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Show 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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