Alternating Skew on Lateral Gaze Neuroanatomic Pathway and Relationship to Superior Oblique Overaction Latif M. Hamed, MD,l Bernard L. Maria, MD,Z Ronald G. Quisling, MD,3 ]. Parker Mickle, MD4 Background: Previous studies of patients with heterogeneous, often diffuse neurologic disorders concluded that the neurologic substrate for alternating skew on lateral gaze may be localized at the level of the brain stem tegmentum or the cervico-medullary junction , or both. The localized nature of brain tumors offers an opportunity to further investigate the anatomic localization for this as well as other conditions. Methods: To test the hypothesis that cerv ico-medullary and cerebellar lesions are responsible for alternating skew on lateral gaze , the authors investigated a series of 50 children with brain tumors , 39 of whom showed neuro-ophthalmologic abnormalities on clinical testing. Seven children had alternating skew on lateral gaze. Results: All seven children with alternating skew on lateral gaze showed neoplastic involvement at the level of the cervico-medullary junction and/or the cerebellum on critical analysis of neuro-imaging studies. Conclusion: The authors conclude that the neuroanatomic substrate for alternating skew on lateral gaze is localized at the level of the cervico-medullary junction and/or the cerebellum . Knowing that (1) alternating skew on lateral gaze closely mimics superior oblique overaction clinically, (2) superior oblique overaction is frequently found in patients with myelomeningocele, and (3) myelomeningocele is uniformly associated with ArnoldChiari type II which includes cerebellar and cervico-medullary region abnormalities, the authors propose that alternating skew on lateral gaze and superior oblique overaction associated with myelomeningocele have similar neuroanatomic pathways. Ophthalmology 1993; 100:281-286
Originally received: June 4, 1992. Revision accepted: September 28, 1992. I Department of Ophthalmology, Un iversity of Florida College of Medicine, Gainesville. 2 Department of Pediatrics, University of Florida College of Medicine, Ga inesville. 3 Department of Radiolog y, University of Florida College of Medicine, Gainesville. 4 Departm ent of Neurosurgery, University of Florida Collegeof Medicine, Ga inesville. Presented as a poster at the American Academy of Ophthalmology Annual Meeting, Dallas, November 1992. Supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York. Reprint requests to Latif M. Hamed, MD, Section of Pediatric Ophthalmology, Department of Ophth almology, Un iversity of Florida College of Medicine, Box 100284, JHMHSC, Gainesville, FL 32610-0284 .
Skew deviation is a supranuclear, comitant or incomitant, vertical misalignment of the eyes, usually associated with disorders of the posterior cranial fossa.l' Some forms of incomitant skew deviation may mimic a primary overaction of an oblique muscle.' Alternating skew on lateral gaze (bilateral abducting hypertropia) is a subtype ofskew deviation that resembles bilateral superior oblique overaction.v' The patients show right hypotropia on downgaze and to the left, and left hypotropia on downgaze and to the right. A hypertropia mayor may not be present in the primary position." Previous reports described alternat ing skew on lateral gaze in association with a variety of disorders of the posterior cranial fossa. The specific topographic localization of the causati ve lesion remains under debate , and has been suggested to be at the level of the midbrain pretectum" or the cervico-medullary junetion ," or both. The series of patients cited in these studies
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included a widely heterogeneous group of disorders.v" some with a propensity to show widespread, rather than localized, involvement of the central nervous system. This may explain the disparity of proposed topographic localization for alternating skew on lateral gaze. In contrast, the localized nature of brain tumors offers an opportunity to gain valuable information regarding the localization of neuroanatomic pathways that may not be as reliably extracted from demyelinative, degenerative, toxic, metabolic, or traumatic disorders due to the difficulty of definitively pinpointing a specific site of dysfunction in these latter conditions. Recently, progress has been made in determining the anatomic and physiologic substrate of certain neuro-ophthalmologic mechanisms in children with brain tumors.v? We tested and confirmed the concept that some children with alternating skew on lateral gaze have cervico-medullary or cerebellar lesions.
Patients and Methods Between July 1989 and April 1992, we studied 50 consecutive cases of brain tumors in children with attention to the neuroradiologic and neuro-ophthalmologic findings. All patients had undergone a thorough neuroophthalmic evaluation as a part of a coordinated multidisciplinary approach. Ocular misalignment was measured with the prism and alternate cover test. In sufficiently cooperative patients, a Maddox rod and muscle light also were used to subjectively survey the presence and nature of ocular misalignment. All patients had undergone at least one magnetic resonance imaging study to localize the tumor and associated surgical alterations. The type of brain tumors, neuro-ophthalmic findings, and neuroradiologic localization were analyzed. The procedure for localizing the tumors involved the review of neuroimaging studies by a pediatric neuroradiologist who was unaware of the subjects' clinical status. Localization of brain tumors involved coding in 90 brain sites along traditional neuroanatomic divisions. A brain structure or area was deemed to be involved if tumor or associated damage was indicated by the neuroradiologist. The aim of the system was to provide a coherent description of relevant brain areas involved by tumor and associated peritumoral changes (surgical changes, edema).
Results The 50 patients ranged in age from 2 to 22 years (mean, 10.1 years). There were 32 males and 18 females. Of the 50 children, 39 (80%) showed associated neuroophthalmic disorders (Table 1). In 12 (24%), the ocular findings were among the initial presenting signs, and in 6 the ophthalmic signs and symptoms were the sole presenting manifestations. Seven patients (6 males, 1 female) had alternating skew on lateral gaze, a condition resembling superior oblique overaction, all with tumors of the posterior fossa (Fig 1). These seven patients ranged in age from 6 to 16 years (mean, 9.9 years). None of these pa-
Table 1. Neuro-ophthalmic Findings in 50 Children with Brain Tumors Neuro-ophthalmic Findings VI nerve palsy IV nerve palsy III nerve palsy V nerve palsy VII nerve palsy Nystagmus Optic atrophy Papilledema Horizontal gaze palsy Vertical gaze palsy Dorsal midbrain syndrome Visual field defect Horizontal OKN asymmetry OKN
No. of Patients
12 5 3 3
7 6 3 2 3 5 1
tients had a history of childhood strabismus. The average measurement of the skew deviations was 4.5 prism diopters. The amount of deviation was greatest on maximal downgaze and laterally. Table 2 lists the types and locations of their brain tumors along with the associated neuro-ophthalmic findings. All seven patients with alternating skew on lateral gaze showed anatomic involvement at the level of the cervico-medullary junction or the cerebellum, or both (Figs 2 and 3B).
Discussion Patient 1 showed concomitant, non paralytic esotropia which had been noted 6 months before initial presentation, Although paralytic strabismus is well described in patients with brain tumors, the occurrence of acute concomitant, nonparalytic esotropia in such patients warrants emphasis." The ability to clinically diagnose alternating skew on lateral gaze is not affected by the concurrent presence ofesotropia. This is similar to the ability to diagnose superior oblique overaction in such patients. Patient 2 showed bilateral gaze paresis, limiting the horizontal versions to approximately 7:% of normal. Patient 4 showed mild bilateral abducens palsy, with approximately 1.5 mm of scleral show still remaining on maximal abduction of each eye. These horizontal movement abnormalities did not interfere with the ability to detect the alternatingskew deviation on lateral gaze, which manifested with an alternating vertical imbalance with the adducted eye being hypotropic. Alternating skew on lateral gaze has been diagnosed by other investigators in the presence of an abducens paresis.' Slavin? reported that many patients with isolated unilateral abducens palsies have idiopathic hyperdeviations ranging from 4 to 18 prism diopters, noted in primary and/or eccentric gaze. He speculated that mechanical factors, and vertical substitution movements, may explain the hyperdeviation. However, some author-
Hamed et al . Alternating Skew on Lateral Gaze
Figure 1. Case 7, ocular versions show the typical findings of alternating skew on lateral gaze (bilateral abducting hvpertropia), which closely resembles bilateral superior oblique overaction.
ities believe that if the condition were associated with brain stem dysfunction, this hyperdeviation may represent "nothing more" than a skew deviation. 10 Two previous series of patients with alternating skew on lateral gaze offered different conclusions regarding the presumed localization of this disorder.t' In 22 patients with alternating skew on lateral gaze, Keane 4 found 11 with a pretectallesion, 2 with a lesion at the pons-medulla level, and 9 patients in whom the responsible lesion could not be localized. Moster and associates' described 33 patients with alternating skew on lateral gaze and were able to ascribe a cervico-medullary localization in 25 patients (76%). This was done on the basis of surgical or neuroradiologic visualization (8 patients), or due to the concurrent presence of downbeat nystagmus which is considered to be localizing to the cervico-medullary junction. Only one patient was ascribed a pretectallocalization, in marked contrast to Keane's study. An inherent problem in both studies is the predominance of patients with dis-
eases that are not particularly of a localized nature, for example, multiple sclerosis, neurodegenerative disorders, trauma, and alcohol or lithium toxicity. Both studies combined included only four patients with brain tumors. Because posterior fossa tumors are more common than supratentorial tumors in children, we believe that children with brain tumors provide an opportunity to make relatively more accurate inferences regarding the neuro-anatomic substrate of a variety of neuro-ophthalmologic findings, including alternating skew on lateral gaze. All of the seven patients with alternating skew on lateral gaze in this report had a lower brain stem or cerebellar lesion. The results of our study are in agreement with the conclusion of Moster and associates' regarding a cervicomedullary or cerebellar localization in alternating skew on lateral gaze. There is supportive evidence that alternating skew on lateral gaze and superior oblique muscle overaction, which may mimic one another on ocular motility testing, also
Table 2. Clinical and Neuroradiologic Data in Seven Patients with Alternating Skew on Lateral Gaze Patient No./ Age (yrs)/Sex
Ependymoma Glioblastoma multiforrne Medulloblastoma
4/13/M 5/16/M 6/9/F
Astrocytoma Medulloblastoma Brain stem glioma
Left cerebellum, medulla, upper cervical cord Medulla, basis pontis, pontine tegmentum
Nystagmus Bilateral gaze paresis
Cerebellar vermis and tonsils
Bilateral optic atrophy, nystagmus, esotropia Nystagmus
Cerebellar vermis and tonsils, pineal body Left cerebellum Red nucleus, substantia nigra, cerebral peduncle, medulla, basis pontis Medulla~ basis pontis, pontine tegmentum
Bilateral VI, R V, R VII, R XII Papilledema
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Figure 2. 'Tl-weighted (resolution time/echo time, 500/15 mseconds; 4 NEX) sagittal magnetic resonance imaging(MRI) (1.0-Tesla [A2.11 magnet). This midline MRI section illustrates the location of the medullary component of an astrocytoma (i.e., patient 6; Table 2) presenting with alternating skew on lateral gaze. Magnetic resonance imaging was performed after partial resection and biopsy, which accounts for both the suboccipital craniotomy site and the contrast enhancement (gadolinium-DTPA 0.10 mmol/kg] in the resection site. The mass, which exhibits no apparent enhancement, expands the medulla and upper cervical spinal cord from the pontomedullary junction to C3. Concurrent T2-weighted MRI (not shown) demonstrated abnormal signal within the medulla, upper cervical cord, and the basis pontis.
may have a similar neuro-anatomic substrate (Fig 3). Superior oblique overaction is an ocular motility disturbance occasionally seen in association with horizontal strabismus of childhood.!':'? Various simulating conditions with overdepression of the adducted globe on downgaze when testing ocular versions such as pseudo- or apparent superior oblique overaction, "downshoot" in Duane's retraction syndrome, or inferior oblique muscle palsy are readily attributable to a specific pathophysiologic mechanism. However, the etiology of "true" superior oblique overaction remains elusive. 13 A recent hypothesis explains oblique muscle overaction and underaction to be the result of "sensory torsion" occurring in the absence of fusion
and the presence of a constant non-zero torsional bias (unpublished data: Weingarten PE; presented at the 1992 AR va Annual Meeting). Other previous speculations regarding its etiology include: (1) hypercontraction of the superior oblique muscle on a neural or muscular basis, (2) subnormal contraction of the ipsilateral inferior oblique muscle or the contralateral inferior rectus muscle, (3) reduced "checking" of the overacting eye in extreme positions of gaze, (4) anatomic variables in the bony orbit, the check ligaments, the fascial connections, and the attachments and insertions of the extraocular muscle, and (5) some abnormalities in the central neural control mechanisms. The possibility that oblique muscle overaction or the closely related A- and V-pattern strabismic syndromes may be the result of abnormal central neural pathways has been raised previously. As early as 1916, Ohm 14 - 16 postulated that inferior oblique overaction and the A-V strabismic patterns may be due to abnormal vestibular innervation. In 1933, Vestergaard'" specifically postulated a possible relationship between these abnormalities and skew deviation. In 1964, Smith and co-workers' pointed out that some forms of noncomitant skew deviation may mimic a primary overaction of an oblique muscle. Given the close similarity between alternating skew on lateral gaze and superior oblique overaction, we propose that the two conditions may have a similar neuroanatomic pathway (Fig 3).18 Previous investigators have speculated that superior oblique overaction may be supranuclear in nature, citing the frequency with which it occurs in patients who have other supranuclear disorders, such as the setting sun sign and defective upgaze in patients with myelomeningocele. 18-20 Various studies have demonstrated that children with myelomeningocele and hydrocephalus'v:" or cerebral palsy" show a high frequency of superior oblique overaction and A-pattern strabismus. Children with myelomeningocele typically have an associated Arnold-Chiari type II malformation." which is sometimes cited as a prototype of disorders affecting the cervico-medullary junction. This is a similar neuroanatomic localization to that seen in our seven patients with posterior fossa tumors who had alternating skew on lateral gaze (Fig 3). Posterior fossa dysfunction in patients with myelomeningocele has been demonstrated by means of electrophysiologic and neuroradiologic techniques. Docherty et al 28 showed that patients with myelomeningocele have abnormal brain stem auditory-evoked responses. Lennerstrand et at29 attempted to correlate the neuroophthalmologic findings in patients with myelomeningocele with neuroradiologic alterations using magnetic resonance imaging. They demonstrated that superior oblique overaction in these patients correlated with the extent of anatomic alterations in the tectal plate and the medulla oblongata. This evidence supports the concept that, at least in the setting of myelomeningocele, superior oblique overaction has a neurologic basis rather than being the result ofalteration ofthe anatomy ofstructures within the orbit. It also should be noted that the tectal plate and the medulla oblongata are among the anatomic sites
Hamed et al . Alternating Skew on Lateral Gaze
Figure 3. A, midline sagittal T'l-weighted MRI performed in a patient with a lumbar meningocele reveals an associated Chiari type 2 malformation of the brain. Most characteristic of the Chiari malformation is caudal displacement of the cervicomedullary junction. The latter is best approximated by locating the juxtaposed obex of the fourth ventricle and the nucleus gracilis. Normally , the obex-nucleus gracilis position is located 3-10 mm above the plane of the foramen magnum, but typical of Chiari malformations and clearly evident in this case is its caudal migration to the Cl level (arrow). Medullary compression in such cases results from wedging of the cerebellar tonsils within the foramen magnum. The epicenter of such a vector is exerted on the dorsal medulla near the vagal and hypoglossal trigone regions which are located immediately rostral to the obex-nucleus gracilis junction. In this case a posterior fossa decompression has been performed. B, midline sagittal T'l-weighted MRI performed in a patient with an ependymoma involving the dorsal aspect of the medulla. Notice in this instance the invasive nature of the mass within the medulla has both elongated the medulla and caudally displaced the obex/nucleus gracilis junction (arrow). Defining the anatomic relationship between the obex/nucleus gracilis complex and the caudal margin of the mass allows for accurate localization of this tumor to the region of the vagal and hypoglossal trigones . The mass vector being exerted in this case is nearly identical to that of the cerebellar tonsils illustrated in Figure 3A.
within which the substrate for alternating skew on lateral gaze is presumed to reside.v' It is the clinical impression of the authors that true superior oblique overaction may be a useful sign for the possible presence of central nervous system neurologic dysfunction in children with strabismus. In one study, almost one half of a group of strabismic children with true superior oblique overaction showed evidence of concurrent neurologic dysfunction, compared with less than one fifth with neurologic dysfunction in a group of controls consisting of strabismic children without superior oblique overaction (unpublished data: Hamed LM; presented at the 1992 AAO Annual Meeting). In summary, our data support the localization of alternating skew on lateral gaze to the cervico-medullary junction or the cerebellum. We speculate that alternating skew on lateral gaze and some cases of superior oblique overaction (especially those occurring in patients with myelomeningocele) may have the same underlying neuroanatomic substrate.
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