advanced as the pathophysiology of Duane syndrome, the authors raised the possibility of a genetic link, noting that two of their patients were related as uncle and niece ( 40). Multiple Cranial Nerves Dolichoectatic vessels are known to produce neuro­logic symptoms through several mechanisms, including ischemia via thrombosis or emboli, or direct compression of adjacent brainstem structures or cranial nerves ( see also oculomotor etiology section). Of the cranial nerves, the facial and trigeminal nerves are most often affected by these vessels, although ocular motor neuropathies have been reported. The third nerve is the most com­monly involved of the ocular motor nerves, but reports documenting isolated trochlear and abducens neuropa­thies associated with dolichoeetasia exist. Ohtsuka and colleagues reported the case of a 46- year- old man with a left abducens neuropathy related to vascular compres­sion. Magnetic resonance imaging using spoiled GRASS J Neuro- Opluhulmol. Vol. IS. No. J. 1' JVS 216 E. R. EGGENBERGER AND D. 1. KAUFMAN ( gradient- recalled acquisition in steady state) techniques demonstrated compression of the abducens nerve by the vertebrobasilar arteries. The patient remained unchanged at the 12- month follow- up. The authors emphasized the usefulness of the spoiled GRASS technique in demon­strating the relationship of the vessels to cranial nerve anatomy ( 41). ( See also the vestibular nystagmus section for a summary of the auditory and vestibular findings in patients with vertebrobasilar dolichoectasia by Passero and Nuti.) The clinical signs of petroclival meningiomas include various combinations of the third through eighth cranial palsies and cerebellar dysfunction, depending on the ex­act location and growth pattern of the tumor. Kawase et al. reported on the location and symptoms associated with 36 cases of petroclival meningiomas. They identi­fied four distinct categories dependent upon origin and extension: clival origin medial to the trigeminal ( upper clival type), clival origin with dumbbell extension into the cavernous sinus and lateral displacement of the tri­geminal nerve ( cavernous sinus type), tentorial origin over the trigeminal nerve ( tentorial type), and petrous apex origin lateral to the trigeminal nerve with resultant superomedial displacement of the fifth nerve ( petrous apex type). Patients with the upper clival type typically presented with isolated oculomotor palsy if suprasellar extension was present, whereas patients with the cavern­ous sinus type often presented with abducens nerve palsy related to epidural extension around Dorello's ca­nal. The dumbbell extension along the venous drainage routes from the cavernous sinus presented a significant hindrance to surgical resection. The petrous apex type was associated with hearing disturbances, whereas half the patients with the tentorial type presented with trigem­inal neuralgia. These syndromes could be distinguished clinically and radiographically ( by MRI). This informa­tion can help direct the surgical approach and outcome ( 42). Microvascular or " diabetic" cranial neuropathies are commonly encountered in neuro- ophthalmologic prac­tice, and as many as 1% of patients with diabetes will experience a cranial neuropathy over a 25- year period. Generally, these are single cranial nerve palsies, with multiple simultaneous cranial neuropathies reported less frequently. Three patients with the simultaneous occur­rence of multiple cranial neuropathies including combi­nations of oculomotor, abducens, and facial nerves with spontaneous resolution were reported by Eshbaugh et al. Although this does not alter the clinical dictum that pa­tients with diabetes are allowed one cranial neuropathy at a time, it does serve to reemphasize the rare occurrence of this entity, which remains a diagnosis of exclusion ( 43,44). Miller Fisher syndrome is characterized by ophthal-moparesis, ataxia, and areflexia. The pathophysiology of the ataxia is unknown. Serum from two cases of Miller Fisher syndrome and one ease of Guillain- Barre with ophthalmoparesis showed not only the expected anti- GQlb autoantibodies, but also demonstrated selective immunocytochemical staining of normal human cerebel­lar molecular layer tissue preparations. The authors sug­gested that this staining may be related pathophysiologi­cal^ to the observed ataxia ( 45). INTERNUCLEAR OPTHALMOPLEGIA Internuclear ophthalmoplegia ( INO) is one of the most common patterns of ocular misalignment in clinical prac­tice. Although anything that affects the medial longitu­dinal fasciculus may produce an INO, the most common association in younger patients is MS. Internuclear opthalmoplegia may be absolute ( pursuit), whereby ad­duction is incomplete, or partial ( saccadic), in which ad-ducting lag is noted without impaired adduction ampli­tude. Flipse et al. quantified the adducting and abducting saccadic peak velocities in control eyes and in a group of five patients with definite MS and INO using scleral search coils. The binocular peak acceleration ratio ( ab-ducting/ adducting eye) of the control eyes ranged from 1.10- 1.34, whereas the patients with MS exhibited ratios greater than 1.34, offering an objective means to quantify the degree of ophthalmoplegia ( 46). Thomke reported the findings of 220 patients with INO investigated with electro- oculography ( EOG). Ad­ditional investigation in 12 patients treated with patching was performed to discern the time frame of adaptation of abducting nystagmus. Zee and colleagues ( 47) demon­strated diminished intensity of nystagmus after patching the paretic eye for at least 1 day; the current study in­vestigated the immediate effects of such patching. Patch­ing the paretic eye resulted in an immediate decrease in the pulse- step mismatch, whereas patching the nonp-aretic eye produced an increase in the pulse- step mis­match, supporting the adaptation hypothesis of abducting nystagmus in INO. The author concluded that the imme­diate time frame of these changes suggested a relation­ship with a visual error signal ( 48). Two patients with bilateral INO in association with midbrain clefts were described by Lagreze et al. In ad­dition to bilateral INO, the first patient had ptosis OD, trochlear neuropathy OD, and elevator palsy OD, whereas the second patient had bilateral ptosis, limited upgaze, and right hypertropia. Magnetic resonance im­aging showed a midline cleft extending from the cerebral aqueduct into the midbrain in both patients. The authors speculated that these clefts may represent a congenital predisposition with the potential for manifest symptoms at varying ages, similar to syringomyelia ( 49). Creutzfeldt- Jakob disease ( CJD) is one of the prion disorders and is typically characterized by a rapidly pro­gressive dementia, myoclonus, and pseudoperiodic EEG changes. Although neuro- ophthalmologic concern in this disease is most often related to cerebral blindness ( Heidenhain variant), a particular subclass of CJD dis­plays prominent efferent dysfunction. Growth hormone used to treat deficient patients was previously derived from pituitary glands from cadavers; long- term follow-up has showed that some patients treated in this fashion have developed CJD, presumably related to prion con- .1 Nciiw- Ophllmlmol, Vol. 18. No. J, 1998 OCULAR MOTILITY REVIEW 2/ 7 taminalion of the growth hormone. A report of 34 pa­tients with growth hormone- derived C. ID documented the clinical picture of cerebellar ataxia, ocular motor deficits, and later dementia plus myoclonic jerks. Inter-nuclear ophthalmoplegia was observed in 68%, whereas nystagmus was present in 47% of patients; the vast ma­jority presented with ataxia and/ or visual disturbances unexplained by imaging studies. Although recombinant growth hormone became available in approximately 1988, and, accordingly, the number of potential patients at risk from growth hormone- derived CJD is shrinking, this diagnosis should be considered in patients at risk presenting with ocular dysmotility ( 50). NEUROMUSCULAR JUNCTION Myasthenia ( Iravis The epidemiology of myasthenia gravis ( MG) is not well known, although treatment of the disease has changed dramatically over the past several decades. To study the prevalence and incidence of MG. 33 studies from 1950 through 1995 were analyzed. Although preva­lence and incidence appeared to increase over lime, the regression line for prevalence significantly exceeded that of incidence. Mortality declined slightly during the time studied. The authors concluded that the increasing preva­lence of MG over the past 45 years primarily reflects the longer life span afforded by improved therapy ( 51). The extraocular muscle ( EOM) is the only mature skeletal muscle to express adult and fetal forms of the acetylcholine receptor. The adult acetylcholine receptor is composed of 2 a, and single ( 3. ft. and e- subunils, whereas the fetal isoform substitutes a 7- subunit for the 6- subunit. Approximately 80% of ROMs are innervated by a single fiber similar to other skeletal muscle ( en plaque endplate), whereas 20% are multiply innervated fibers ( en grappe endplates). Orbital and global multiply innervated fibers have en grappe endplates at their proxi­mal and distal ends, whereas orbital multiply innervated fibers also have en plaque endplates in their center. Ka-minski ct al. reported on the occurrence of fetal acetyl­choline receptors in these subgroups of EOMs. All en grappe endplates and certain en plaque endplates were the only mature forms eoexpressing the fetal and adult acetylcholine isoforms. These distinctions may bear rel­evance on antigenicity, contractile properties, and the regulation of protein expression ( 52). Thymectomy is an accepted treatment for generalized MG, although there have been no controlled trials of the procedure, but it is controversial for treatment of the purely ocular form of the disease. Ocular myasthenia often progresses to generalized myasthenia: however, predicting risk for progression at the time of ocular pre­sentation is difficult. Nakamura et al. reported their re­sults of transsternal thymectomy in 22 cases of purely ocular myasthenia. The definition of purely ocular my­asthenia included not only clinical evidence of symptoms confined to the extraocular muscles, but also HMG evi­dence of decrement only in the orbicularis oculi muscles. Remission was defined as complete freedom from symp­toms without medications for greater than 3 months. Re­mission rates increased with time from 1 1.8% at 3 years to 23.1% at 5 years, and 33.3% al 10 years. Those pa­tients undergoing thymectomy within 12 months of symptom onset showed a significantly earlier and better chance of remission compared with patients undergoing thymectomy longer than 12 months after symptom onset. The authors concluded that thymectomy for ocular MG in the earlier stages of the disease is the preferred treat­ment, just as for generalized MG. Thymectomy for ocu­lar myasthenia will likely remain controversial until fun­damental concepts regarding the disease can be eluci­dated. Key issues include whether ocular myasthenia is merely mild generalized MG in some patients and what are the risk factors for progression to generalized disease after ocular clinical presentation. A controlled treatment trial will shed light on this clinical dilemma ( 53). Several drugs are associated with worsening myas­thenic weakness, including antiarrhythmic medications and certain antibiotics. The case of a 33- year- old patient with myasthenia worsened by cocaine was reported by Daras et al. Within 24 hours of cocaine use. the patient experienced five exacerbations associated with respira­tory difficulty requiring intubation twice. Elevated cre­atine kinase levels were noted with four of these exac­erbations. The authors reviewed animal data indicating a pre- and postsynaptic inhibitory effect on the neuromus­cular junction. Cocaine dripped on isolated rat muscle preparations demonstrates creatine kinase leakage. These effects may explain the associated worsening of symp­toms in this patient and serve to emphasize the potential effect of cocaine on the compromised neuromuscular junction ( 54). The association of intestinal pseudo- obstruction with myasthenia gravis and thymoma was found in two pa­tients reported by Anderson et al. Both patients had oph-thalmoparesis and thymomas and had elevated acetyl­choline receptor titers. Duodenal biopsy in one patient showed inflammatory cell infiltrate and degenerating neurons. The gastrointestinal symptoms resolved in both patients with pyridostigmine use. The authors suggested that intestinal pseudo- obstruction may be a paraneoplas­tic condition related to thymoma ( 55). Although the peripheral effects of MG on nicotinic acetylcholine receptors is well known, little understand­ing exists regarding the potential central nicotinic recep­tor effects. Evidence for central nicotinic involvement is indirect, with reports of acetylcholine receptor antibody presence in the cerebrospinal fluid and cognitive dys­function as measured by standard memory and naming tests in patients with MG. A study of I 1 patients with MG using a standard battery of cognitive assessment tools at the start of immunotherapy and while in remis­sion was reported by Glennersler and colleagues. Al­though muscle strength improved significantly over the treatment period, testing of memory and attention did not. These results failed to identify a significant and re­versible MG- related central nervous system effect ( 56). ,/ A'curo• Ophllicilimil. Vol. IN. No. .<. IWN 218 E. R. EGGENBERGER AND D. I. KAUFMAN Lambert- Eaton Myasthenic Syndrome The Lambert- Eaton myasthenic syndrome ( LEMS) appears to be related to the presence of calcium- channel autoantibodies. Although plasmapheresis may be benefi­cial for such patients, the effects of intravenous immu­noglobulin ( IVIG) were not previously studied. The ef­fects of two consecutive- day treatments with 1 gm/ kg IVIG on strength and antibody titer were assessed in nine patients in a randomized, double- masked, placebo-controlled crossover trial. Improvement in strength and antibody titers was observed with a peak at 2 to 4 weeks posttreatmcnt and decline by 8 weeks posttreatment. The authors concluded that the short- term improvement in these patients with LEMS was due to induced reduction of calcium- channel autoantibodies and suggested that IVIG in other immune- mediated diseases may work in a similar manner ( 57). Respiratory failure is uncommon in LEMS, and treat­ment strategies that are effective in MG are typically of minimal benefit in the patient with LEMS. Smith and Wald reported a case of LEMS with respiratory failure treated with 3,4- diaminopyradine ( 3,4- DAP) and re­viewed 12 previously reported cases of LEMS-associaled respiratory failure. Prompt improvement in general strength and respiratory parameters was ob­served after 3,4- DAP institution. Clinical deterioration was noted with discontinuation of 3,4- DAP. The authors emphasized the usefulness of 3,4- DAP as a rapid method of effecting symptomatic relief ( 58). EXTRAOCULAR MUSCLE Porter and Baker's review of the unique properties of the EOMs appeared in Neurology. They began by point­ing out that the EOMs do not fit into the traditional scheme of muscle classification. In contrast to skeletal muscle, EOM normally demonstrate large fiber varia­tion, only undergo mild atrophy in the face of denerva­tion, and are only mildly affected by local anesthetic; furthermore, there are diseases that commonly spare ( amyotrophic lateral sclerosis, Duchenne muscular dys­trophy) or preferentially affect the EOM ( myasthenia, oculopharyngeal, or mitochondrial dystrophy). Although skeletal muscle is divided into slow- twitch, fatigue re­sistant ( I), fast- twitch, fatigue resistant ( IIA), fast- twitch, fatigable ( IIB), and fast- twitch, intermediate ( IIC), EOM are separated into six classes based on location within the muscle, color, and innervation pattern ( orbital singly in­nervated, orbital multiply innervated, global red singly innervated, global intermediate singly innervated, global pale singly innervated, and global multiply innervated fiber types). Although 80% of EOM exhibit the tradi­tional skeletal muscle pattern of single, midbelly synap­tic innervation leading to all- or- none twitch responses, the remaining 20% demonstrate a unique pattern with multiple neuromuscular junctions, with a segmentally graded, nonpropagating potential. Ocular muscle motor units are among the smallest in the body, with approxi­mately 10 muscle fibers per motor neuron allowing small incremental adjustments in force. Neuromuscular spindles and Golgi tendon organs are not the primary sensory receptors in EOM; the palisade endings associ­ated with the extrafusal global multiply innervated fiber type plays the predominant feedback role. This informa­tion is carried by the trigeminal nerve and appears to influence long- term calibration of the EOM. The unique expression of the acetylcholine receptor subunit T- ( em­bryonic) may contribute to EOM susceptibility to im­mune- mediated diseases such as MG. Thyroid eye dis­ease ( TED) may specifically target the EOM due to the uniqueness of the orbital fibroblasts. T- cells appear to recognize an antigen on these cells and stimulate their proliferation and the production of glycosaminoglycan via interferon gamma, interleukin 1 alpha, and tumor necrosis factor. This treatise provides an excellent com­pilation of EOM function ( 59). The existence of a pulley system in the human medial rectus muscle was reported by Demer et al. in 1995 ( 60). The structure- function correlations and microanatomy of this pulley were the subject of a report by Porter et al. Pulley structures were composed of a dense collagen matrix with alternating bands of collagen fibers arranged perpendicular to each other and were located within Ten­on' s fascia. Connective tissue and smooth muscle bundles serve to suspend the pulley from the periorbita. The authors emphasized that the existence and structure of these pulleys is important in understanding the func­tional origins and dynamics of the EOMs, and the nature of this system suggests that the vector forces of the EOM may be adjustable ( 61). Thyroid Eye Disease Devron Char published a perspective on TED summa­rizing new developments. Autoantibodies secreted by clonally restricted intrathyroidal B- cells figure in the pathophysiology, with either fibroblasts or EOM serving as the antigenic target. Fibroblasts and fibroblast produc­tion of glycosaminoglycan play a key role in TED, and these are influenced by several cytokines as well as cor­ticosteroids. Glycosaminoglycan directly increased or­bital volume; hypoxia is also among the factors that in­crease glycosaminoglycan production, and others have speculated that this link may explain the connection be­tween smoking and TED. Fewer than 5% of hyperthyroid patients will develop significant TED. Although middle-age women represent the largest subgroup of patients with TED, older men often develop more severe oph­thalmopathy. The controversy regarding treatment ef­fects on TED was discussed, noting the potential con­founding features of Tallstedt et al.' s study ( 62a) dem­onstrating an apparently greater risk of TED among patients with hyperthyroid treated with radioactive io­dine as compared with patients treated with surgery or medical suppression. It would appear that posttreatment hypothyroidism, especially if prolonged, is a risk factor for TED. Treatment issues have not dramatically ad­vanced; several articles demonstrating combination therapy's benefit compared with single- agent treatment are discussed ( prednisone plus cyclosporine versus pred- ./ Ncum- Ophllmlmol, Vol. IS. No. . i, IWH OCULAR MOl'Il. ll) REVIEW 219 nisonc alone: prednisone plus radiation versus radiation alone) ( 62). Thyroid eye disease is an immune- mediated process affecting the liOMs. Driven by the successful use of immunoglobulins in other immune- mediated diseases, pilot studies were conducted on the use of this agent in TED. Although these previous studies demonstrated a positive effect on the disease course, a third pilot slud\ reported by Seppel et al. did not show any effect on clinical ophthalmopathy, thyroid- specific autoantibodies levels, or eye muscle index ( CT- assessed) in 10 patients treated with 20 g/ day over 5 days and four further doses of 20 g administered at intervals of 4 weeks ( 6.1). NYSTAGMUS. VESTIBULAR, AND EPISODIC DISORDKRS Congenital, Latent, Optokinetic, and Early- Onset Nystagmus Brodsky reported a mother and daughter with congen­ital downbeat nystagmus, lie contrasted this rare disorder with the more familiar congenital hori/ ontal nystagmus which typical!} appears between the ages of N and 12 weeks, is associated with anterior visual pathway disor­ders in most patients ( e. g.. optic nerve hypoplasia), and persists for lite. Congenital upbeat nystagmus also ap­pears to be linked to anterior visual pathway abnormali­ties. Conversely, congenital downbeat nystagmus is typi­cally hereditary, unassocialed with a structural central nervous system lesion, and tends to resolve spontane­ously within the first few years ( 64). Congenital nystagmus pedigrees characterized by \ - linked. aulosomal- dominant. and aulosomal- reccssive in­heritance have been described, however, no genetic map­ping studies of the disorder have been published. Kerri-son et al. reported a genomic search in a large African- American kindred with congenital nystagmus inherited in an autosomal dominant fashion. The gene in this kin-tired with congenital nystagmus localized to chromo­some 6p I 2 ( 65). Ocular movements in patients with congenital nystag­mus while reading were reported by Kudo and col­leagues. Control subjects exhibit a series oi regular head movements and saccades intermixed with rest periods when leading horizontal text. While reading, the four patients with congenital nystagmus in this study had very lew rest periods; the head movements during reading did not cancel nystagmus but served to stabilize gaze. Two of the patients exhibited pendular- jcrk waveforms with quick phases lo the right, which is a favorable pattern for reading right- to- left oriented text. The authors query whether there is a relationship between nystagmus pat­terns and reading habits ( 66). The infantile strabismus syndrome includes strabis­mus, plus monocular pursuit and optokinetic nystagmus ( OKN) delects involving temporally directed stimuli, la­tent nystagmus, anil adduction preference ol the fixing eye. Kommerel detailed a hypothesis concerning the re­lationship between latent nystagmus and infantile stra­bismus, postulating that impaired cortical binocularitv occurs, either as a primary delect or secondary to stra­bismus, which prevents normal maturation of visual cor­tex to brainstem signals resulting in poor pursuit and OKN responses to monocular, temporally directed stimuli. The direction ol this pursuit and OKN bias, which is also evident as latent nystagmus, results from the inability of temporally directed stimuli to reach the ipsilateral nucleus of the optic tract and dorsal terminal nucleus of the accessory optic tract, as proposed by I lolT-man ( 67 6')). Adduction preference of the fixating eve with compensatory headturn is due to the addition ol gaze- evoked nystagmus to latent nystagmus, which serves to dampen nystagmus in adduction. . Although horizontal OKN is commonly studied, ver­tical OKN is poorly understood, in part because of the technical difficulties involved in vertical OKN recording. In a study of 20 subjects with normal vertical OKN. Oginoet al. reported the difference between up and down characteristics of vertical OKN in response to a variety of stimulation velocities. Slow- phase velocities during up­ward OKN were significantly higher than those during downward- directed stimuli for frequencies from M) de­grees/ sec to 60 degrees/ sec; vertical OKN saturated at approximately 40 degrees/ sec lo 50 degrees/ sec. The au­thors speculated that otolith input accounted for the ver­tical disparity in OKN. This difference is analogous to the disparity between supra- and infraducting eye move­ments and stands in contrast to the horizontal eye move­ment system ( 70). Acquired and Vestibular Nystagmus Benign paroxysmal positional vertigo ( BPPV). the most common cause of vertigo in most vestibular clinics, produces episodic vertigo lasting seconds precipitated bv postural change. The associated nystagmus is related to the posterior semicircular canals connections with the ipsilateral superior oblique and contralateral inferior rec­tus muscles, and produces slow phases in the plane of the posterior semicircular canal. Benign paroxysmal posi­tional vertigo results from debris in the posterior semi­circular canal and is effectively treated bv maneuvers designed to rid the canal of this debris. In a report ot 160 patients with BPPV, more than 50'/< achieved complete recovery after a single Semonl maneuver, anil after a maximum of live such procedures, almost all patients were asymptomatic ( 71). Similar results have been re­ported using the Epley procedure ( 72). After repositioning treatments for BPPV. patients are commonly instructed to remain upright lor 2 days and then avoid sleeping on the affected side for an additional 5 days. This posttreatment instruction is often the most difficult part oi the therapy for patients. Massoud and Ireland studied 96 patients with BPPV treated with re­positioning maneuvers cither with or without posttreat­ment instructions and found similar results in all groups. The authors concluded that posttreatment instructions are not necessary in the treatment of BPPV ( 7.3). Vestibular neuritis is the second most common cause of vertigo in vestibular clinics. The cause is presumed to be a viral infection, better and Dichgans studied 16 pa- / V, .•('.' I>:: il! ll,:! nu'l. \ ,' l IS. .\, i ; I'l'/. S 220 E. R. EGG EN BERG ER AND D. 1. KAUFMAN tienls within 10 days of the onset of vestibular neuritis using search coils to discern the pattern of spontaneous nystagmus and the results of rotation in the plane of the three semicircular canals. Spontaneous nystagmus and asymmetries of the vestibular ocular reflex ( VOR) im­plicated the anterior and horizontal semicircular canals in these patients. The authors concluded that vestibular neu­ritis is a partial unilateral vestibular lesion primarily af­fecting the superior division of the vestibular nerve; the findings would be consistent with cither infectious or ischemic pathophysiologies ( 74). Although the vast majority of BPPV affects the pos­terior semicircular canal, horizontal and anterior canal variants have been described. A burst of horizontally directed nystagmus is exhibited in patients with horizon­tal canal BPPV and precipitated by head turning from the supine to lateral positions with slow phases directed away from the undermost ear. Horizontal BPPV nystag­mus shows no clear latency and does not appear to fa­tigue compared with the more common posterior canal BPPV. Lempert and Tiel- Wilck reported a modified po­sitional maneuver to treat horizontal canal BPPV con­sisting of three 90- degree turns toward the unaffected ear; this technique successfully eliminated symptoms in three patients in this report ( 75). The VOR allows stabilization of the retina during an­gular head movements. Suppression of the VOR is used to maintain retinal stability when head and target are moving simultaneously. Smooth pursuit and VOR sup­pression are thought to be directionally and perhaps functionally related, both largely acting as ipsilateral sys­tems. Lesions involving the cerebellum or connections generally produce saccadic ipsilateral pursuit and im­paired ipsilateral VOR suppression. A case of a patient with agenesis of the left hemicercbellum who exhibited ipsiversive defects of smooth pursuit, but VOR suppres­sion abnormalities for contralateral rotation, has been reported. The authors hypothesized that this case indi­cated a separation of the smooth pursuit and VOR sup­pression pathways ( 76). Vestibular nystagmus is often studied with sophisti­cated electronystagmography equipment. Before the ad­vent of this equipment, Frenzel lens were routinely used. These high plus lenses block fixation- thus allowing clear visualization of peripheral vestibular nystagmus- and also magnify the clinician's view. Frenzel lenses were studied in addition to cleclronystagmograms to de­termine their current usefulness. Compared with electro-nystagmogram recordings with the eyes closed, Frenzel lenses did not show any significant difference when re­cording spontaneous nystagmus or with Hallpike testing. Frenzel lenses remain a useful tool for any clinician in­volved in the evaluation of nystagmus or vertigo and have the additional benefits of portabilty and ease of use ( 77). A patient with oscillopsia related to bilateral vestibular dysfunction in association with chronic inflammatory cle-myelinaling polyneuropathy ( CIDP) and an immuno­globulin M kappa monoclonal gammopathy was reported ,/ Nciirii- Ophlhciliiiol. Vol. IS. No. .1. IVVN by Frohman el al. The patient also had foot numbness, limb weakness, and gait and postural instability. The vestibular loss fluctuated over a 6- year period in striking association with the patient's CIDP severity. Magnetic resonance imaging demonstrated enhancement of the VI-I- VIII nerve complex bilaterally. Prednisone, IVIG, plasmapheresis, and azathioprine successfully managed symptom relapses over time. This report describes the closely linked nature of ( he vestibular dysfunction and CIDP symptoms as documented by sophisticated vestib­ular testing and bedside examination. The dynamic vi­sual acuity, or Snellen acuity during head movement, is an easy and reliable test to quantify the effects of bilat­eral vestibular dysfunction ( 78). Fabry's disease, or angiokeratoma corporis diffusum, is a rare, sex- linked disorder related to a- galaclosidase deficiency leading to accumulation of lysosomal gly-cosphingolipids, primarily in vascular endothelium, but also in cardiovascular, renal, corneal, and perineural tis­sues. The primary complication and cause of death re­lates to tissue ischemia and infarction. A report of two cases and review of the literature ( 43 hemizygotes and 10 heterozygotes) regarding cerebrovascular complication of Fabry's disease was reported by Mitsias and Levine. The average age at onset of cerebrovascular symptoms was 33.8 years for hemizygotes and 40.3 years for het­erozygous individuals. The vertebrobasilar system was implicated in 67% of hemizygotes and 60% of heterozy­gotes. Hemiparesis was the most frequent symptom ( 63% and 40%) for hemi- and heterozygotes respec­tively), whereas vertigo or dizziness ( 39% and 50%, re­spectively), diplopia ( 37% and 0%, respectively), and nystagmus ( 26%' and 0%>, respectively) were also com­mon. Although no specific therapy exists, antiplatelet agents are often prescribed. The authors noted the fre­quency of vertebrobasilar involvement, dilative aden­opathy, and frequent recurrence of cerebrovascular events in this population ( 79). The rostral interstitial nucleus of the medial longitu­dinal fasciculus ( riMLF) and the interstitial nucleus of Cajal are critical in the generation and gaze holding of vertical and torsional eye movements. Lesions of the riMLF or interstitial nucleus of Cajal are associated with a contralesional ocular tilt reaction, whereas interstitial nucleus of Cajal lesions produce torsional nystagmus with contralesional slow phases. A patient with a right midbrain lesion presumed to be due to infarction exhib­ited upgaze palsy, torsional nystagmus with ipsilesional slow phases, and a tonic ocular lilt reaction to the con­tralesional side. The authors suggested that the unique direction of the torsional nystagmus was the result of a lesion involving the riMLF ( 80). Agcotropic nystagmus, in which the slow phases are directed toward the ground with either ear downward in the lateral position, is considered a nonlocalizing sign of a vestibulopathy. Although central causes are perhaps most common, agcotropic nystagmus has been reported with peripheral vestibulopathies. Proton- weighted MRI was used to investigate basilar flow characteristics in a OCULAR MOTILITY REVIEW 221 group of patients with ageolropie nystagmus, and results were compared with a group witli geotropic nystagmus and an age- matched control group. The patients with ageolropie nystagmus were more likely to have slow basilar flow and brainstem lacunar infarcts than the other two groups. The authors believe that these data suggest the possibility of a link between vertebrobasilar ischemic disease and ageotropic nystagmus in some patients ( SI). The auditory and vestibular findings in patients with vertebrobasilar dolichoectasia was also investigated by Passero and Nuli. Auditory and vestibular testing was performed on 2} symptomatic patients with verte­brobasilar dolichoectasia as documented by MRI, com­puted tomography, or angiography with elongation de­fined as lateral extension of the basilar artery beyond the margin of the clivus or dorsum scllae or bifurcation of the basilar artery above the plane of the suprasellar cis­tern, whereas ectasia was defined as basilar diameter greater than 4.5 mm. Evidence of auditory or vestibular impairment was observed in 83% of patients; peripheral impairment was noted in 47'/ r. whereas I6'< had find­ings consistent with central dysfunction anil 37% had evidence of both central and peripheral disease. Al­though direct compression is an important mechanism of brainstem dysfunction in this population, these authors emphasi/ ed the potential role for ischemia in the patho­physiology of the patient's symptoms, especially in those patients in whom a cerebellar lesion was implicated ( 82). | See also the section on multiple cranial neuropathies for the article by Ohtsuka el al. regarding compressive cra­nial neuropathies related to ectatic arteries.| The clinical findings in I I patients with medial med­ullary infarctions were reported by Toyoda el al. Al­though limb weakness was the major symptom in all patients, the next most frequent sign was ga/ e- evoked nystagmus ( six patients). In seven patients, the distal vertebral artery was occluded, producing anleromedial infarcts ( 83). The eye movements of syncope were studied in 25 healthy volunteers. Syncope was induced in 14 of these volunteers by hyperventilation and the Valsalva maneu­ver on a lilt table. Six patients exhibited downbeat nvs-tagmus at syncope's onset that evolved into upward eye deviation, whereas seven subjects showed tonic upward deviation, and one volunteer's eyes remained in primary position. The nystagmus began several seconds after syn­cope onset and persisted for I to 5 seconds. The gain of the VOR increased by an average of 65' 7< ( to values greater than 1.0) dining syncope in three patients induc­ing syncope during vestibular stimulation. The authors speculated that the findings were consistent with vestib­ular disinhibition secondarv to cerebellar hypoperfusion ( 84). The ability to suppress Ihe vestibular ocular reflex is important during head movement while foveating a mov­ing target. Vestibular ocular reflex suppression abnor­malities are observed in a variety of disease stales, in­cluding 75% of clinically definite patients with IV1S. making an understanding of this abnormality important. Impaired VOR suppression results in oscillopsia when the head moves, which can be disabling. The cerebellum and connections appear to he important in VOR suppres­sion, and the flocculo- nodular lobes are especially in­volved. 1 larder and Reker explored the effects of alcohol on VOR suppression. Al blood alcohol concentrations of 20 mg/ 100 ml. significant deterioration in VOR suppres­sion was observed, and this effect increased constantly with greater blood alcohol concentrations. The authors concluded that alcohol has a deleterious effect on VOR suppression, and vestibular nystagmus with resultant os­cillopsia may result from relatively low blood alcohol concentrations and the angular acceleration achieved while driving a car ( 85). . Acquired pendular nystagmus is considered a form of central vestibular nystagmus. The clinical and MRI cor­relates of 27 patients with pendular nvstagmus were re­ported by Lopez el al. The most common underlying etiology was MS ( 21 patients), followed by brainstem stroke. Magnetic resonance imaging analysis primarily reflected that of the most common etiology ( MS); statis­tically significant overlap occurred in the region of the red nucleus, the central tegmental tract, the medial ves­tibular nucleus, and ihe inferior olive. Horizontal pen­dular nystagmus was associated primarily with pontine lesions, whereas patients with torsional pendular nystag­mus demonstrated predominantly medullary lesions. Ap­proximately half of the patient's nystagmus was conju­gate; these patients had a higher incidence of symmetric MRI lesions. The authors believe that their findings sup­port the hypothesis that the inferior olive's oscillatory properties are pathophysiological!) related to pendular nystagmus. The MRI findings seem to indicate thai asymmetric brainstem lesions are responsible for dys-conjugate nvstagmus. not internuclear ophthalmoplegia or visual loss ( 86). Acquired pendular nystagmus often produces dis­abling oscillopsia. The result of a pilot trial involving three patients with pendular nystagmus treated with gabapentin was reported by Slahl el al. A single 600- mg dose of gabapentin produced improved vision, whereas treatment with 900 mg/ day to 1500 mg/ day in divided doses was associated with sustained positive results after a 5- week trial. The authors emphasi/ ed ihe potential use­fulness of gabapentin and called for a controlled trial ( 87). Ocular Neuroniyotonia Ocular neuromyotonia is a rare disorder resulting in paroxysmal diplopia due to abnormal persistent electrical activity of the ocular motor nerves. Most patients have had preceding radiation to the skull base or sellar region, but the disorder may occur spontaneously. Ocular neu­romyotonia may be overlooked clinically unless patients are observed after sustained effort of individual ex­traocular muscles is performed. K/. ra and colleagues re­ported 3 cases of ocular neuromvolonia and reviewed the 14 cases currently in the literature. One of their cases of oculomotor neuromyotonia was unique in that the patient had a posterior communicating artery aneurysm; a pre­vious case described by Bateman and Saunders with a ./ . V, HI,: Ophlllillmnl \,./. IS. . V:.. ..'. / W. S 222 E. R. EGGENBERGER AND D. I. KAUEMAN supraclinoid aneurysm and third- nerve palsy with synki­nesis and paroxysmal spasm perhaps also represents ncu-romyotonia related to aneurysmal compression. The au­thors advocated imaging all patients with neuromyoto­nia, especially those with no preceding history of radiation therapy, based on these two cases. Their third case was also unique in that the trochlear neLiromyotonia was only induced after consumption of alcohol. The au­thors speculate that increased susceptibility of previously damaged axons to elevations of extracellular potassium and cphaptic transmission might play a role in the patho­physiology of neuromyotonia ( 88,89). Morrow and colleagues described a 45- year- old woman with bilateral ocular neuromyotonia. The patient underwent transsphenoidal hypophysectomy and radia­tion therapy ( 5000 cGy) for a prolactinoma 18 years before developing episodic diplopia. Examination during symptomatic periods showed tonic adduction consistent with bilateral oculomotor nerve involvement ( 90). LIDS The Gunn " jaw- wink" phenomenon of levator acti­vation with external pterygoid contraction is the best known example of cranial nerve synkinesis. Hwang and coworkers reported the case of a child with unilateral lid retraction induced by supine to sitting postural change. The authors noted that although other stimuli including Valsalva maneuver, cough, smile, sternocleidomastoid contraction, tongue protrusion, inspiration, or voluntary nystagmus have been reported to activate the levator muscle, their patient's posturally induced retraction was novel. The mechanism for this synkinesis remains un­known ( 91). Averbuch- Hcller et al. described three patients with right hemisphere infarctions in whom bilateral ptosis and impaired upga/. e was noted. These authors postulate par­tial lateralization of levator and supraduction function relates to the nondominanl hemisphere's contribution to attention ( 92). Blepharospasm generally occurs as a primary, idio­pathic disorder, although symptomatic forms have been reported in association with basal ganglia, brainstem, or hemispheric lesions. A patient with neurofibromatosis type I and breast cancer developed bilateral, but asym­metric ( left greater than right), blepharospasm and left abducens nerve palsy associated with an MR1- demonstrable left dorsomedial caudal pontine lesion ( probable metastatic lesion) bulging into the fourth ven­tricle in the region of the facial nerve genu. The authors noted the rare occurrence of a pontine lesion in blepha­rospasm ( 93). The evaluation of ptosis initially focuses on etiology. One clinical measure of lid function is eyelid excursion or levator action. This measurement is useful in separat­ing ptosis associated with normal levator function ( e. g., aponeurotic ptosis) from nerve, neuromuscular, or myo­pathic ptosis ( the lower limit of eyelid excursion is ap- ./ Neiiro- Oplulmhntil. Vol. IS. No. . i. IWK proximately 12.5 mm). Frueh and Musch evaluated a measure of levator force generated with upgaze as mea­sured by a clamp attached to the upper lashes connected to a force transducer. Results of testing and ability to correctly diagnose the cause of ptosis were compared with surgical diagnosis in 187 patients. Eyelid excursion predicted the correct diagnosis in 78.2% of patients, and eyelid excursion combined with examination results was successful in 84% of patients. Levator force predicted the correct diagnosis 95.2% of the time, whereas levator force measurement and examination was correct in 97.9% of patients. The authors stressed the usefulness of the force measurement in the evaluation of ptosis ( 94). Brueghel syndrome and Meige syndrome have been used interchangeably in the past. Gilbert described the distinctiveness of Brueghel syndrome; Brueghel syn­drome has the essential sign of a widely, dystonically opened mouth, and most patients lack blepharospasm, unlike patients with Meiges syndrome. A patient with Brueghel syndrome, paroxysmal hypernea, and upbeat nystagmus suggestive of pontine is described. An excel­lent review of the eponymic origins of these two distinct syndromes is included. Incidentally, the Brueghel syn­drome is reported to be the only neurologic eponym not named after a neurologist/ author; rather, it is named for the painter thought to have depicted the syndrome ( in actuality, Brueghel's painting is probably of a yawn, symbolic of idleness) ( 95). Blink movements involve coordination between the eyelids and share several of the characteristics of sac­cadic eye movements, such as a main sequence. Disrup­tion of unilateral eyelid movements occurs after a facial nerve lesion. Huffman and colleagues reported recovery characteristics of lid function using electromagnetic search coil techniques. Evidence of adaptation in the form of an altered main sequence was noted bilaterally, and the degree of adaptation was related to the degree of paresis ( 96). Brodsky and Boop ( 97) reported the case of a 6- ycar-old boy with signs and symptoms of ocular myasthenia and lid nystagmus. The child exhibited ptosis and 45 diopters of exotropia. Large amplitude lid nystag­mus was evoked by horizontal gaze and increased in upgaze. The nystagmus persisted for the duration of lateral gaze. Magnetic resonance imaging showed a low- grade astrocytoma in the midbrain tegmentum, and after radiation therapy, ptosis resolved. The authors re­viewed lid nystagmus, dividing previous reports into convergence- evoked and horizontal gaze- evoked forms. Various pathophysiologies have been reported in asso­ciation with convergence- induced lid nystagmus, ranging from Miller Fisher syndrome to Parinaud's syndrome to a cerebellar sarcoma. Gaze- evoked lid nystagmus has been reported in association with brainstem dysfunc­tion including Wallenberg's syndrome. Lid nystagmus as reported in this case and in previous literature mitigates for neuroimaging of the brainstem, although more spe­cific localization depends on associated signs and symp­toms. OCT TAR MOTILITY REVIEW 22J Saccades and Pursuit Several areas oldie brain parlicipale in the generation and control of saccades. ' I'he frontal eye fields have been postulated to represent the principle region ot saccadic control and correspond to Brodniann's area 8 in the macaque monkey. I'aus reviewed blood flow ( position emission tomography scans) and lesional data in humans regarding the location of the frontal eye fields. Although a remarkable consistency of rostral- caudal localization was found, marked variability was detected in the me­dial- lateral plane. The data from this neuropil) siologic approach indicated that the frontal eye field in humans is located either in the vicinity of the precentral sulcus and/ or depth of the caudal- most portion ot the superior Iron-tal sulcus, challenging the traditional notion that the fron­tal eye field is located in Brodmann's area 8. In addition, these studies did not find a role for the frontal eye fields in cognitive aspects of oculomotor control, such as that noted in the anlisaccadc test. I'he author stressed the need for further study of this area, focusing on the visuo-motor rather than cognitive aspects of oculomotor con­trol OS). In \{) 52, C'ogan ( W) described four children who hail difficulty generating hori/ ontal saccades and named the disorder congenital ocular motor apraxia n- OMA). Children with DMA often exhibit a distinct head thrust to shift ga/. e hori/ ontallv: however, this head thrusting is not universalis present. This disorder has been re­ported in association with numerous diseases, including ( iauchers disease, Cockayne syndrome, posterior fossa masses. NP type I. Alagille syndrome. Lowe syndrome, juvenile nephronophthisis. Wilson disease. X- linked muscle atrophy, and Huntington disease. Ocular motor apraxia is strongly associated with spinocerebellar de­generations and ataxia telangiectasia. 1 larris et al. studied 74 children with OMA, with ages ranging from 17 days to 14 years ( median, 3.2 years). Of the 74 children. 73 children demonstrated an intermittent failure of nystag­mus quick phases, whereas I patient exhibited a total failure of quick phases. Abnormal head movements were delected in approximately half of these patients. Other s'isual abnormalities were common, including sac­cadic hypomelria ( K. V/ r). low gain pursuit ( 70%), nystagmus ( 28%), strabismus ( 22'/ i ), and vertical eye movement abnormalities ( 1 1' r ). Sssiemic abnormali­ties were also common in the group, including hypo- Ionia ( 61'/), motor delay ( 77%), and speech delay ( 87'/). A wide range of underlying conditions were dis­covered, including agenesis ol the corpus callostim. . lou-berl syndrome. Dandy Walker malformation, micro­cephaly, hydrocephalus, vermis hypoplasia, porencepha­lic cyst, megalocephaly. Krabbe leukodystrophy. 1' eli/ aeus Mer/ bacher disease, infantile Gaucher dis­ease, GM1 gangliosidosis, Refsum disease, I'roprionic acidemia, ataxia telangiectasia. Bardet Biedl syndrome, vermis aslrocs tonia. vermis evst. carotid libromuscu-lar dyplasia. Cornelia de Pange syndrome, and mi­crophthalmos. Only 27'/ of their eases were idiopathic. The authors stressed that ocular motor apraxia is best described as intermittent saccadic failure rather than true apraxia and that OMA is not a diagnosis but is associated with a wide spectrum of central nervous svstem disorders i 100). Shawkat and colleagues evaluated 53 children with OMA to discern the usefulness of electroielinogiam. vi­sual evoked potential, and eye movement recordings in the separation of idiopathic and symptomatic cases. Their series consisted of seven patients ( l3.2';/<) with idiopathic OMA. whereas the remaining 86.8'< hail as­sociated conditions. () nl\ 57' < of these patients exhibited head thrusting, flash clectrorclinograni was abnormal in seven ( 13.2'/) patients, six of whom had a pigmentary retinopathv i. louberts ssndroine. Bardet Biedl. infantile Refsums. Kearns- Sayre syndrome) and one who had a cone dystrophy. Visual- evoked potential was normal in all seven idiopathic cases i)\ OMA and in 28' < of the sv mptomatie group. An abnormal visual- evoked poten­tial was significantly correlated with poor OKN gain. ' I'he authors concluded that visual- evoked potential and electroretinograni are useful tools to help distinguish id­iopathic OMA from those with more widespread neuro­logic abnormalities ( 101). lixtrapy ramidal diseases, also known as parkinsonian sv ndromes. are a diverse group occasionally associated with ocular motility disturbances, live movements in a group of 23 patients were studied by Rottach and col­leagues. This group included patients with idiopathic parkinsonism, multiple system atrophy, pure akinesia, progressive supranuclear palsy, and cortico- basal gangli­onic degeneration. Patients in all groups showed saccadic hvpometria, most marked in the vertical plane. Only pa­tients with PSP had slowed saccades. and increased sac­cadic latency was onls observed in patients with eortieo-basal ganglionic degeneration. The authors believe these findings indicate that the brainstem burst cells are prob­ably spared in the parkinsonian syndromes except l'SP; however, the signals sent to the hurst cells are flawed. These findings hold the potential for diagnostic use in the future pending further study ( 102). A patient with a MRl- demonstiahle high- signal lesion within the left rostral midbrain in the region of efferent pathways from the riMIT' was reported by Riordan- liva and colleagues, lixamination ol this patient showed convergence- retraction nystagmus, vertical ga/ e palsy, alternating adducling hyperlropias. and 4 degrees of relative excvelotorsion. Magnetic search coils demon­strated slowing o\' ipsilateral torsional fasl- phase eve movements without torsional slow- phase abnormalities. The authors concluded thai the findings in this ease sup­ported the hypothesis that unilateral inaelivation of the riMFP results in loss of ipsilateral torsional last phases ( 103). Oculomotor findings in two sisters with dy ssv nergia cerebellaris mvoclonica were reported bv W'iest el al. Dyssynergia cerebellaris myocliniea, also known as the Ramsey- Hunt syndrome, is a progressive neurologic dis­order eharacleri/ ed by action myoclonus, sei/ ures. ataxia, and mild cognitive dysfunction ihat perhaps is 224 E. R. EGGENBERGER AND D. I. KAUFMAN part of the olivopontocerebellar atrophy spectrum. The two patients with cyssynergia cerebellaris myoclinica ex­hibited slowed saccades, increased saccadic latencies, and low gain pursuit ( 104). The interstitial nucleus of Cajal and the riMLF are involved in the generation of vertical and torsional sac-cades and gaze holding. Experimental lesional studies in cat and monkey mesencephalon produce conlraversive tonic ocular torsion, whereas stimulation results in ip-silesional tonic ocular tilt. Patients with unilateral meso-diencephalic lesions had tonic conlraversive ocular lilt reaction ( conlraversive ocular torsion, head tilt, and hy-polropia). Torsional nystagmus has been variably present with contradicting direction either ipsi- or contra-lesionally. Helmchem el al. reported the case of a 45- year- old woman with a right mesodiencephalic lesion in the region of the riMLF and interstitial nucleus of Cajal. The patient had the ocular tilt reaction, vertical gaze palsy, and torsional nystagmus. Torsional nystagmus is defined from the patient's view; rotation of the upper poles of both eyes to the patient's left- counterclock­wise from the patient's perspective- is known as nega­tive torsion. The patient had the unique feature of " nega­tive" torsional nystagmus ( i. e., contralesionally beating torsional nystagmus) which the authors speculated arose from a riMLF lesion; they indicated that the direction of torsional nystagmus is poorly correlated with the side of the lesion and the presence or absence of torsional nys­tagmus may depend on combined interstitial nucleus of Cajal and riMLF damage ( destruction of both is associ­ated with no torsional nystagmus) ( 105). The ocular motor dysfunction in 13 HIV- 1- infected patients with CD4 counts < 500 cells/ mm3 was reported by Johnston el al. Significantly worse performance on anlisaccade task was observed in the HIV- infected group, in whom initial movement in the correct direction was made in only 33% of trials. In addition, the inves­tigators found that relative asymmetries for vertical eye movements were more sensitive indicators of central ner­vous system dysfunction than horizontal eye movements. Vertical saccadic latencies in the HIV- 1- infected group were significantly prolonged compared with control sub­jects. The authors suggested that specific neuropatho-logic attention to regions involved in the control of ver­tical gaze and the anlisaccade task may be helpful in understanding these findings ( 106). Opsoclonus consists of back- to- back saccades without an intcrsaccadic interval. This motility disturbance oc­curs as part of the opsoclonus- myoclonus syndrome, which may be paraneoplastic in origin. Pless and Ronthal reported the case of an adult patient with opsoclonus-myoclonus with negative paraneoplastic serum and ce­rebrospinal fluid markers that was resistant to steroid treatment. Intraveneous immunoglobulin was initiated al 1 mg/ kg/ d for 5 days and corresponded with a dramatic improvement in symptoms. The authors suggested that further experience with IVIG treatment of this rare dis­order is required ( 107). A genetically distinct form of vestibulocerebellar ,/ Ncuro- Ophlhulmol. Vol. IS. No. . i, IWH ataxia characterized by defective smooth pursuit was re­ported by Damji et al. This North Carolina kindred with autosomal dominant inheritance displays gaze- evoked nystagmus, ataxia, and vertigo presenting between the third and sixth decades. This syndrome appears geneti­cally distinct from other autosomal dominant ataxias for which chromosomal localization has been established ( 108). Pursuit movements were examined in a group of patients with extrapyramidal disorders including idio­pathic parkinsonism, multiple- system atrophy, pure aki­nesia, progressive supranuclear palsy, and cortico-basal ganglionic degeneration. Sinusoidal protocols did not differentiate this group from control subjects; how­ever, use of the step- ramp stimuli ( which eliminates the initial pursuit segment) showed impaired pursuit accel­eration in all patients compared with control subjects ( 109). 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