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© 2001 American Academy of Neurology Editorials Keeping an eye on MSFrom the Veterans Affairs Medical Center and Case Western Reserve University (Dr. Leigh), Cleveland, OH; and University of Texas–Houston (Dr. Wolinsky), Health Science Center. Address correspondence and reprint requests to Dr. R. John Leigh, Department of Neurology, University Hospitals, 11100 Euclid Avenue, Cleveland, OH 44106-5040; e-mail: rjl4{at}po.cwru.edu Judging the effectiveness of MS treatments is tricky, largely as a consequence of the unpredictable clinical course of MS. Another challenge is to document disease progression, a problem accentuated by subclinical lesion activity and progressive atrophy found on MRI that neither the patient nor the physician can suspect.1 Clearly, we must seek improved clinical methods for evaluating patients with MS2 that extend the standardized disability status scales introduced by Kurtzke 40 years ago.3 Modern eye movement testing offers several possible advances. Eye movement examination has become more sensitive as clinicians have applied physiology to develop new tests.4 Topologic diagnosis grows ever more specific as anatomists refine the neural circuitry of eye movement control.5 This issue of Neurology contains two reports that demonstrate how the sensitivity and specificity of eye movement disorders can be productively used in evaluating MS. Frohman et al.6 describe how an eye movement disorder can be used to identify an optimal technique for imaging brainstem lesions. They demonstrate that proton density imaging is particularly sensitive for lesion detection in the medial longitudinal fasciculus (MLF) in patients with documented internuclear ophthalmoplegia (INO). The neural circuitry involved in INO is well known.4 In order for the two eyes to move together in the horizontal plane, contractions of the lateral rectus muscle of one eye and the medial rectus of the other must be coordinated. The abducens nucleus contains two neuronal pop-ulations that encode conjugate eye movement commands—motor neurons and internuclear neurons. Abducens motor neurons innervate the lateral rectus, but abducens internuclear neurons project via the medial longitudinal fasciculus to medial rectus motoneurons in the contralateral oculomotor nucleus. Thus, the axons of abducens internuclear neurons in the MLF ensure that abducens motor neurons and contralateral medial rectus motoneurons discharge at similar rates so that the eyes can move together. Demyelination of the MLF may not limit the range of eye adduction due to the medial rectus, but it often slows down rapid eye movements when the MLF can no longer conduct high-frequency signals between the abducens nucleus and the medial rectus motoneurons in the oculomotor nucleus. The most sensitive way to detect INO at the bedside is to test horizontal saccades by asking the patient to look alternatively between fixed targets such as the examiner’s finger and nose; affected patients show relative slowing of the affected adducting eye. Frohman et al. increased the sensitivity for detecting INO by measuring the ratio of the speeds of the two eyes,6,7 and developed a statistic to compare this ratio with values from normal controls. In 58 patients with INO so defined, they systematically compared several standard MRI techniques to determine the most sensitive. In their experience, proton density imaging was more sensitive than T2-weighted or fluid-attenuated inversion recovery (FLAIR) imaging in detecting MLF lesions. Currently, T1-weighted images are used to demonstrate "black holes" that indicate the more severe areas of demyelination, axonal loss, and tissue disruption in the white matter of the cerebral hemispheres. The current study suggests that neither T1 nor FLAIR are as sensitive in detecting brainstem lesions as proton density imaging, perhaps because the different geometric organization of axon bundles in the brainstem dictates differences in the histopathologic characteristics of brainstem plaques compared to their hemispheric counterparts. It is of interest that all patients with objectively defined unilateral or bilateral INO evidenced appropriately located brainstem lesions on proton density images, even those in whom INO was not detected on clinical examination. This suggests that the "clinical–MRI paradox" may largely reflect our inability to detect the pathophysiologic consequences of MRI-defined lesions with relatively crude bedside tools like the Expanded Disability Status Scale. More sensitive, anatomically based tests of neural pathophysiology and advanced MRI will likely narrow this gap. In the second report, Minagar et al. studied a patient with vertigo.8 Vertigo is common in MS and usually reflects disturbed central vestibular connections, including those of the cerebellum. Little may be found on traditional examination in vertiginous patients because the vestibular system has considerable adaptive abilities and can compensate even for some central disorders. Newly developed tests can detect prior vestibular imbalance that has not been fully compensated.4,9 For example, the patient is asked to rotate the head vigorously from side to side at about two cycles per second for 15 seconds. The examiner then looks for nystagmus, preferably with the patient wearing Frenzel goggles, which prevent visual fixation. The vestibular system possesses a form of "memory" for persistent vestibular stimuli referred to as "velocity storage."10 When normal subjects shake their heads from side to side equal inputs from the two ears cancel with no net memory of the prior rotation—there is no nystagmus after head shaking stops. When the velocity storage mechanism is disrupted, nystagmus may follow head shaking that is not in the same plane as the prior head rotation. Horizontal head shaking induced marked and sustained downbeating nystagmus in the patient described by Minagar et al.8 This "perverted" form of vestibular nystagmus is due to abnormal cross coupling of a vertical response to a horizontal stimulus. Although the responsible lesion in this patient was relatively large, its location in the medulla made it possible to offer an explanation for the patient’s perverted nystagmus. Basic research has established that only a few structures at this level of the brainstem are concerned with eye movement control. Specifically, a network of neurons in several adjacent medullary nuclei4,5,11 act in concert with the cerebellum to coordinate horizontal and vertical gaze, so that eye movements are in the appropriate direction to compensate for head rotations and hold the eye on target. Lesions affecting components of this neural network, including the vestibular cerebellum,12 produce perverted nystagmus.
Acknowledgments Supported by NIH grant EY06717; Office of Research and Development, Medical Research Service, Department of Veterans Affairs; and Evenor Armington Fund. Footnotes References
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