Pearls & Oy-sters: The medial longitudinal fasciculus in ocular motor physiology
T. C. Frohman, BA,
S. Galetta, MD,
R. Fox, MD,
D. Solomon, MD, PhD,
D. Straumann, MD,
M. Filippi, MD,
D. Zee, MD and
E. M. Frohman, MD, PhD
From the Departments of Neurology (T.C.F., E.M.F.) and Ophthalmology (E.M.F.), University of Texas Southwestern Medical Center at Dallas; Department of Neurology, University of Pennsylvania (S.G.), Philadelphia; Mellen Center for Multiple Sclerosis (R.F.), Department of Neurology, Cleveland Clinic, OH; Department of Neurology (D. Solomon, D.Z.), The Johns Hopkins Hospital, Baltimore, MD; Department of Neurology (D. Straumann), Zurich University Hospital, Switzerland; and Department of Neurology (M.F.), Scientific Institute, Neuroimaging Research Unit, University Ospedale San Raffaele, Milan, Italy.
Address correspondence and reprint requests to Dr. Elliot M. Frohman, Department of Neurology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX75235
Objective: To review the role played by the medial longitudinalfasciculus (MLF) in ocular motor physiology and to characterizea number of syndromes that result from lesions in this eloquentbrainstem tract system.
Background: The MLF is responsible for transmitting informationthat is crucial for the coordination and synchronization ofall major classes of eye movements. A number of disease processescan produce lesions within this small yet highly strategic whitematter pathway resulting in a myriad of neuro-ophthalmologicsigns and symptoms.
Methods: We carefully reviewed both the literature and ourcollective experiences to systematically consider the neuroanatomyand physiology of the MLF and the pathophysiologic mechanismsthat underlie syndromes deriving from lesions in this pathway.
Results: The MLF is an important structure and is composedof numerous projection systems involved in the regulation ofeye movements. Pathology at this location can produce a constellationof abnormalities, many of which can be identified upon carefulbedside neurologic examination.
Conclusion: This review of the medial longitudinal fasciculusand its constituent pathways is germane to understanding a numberof important principles in neuro-ophthalmology.
GLOSSARY: FEF = frontal eye field; FPA = first-pass amplitude;INC = interstitial nucleus of Cajal; INO = internuclear ophthalmoparesis;MLF = medial longitudinal fasciculus; MS = multiple sclerosis;NPH = nucleus prepositus hypoglossi; NRTP = nucleus reticularistegmenti pontis; OD = right eye; OS = left eye; OTR = oculartilt reaction; PPRF = paramedian pontine reticular formation;PSP = progressive supranuclear palsy; r-VOR = rotational vestibularocular reflex; riMLF = rostral interstitial nucleus of the MLF;SC = superior colliculus; SVN = superior vestibular nucleus;VDI = versional disconjugacy index; VLVN = ventral lateral vestibularnucleus.
The medial longitudinal fasciculus (MLF) is organized as a pairof white matter fiber tracts that extend through the brainstemand lie near the midline just ventral to the fourth ventricle(in the medulla and pons) and cerebral aqueduct (in the midbrain).The MLF contains fibers that ascend and some that descend withinthe brainstem tegmentum and interact with ocular motor controlcircuitries involved in the coordination of horizontal, vertical,and torsional eye movements.1,2
The MLF is a central conduit for many brainstem pathways andis the final common pathway for all classes of conjugate eyemovements including saccades (rapid refixations), smooth pursuit,and vestibuloocular reflexes, including semicircular and otolithmediated ocular motor reflexes. The six ocular motor nuclei(pairs of cranial nerve III, IV, VI) are interconnected viathe MLF, which transmits vital information for the purpose ofcoordinated and synchronized movements of the eyes to a visualtarget. Within this system are both excitatory as well as reciprocalinhibitory projections that serve to precisely regulate theinterplay between agonist and antagonist muscles of the eyes.
In this review, we characterize the physiology of the componenttract systems contained within this central ocular motor circuitry,and provide a detailed discussion of the most common neurologicsigns and symptoms associated with lesions of this structure.
The saccadic apparatus includes neurons in the frontal eye field(FEF) which project to a number of subcortical structures thatserve to mediate rapid gaze shifts to remembered targets.3 TheFEF sends a signal to the ipsilateral superior colliculus (SC)and to the contralateral paramedian pontine reticular formation(PPRF) for horizontal saccades and to the rostral interstitialnucleus of the MLF (riMLF) for vertical saccades. The PPRF containsexcitatory burst neurons that produce the supranuclear horizontalsaccadic eye velocity command sequence (the pulse).4 These neuronsproject to the adjacent VI (abducens) nerve nucleus. The abducensnucleus consists of two types of neurons that mediate conjugatehorizontal eye movements. Abducens motoneurons innervate theipsilateral lateral rectus muscle whereas axons from abducensinterneurons cross to the contralateral pons and ascend viathe MLF to innervate the medial rectus subnucleus of cranialnerve III, which ultimately projects to the medial rectus muscle(figure 1). The parietal cortex is central in the productionof smooth pursuit eye movements but also participates in theproduction of saccades and has a direct projection to the SC.In contrast to the FEF, the parietal cortex is more involvedin the production of saccades to novel visual stimuli ratherthan to remembered targets.3 As with saccades, smooth pursuitpathways ultimately converge upon the MLF for the executionof both horizontal and vertical eye movements.
Figure 1 Details of the descending projection involved in the volitional control of horizontal saccadic eye movements
Excitatory pathways are shown in orange and the reciprocal inhibitory pathways are shown in blue. The particular pathway shown emanates from the frontal eye field (FEF), which projects through the anterior limb of the internal capsule, decussates to the opposite side at the midbrain-pontine junction, and then innervates the paramedian pontine reticular formation (PPRF). From there, projections directly innervate the lateral rectus (ipsilateral to the PPRF). A second decussation, back to the side of origin of FEF activation, via the MLF, innervates the medial rectus subnucleus of cranial nerve III and then neurons here project to innervate the medial rectus muscle. The right FEF command to trigger a saccade culminates in conjugate eye movements to the left. According to Herring's law, the horizontal yoke pair, the medial and lateral recti, are activated in synchrony.
Canal system afferents.
The MLF is the principal tract system by which signals reachthe ocular motoneurons for eye movements generated in responseto vestibular stimuli.3 There may, however, be differences inthe anatomic circuitry underlying these reflexes depending uponwhether the eye movements are compensatory for angular motionof the head mediated by the semicircular canals (called therotational vestibular ocular reflex; r-VOR), or for linear accelerationof the head, mediated by the otolith organs (utriculus and sacculus).
Lateral semicircular canal projections in the MLF.
The pathways underlying the angular VOR are reasonably wellunderstood. For the lateral canal system, the r-VOR is mediatedby the same pathway carrying information for the other conjugateeye movement systems (saccade and pursuit). The abducens nucleusis the gaze center for the final pathway of horizontal eye movements.Stimulation of the lateral semicircular canal results in transmissionof information (from horizontal head motion or caloric activation)within the ipsilateral VIII nerve and nucleus.5 Projectionsthen emanate from the medial vestibular nucleus to innervatethe contralateral VI nucleus. Abducens motoneurons then projectto the lateral rectus muscle, while abducens interneurons projectinto the contralateral MLF where their axons innervate the medicalrectus subnucleus of the ocular motor nucleus with a final projectionto the medial rectus muscle (figure 2).
Figure 2 Projections involved in the activation of the left lateral semicircular canal
This figure illustrates the projections involved during the activation of the left lateral semicircular canal. For instance, during a leftward rotation of the head while attempting to maintain straight ahead gaze, axons from left lateral canal (on the right side of the figure) canal neurons project to ipsilateral vestibular nucleus (primarily the medial) which then projects across the brainstem to innervate the opposite right abducens (VI) nucleus. This nucleus has two populations of neurons; a direct projection to the same side lateral rectus (right) and an interneuronal projection that crosses back to the left side via the MLF and then innervates the medial rectus subnucleus of cranial nerve III, which ultimately innervates the left medial rectus muscle.
Anterior semicircular canal projections in the MLF.
For the anterior canal system, there may be three excitatorypathways by which information is carried rostrally for the verticalr-VOR. Excitatory cells in the medial vestibular nucleus oradjacent ventral lateral vestibular nucleus (VLVN) project mediallyand dorsally, crossing the midline caudally.5 After crossing,they ascend in or just below the MLF to contact the superiorrectus and inferior oblique subdivisions of the oculomotor complex.Importantly, the superior rectus subnucleus sends fibers thatdecussate to innervate the superior rectus muscle on the sideof anterior canal activation (figure 3). In this way, one semicircularcanal can innervate muscles in both eyes for appropriate yokingof eye movements. Inhibitory neurons for the anterior canalsystem lie in the superior vestibular nucleus (SVN). Their axonsexit from the rostromedial aspect of this nucleus and coursemedially and rostrally in the lateral wing of the ipsilateralMLF, to contact superior oblique motoneurons in the trochlearnucleus, and inferior rectus neurons in the oculomotor nucleus,to antagonize those eye movements mediated by an activated anteriorcanal system.3
Figure 3 Projections involved in the activation of the left anterior canal
Axons from anterior semicircular canal neurons project to the ipsilateral vestibular nucleus and from there decussate across the brainstem to innervate the contralateral inferior oblique nucleus of cranial nerve III (and then the muscle itself) and the ipsilateral superior rectus muscle via a second decussation from the superior rectus subnucleus on the right, which completely crosses back to the left (on the right side of the figure). The excitatory pathways are shown in orange and the reciprocal inhibitory pathways are shown in blue. Activation of both canals (as with pitching the head downward and attempting straight ahead fixation) will result in cancellation of the torsional vector components, but addition of the vertical vector components resulting in upward movement of the eyes.
Another cell group that may contribute excitatory inputs fromthe anterior canal system lies in the SVN. Their axons crossthe midline in the ventral tegmental tract, close to the mediallemniscus at the rostral pole of the nucleus reticularis tegmentipontis (NRTP), and then abruptly turn rostrally, passing throughthe decussation of the superior cerebellar peduncle, to terminatemainly on the superior rectus and inferior oblique subdivisionsof the oculomotor complex.3 Also, in some species (perhaps alsoin humans), the SVN projects rostrally, just near the brachiumconjunctivum, to the oculomotor nuclei. Thus, three pathwaysmay contribute to the generation of eye movements during stimulationof the anterior semicircular canal.
Posterior semicircular canal projections in the MLF.
For the posterior canal system, excitatory neurons project fromthe vestibular nuclei at the junction of the MVN and VLVN rostrally,medially, and dorsally through MVN until, at the level of thecaudal abducens nucleus, they turn medially and cross the midlinebeneath the nucleus prepositus hypoglossi (NPH) and abducensnucleus, ventral to the MLF. After crossing the midline, theyenter the MLF and project rostrally to the trochlear nucleusand inferior rectus subdivision of the oculomotor complex.5The trochlear axons within cranial nerve IV then exit the brainstemposteriorly (the only cranial nerve to do so) and completelydecussate before projecting forward to innervate the superioroblique muscle (on the side of posterior canal activation) (figure 4).Inhibitory neurons subserving the posterior semicircular canalsare found in the SVN and rostral MVN. Their axons project throughthe pontine reticular formation to reach the ipsilateral MLFand then contact the superior rectus and inferior oblique subdivisionsof the oculomotor complex in order to avoid movements antagonisticto those mediated by the posterior canal system.
Figure 4 Projections from the left posterior semicircular canal
Axons from the canal project to the ipsilateral vestibular nuclei and then decussate to innervate the contralateral inferior rectus subnucleus of the oculomotor complex of cranial nerve III and the trochlear nucleus. The trochlear neurons then exit the brainstem posteriorly and decussate back to the left side innervating the superior oblique muscle. Activation of both canals (as with pitching the head upward and attempting straight ahead fixation) will result in cancellation of the torsional vector components, but addition of the vertical vector components resulting in downward movement of the eyes.
An important clinical implication of the difference in anatomicprojections of the posterior and anterior canal pathways isthat patients with MLF lesions may have a dissociated verticalnystagmus and relative sparing of response to upward vs downwardrotation of the head.6,7
Otolithic projections in the MLF.
The otolith organs detect linear acceleration. The projectionsfrom the vestibular nuclei that mediate otolith-ocular reflexesare less well defined and there is a paucity of evidence fora direct three neuron arc (e.g., otolith organ, vestibular nucleus,ocular motor neuron) comparable to the three neuron arc forsemicircular canal mediated reflexes. Presumably the horizontaltranslational VOR is mediated by the same abducens nucleus pathwayas are the other conjugate systems, though there is some evidencefor a direct projection of utricular afferents to the abducensnucleus.
Responses to static head tilt, especially lateral tilt of thehead (ear to shoulder), have been long known to produce ocularcounterrolling, due to activation of the cyclovertical ocularmuscles.8 Under normal circumstances, when the head is tiltedto the left, the eyes counterroll in the opposite direction(upper poles of the eyes slowly moving away from the side ofthe tilt). This reflex is mediated by projections that innervatethe left eye intorters (superior rectus and superior oblique)and the right eye extorters (inferior rectus and inferior oblique)(figure 5). Following the slow phase counterroll, there is afast torsional movement in the opposite direction (upper polesbeating to the side of the head tilt) which is mediated by theriMLF in the rostral midbrain.9
Figure 5 Pathways involved in the counterroll of the eyes (dotted arrows) during a head tilt
In this example, a left head tilt results in a counterclockwise (with respect to the examiner) torsional counterroll of the upper poles of the eyes. This response is mediated by a crossed otolith projection to the extorters in the patient's right eye (the inferior oblique and inferior rectus muscles) and a double crossed projection to the intorters of the left eye (the superior oblique and superior rectus muscles). These slow phases are punctuated by torsional fast phases that are mediated by the rostral interstitial nucleus of the medial longitudinal fasciculus. The interstitial nucleus of Cajal (INC) is also shown (without connections). This important midbrain structure contains circuitry important for neural integration of vertical and torsional gaze, eye-head coordination during roll movements, and contains inhibitory burst neurons for vertical eye movements.3 Lesions of these otolith projections result in the opposite reciprocal effects leading to intorsion and elevation of the right eye and extorsion and depression of the left eye, the so-called skew deviation. If the lesion occurs prior to the otolith pathway decussation (here on the left) then the lower left eye is on the side of the lesion. Alternately, if the lesion is within this pathway after the decussation (in the pons or midbrain), then the higher eye is on the side of the lesion.
Anatomically, these graviceptive pathways cross to the otherside of the brainstem approximately in the middle of the ponsand further ascend in the MLF to the ocular motor nuclei (nucleiIII and IV) and the premotor gaze centers in the rostra1 midbrain(interstitial nucleus of Cajal [INC] and riMLF).10 From there,further connections reach multiple cortical areas through thalamicprojections.
A common clinical finding in patients with unilateral MLF lesionsinvolving the central otolith pathway is the ocular tilt reaction(OTR), which consists of a head tilt, ocular counterrolling(generally with the upper pole of the eyes rotating toward alesion below the pons and away from a lesion at the level ofthe pons or midbrain), and skew deviation (a supranuclear verticalmisalignment of the two eyes).11 The head tilt is typicallyaway from the side of the higher eye.
In typical skew deviations, the higher eye is contralateralto a medullary lesion and ipsilateral to a mid pontine (thelevel at which otolith projections decussate the brainstem)or midbrain lesion. Ocular counterroll may be recognized duringfunduscopic examination, where the nearly horizontal plane betweenthe optic disc and macula (the macula-disc line) is now deviated.12For example, in the case of a left lateral medullary syndrome,an ocular tilt reaction might involve left head tilt, righthyperdeviation, and counterroll of the eyes (upper poles) towardthe left shoulder (or clockwise rotation with respect to theobserver). In essence, the macula of the left eye is now furtherbelow the disc than usual, and the macula of the right eye isfurther above the disc (figure 6).
Figure 6 Another consequence of otolithic imbalance that accompanies skew deviation is the phenomenon of ocular counterroll
These fundus photographs show the extorsion (upper pole of the eye rotated away from the nose or toward the left shoulder) of the left eye (OS), with the disc-macular line rotated clockwise (according to the examiner), and the right eye (OD) intorted (upper pole of the eye toward the nose or toward the left shoulder) with the macular-disc line rotated clockwise (again, according to the examiner). A lesion within the otolith projections in the medial longitudinal fasciculus at the level of the left medulla (the side of the lower eye) or right pons or midbrain (side of the higher eye) would result in this appearance.
Tilting the head relative to gravity from upright in an ear-downdirection, so called head roll, elicits dissociated changesof eye position. In healthy subjects, both eyes counterroll(upper poles of the eyes moving away from the side of the headtilt) by roughly 10% of the head roll, but the extorting eyerotates about 1 to 2 deg more than the intorting eye (figure 5).8,13Furthermore, a small skew deviation (vertical misalignment)of about 0.5 deg appears with hypertropia of the intorting eye.10
Unilateral peripheral or pontomedullary lesions below the pontinecrossing of the graviceptive pathways produce a skew deviationand binocular torsion (combination of these signs is sometimescalled skew torsion). For instance, a patient with a left medullarylesion will have a right hypertropia and counterroll of theeyes toward the left shoulder (figure 7). Lesions of the lowergraviceptive pathways tend to produce disconjugate torsion,which is typically greatest in the excyclotorted eye. In contrast,a unilateral pontomesencephalic brainstem lesion leads to contraversiveskew torsion.10 In this case, the hypertropic eye is ipsilateralto the lesion and the ocular torsion is usually conjugate andto the shoulder opposite the side of the lesion. If skew torsionis associated with a head tilt in the direction of the lowereye, this configuration of clinical signs is called ocular tiltreaction. Since both graviceptive pathways and internuclearconnections between ocular motor nuclei travel along the MLF,skew torsion due to pontomesencephalic lesions is frequentlyassociated with internuclear ophthalmoparesis (INO) (see INOsection).2 The hypertropic eye is generally on the side of theINO (figure 8).
Figure 7 A patient with a marked skew deviation and symptomatic complaints of vertical diplopia
Note the severe vertical misalignment of the two eyes. This abnormality is the consequence of otolith disruption and is supranuclear in mechanism (ductions were intact for all individual eye muscles).
Figure 8 One of our patients with multiple sclerosis had a dorsal midbrain syndrome that included a left hyperdeviation consistent with skew deviation and a left internuclear ophthalmoparesis (on attempted right gaze as seen in the lower figure)
The lesion was at the level of the left midbrain (after the decussation of the rightward originating otolith pathways) and involved the medial longitudinal fasciculus. Also note the enlarged left pupil, which exhibited the characteristics of near-light dissociation.
The most commonly recognized syndrome that results from MLFdamage is INO and is characterized by slowing or limitationof adduction (on the same side as the MLF lesion) during horizontaleye movements (figures 8 and 9).1,2,14-17
Figure 9 Volitional saccadic pathway with a lesion in the right medial longitudinal fasciculus (MLF) that results in an internuclear ophthalmoparesis (INO)
Volitional saccadic pathway with a lesion in the right MLF that results in an INO during an attempted saccade to the patient's left.
In patients with INO the contralateral abducting eye will usuallyexhibit a disassociated horizontal nystagmus, although thisdoes not always occur.6 One hypothesis to explain abductionnystagmus implicates an adaptive response to overcome the weaknessof the contralateral medial rectus.6 This is explained by Hering'slaw of equal innervation, which states that attempts to increaseinnervation to the weak muscle in one eye must be accompaniedby a commensurate increase in innervation to the yoke musclein the other eye. Subclinical nystagmus in the adducting eye(not appreciated on bedside examination) has been demonstratedwith electro-ocular techniques.18,19
The diagnosis of INO can now be precisely confirmed neurophysiologicallyby a number of eye movement tracking techniques, such as infraredoculography.18-24 These techniques can identify a variety ofabnormalities in patients with INO including slowing of adductionsaccades, abduction nystagmus, and diminished adduction saccadicamplitude (figure 10). The ratio of saccade metrics betweenthe abducting and adducting eyes, the versional disconjugacyindex (VDI), can be measured by infrared oculography and representsa sensitive measure of the disconjugacy seen in patients withINO.21-23 We have recently defined quantitative oculographicdiagnostic criteria for confirming the presence and severityof INO, utilizing a VDI velocity Z-score methodology in orderto compare patients with multiple sclerosis (MS) with INO witha normal control reference population.23 Further, we have defineda new amplitude measure of disconjugacy in INO, the first-passamplitude (FPA).24 The FPA is the ratio of the abducting/adductingeye at the point where the abducting eye first achieves theeccentric visual target (figure 10).
Figure 10 Infrared oculogram derived from a patient with multiple sclerosis with bilateral internuclear ophthalmoparesis
In this case a rightward (upward tracing) 20 deg saccade results in interocular disconjugacy (note separation of the two tracings). Observe that the right eye (OD in blue) achieves the 20 deg target rapidly, whereas the left eye (OS in red) lags behind. The ratio of the eyes when the abducting right eye achieves the target to the position of the adducting eye at that time is referred to as the first pass amplitude (FPA). Ultimately both eyes achieve the fixation target, the final amplitude (FA). During the trajectory of the saccade, the divergence of the two eyes can result in loss of stereoscopy, diplopia (transiently), difficulty reading, visual blur, and risk of fall while turning, or motor vehicle accident with head turning while driving.
In the most subtle form of INO, the range of adduction is normalwhereas only the velocity is reduced. This mild form of INOcan often be overlooked on clinical examination and may onlybe evident on formal oculographic recording. In one study, morethan 80% of patients with MS with INO had only slight or norestriction of adduction.25 Neurologic examination for detectingthe subtle adduction lag INO can be improved by the use of anoptokinetic tape.
In a recent study we assessed the accuracy of clinical detectionof INO by 279 physician evaluators who were asked to identifythe syndrome when viewing a video of 18 subjects (some of whomhad unilateral or bilateral INO of varying severity, and normalsubjects without INO).19 The utilization of infrared oculographyallowed us to validate the presence of this syndrome by specificcriteria and to quantitatively characterize the relationshipbetween the severity of the syndrome and the accuracy of clinicaldetection. The detection rates were highly accurate across allphysician groups when the degree of adduction slowing was severe.Alternately, milder cases of INO were frequently not identifiedby the majority of evaluators.
Most demyelinating lesions of the MLF are located in the ponsor midbrain, often sparing the vergence pathways, includingthe fibers projecting from the medial rectus subnucleus of cranialnerve III.2 As a result, convergence is intact in the majorityof patients despite adduction weakness on lateral gaze. Thisfinding can help distinguish an INO from partial third nervepalsy. Further, the two eyes are typically well aligned in theprimary position (nearly orthophoric or slightly exophoric oncross cover testing with one eye viewing) compared to thirdnerve palsies, which commonly produce a conspicuous exotropia(a misalignment with both eyes viewing) along with abnormalitiesof the eyelid and pupil and other extraocular muscles.
INO can produce a modest slowing of abduction as well as adductionin the same, affected eye.2 In an extreme example, it has beenreported that a complete horizontal monocular failure of eyemovement can occur (affecting the ipsilateral medial longitudinalfasciculus and possibly the abducens nerve fascicle as well)in association with a dorsolateral pontine tegmentum lesionas the first event of MS.26
One-and-a-half syndrome.
This syndrome consists of a gaze palsy in one direction withan INO when executing a saccade to the opposite side. It isproduced by damage to the PPRF or abducens nucleus and the MLFon the same side within the pontine tegmentum.27 Convergenceis generally spared as cranial nerve III is spared bilaterally.Given the preserved abduction of the eye contralateral to thelesion, one commonly observes a primary position exotropia alsoknown as paralytic pontine exotropia (figure 11).28
Figure 11 An example of the one-and-a-half syndrome in one of our patients with multiple sclerosis
The patient was unable to elicit saccades to the right (i.e., a right gaze palsy), and had evidence of a right internuclear ophthalmoparesis (INO) upon attempted gaze to the left. In this photograph, the patient is looking straight ahead. We can observe an exotropia, the so-called paralytic pontine exotropia with the left eye in exo (the only remaining movement possible). In this circumstance, there is an attempted leftward preference. However, only left eye abduction is possible given the right INO (with slowing and significant ocular limitation). Below is the T2-weighted axial MRI showing the responsible lesion involving the right pontine tegmentum (arrow).
Wall-eyed bilateral INO syndrome.
If the lesion affects the MLF within the pons or midbrain, vergencepathways and the oculomotor apparatus can be coincidentallydisrupted, resulting in a variety of eye movement abnormalitiesthat include impaired convergence.29 These lesions are typicallybilateral and produce divergence of the eyes (wall-eyed) (figure 12).
Figure 12 The syndrome of wall-eyed bilateral internuclear ophthalmoparesis (INO) in an patient with multiple sclerosis with progressive disease and a history of a severe inflammatory demyelinating syndrome involving the tegmentum of the ponto-mesencephalic junction, which affected the medial longitudinal fasciculus (MLF) bilaterally
Note the exotropic appearance of both eyes (i.e., wall-eyed). Attempted gaze to the right or left revealed adduction slowing and limitation consistent with bilateral INO. There was also reduced vertical smooth pursuit and vertical vestibulo-ocular reflexes (both pathways course through the MLF).
INO and trochlear syndrome.
A highly unusual syndrome involves a unilateral lesion of theMLF at the level of the caudal midbrain with extension intothe trochlear nucleus on the same side.30
This lesion produces an INO and contralateral hyperdeviationsecondary to a IV nerve palsy (remember the trochlear nerveexits and decussates to innervate the opposite side superioroblique muscle). This syndrome can be confused with a skew deviation;however, in the case of INO and skew deviation, the hyperdeviationis generally on the side of the INO.
The MLF contains pathways involved in the regulation of verticalpursuit, vertical vestibular signals, and vertical alignment.2,9,31-33Patients with INO will therefore often exhibit abnormalitieswith vertical eye movements, including the following: diminishedvertical gaze holding, abnormal optokinetic and pursuit responses,decreased vertical VOR gain, vertical gaze-evoked nystagmus,convergent-retraction nystagmus, decreased vertical smooth pursuit,and skew deviation.
The clinical manifestations associated with INO include diplopia(typically horizontal binocular), visual confusion, the illusionof environmental movement during horizontal saccades (oscillopsia),vertigo, and blurring of visual image acuity, particularly withreading.2 A less conspicuous, but potentially dangerous featureincludes worsening disconjugacy and a resultant break in binocularfusion during head active turning (which produces a contraversiveslow phase punctuated by saccades in the direction of head movement),while head turning during driving (e.g., changing lanes), andwhile ambulating.
Several pathologic studies have shown a clear anatomic relationshipbetween the presence of lesions along the ipsilateral MLF andthe presence of INO.1,14-17 Due to its high spatial resolution,MRI has allowed us to depict in vivo the anatomic organizationof the human oculomotor nerve complex, the MLF, and relatedstructures in the brainstem (typically white matter tracts havelow signal intensity and nuclei have higher signal intensity).34Moreover, MRI has also contributed to a better understandingof the different stages of myelination of these structures inthe preterm brain.35
In patients with INO, MRI has shown hyperintense lesions inthe region of the MLF on T2-weighted images that were not detectedusing CT.36 T2-hyperintensities in the pontine and midbraintegmentum portion of the MLF have been shown in a high percentageof patients with INO derived from different neurologic disorders(figure 13). In one study involving 58 patients with MS withINO, MRI with proton density imaging detected a higher percentageof MLF involvement (100%) than T2 (88%) and fast-FLAIR (48%).37
Figure 13 A highly conspicuous lesion in the midbrain tegmentum just ventral to the cerebral aqueduct (left image; arrow) and a highly characteristic lesion in the MLF of the pontomesencephalic junction (right image; arrow) (3 mm thick, axial proton density weighted sequences) was noted
Both images were derived from patients with multiple sclerosis and bilateral internuclear ophthalmoparesis. Both lesions demonstrate the eloquence principal of periventricular demyelinating lesions that are localized to the brainstem, in contrast to the non-eloquence of many cerebral periventricular lesions (that often do not correspond to any concomitant clinical manifestations).
We have recently studied the relationship between the severityof INO and corresponding measures of brain tissue injury withinthe MLF, derived from the advanced neuroradiologic techniquesdiffusion tensor imaging and magnetization transfer imaging.38The application of neurophysiologic methods in the quantitativeanalysis of a clinically discrete syndrome, and the characterizationof its corresponding neuroradiologic measures of tissue injury,provide a strategy for studying the relationship between clinicaldisability and the spectrum of brain tissue histopathology inMS.
Two structures responsible for the generation and gaze stabilityof vertical and torsional eye movements, the riMLF and the INC,are located in the mesencephalon. In 11 patients with MRI-identifiedmesencephalic lesions and clinical evidence of torsional/verticalspontaneous nystagmus, Helmchen and colleagues showed that combinedlesions of riMLF and INC are much more frequent than riMLF andINC lesions alone.39
More recently, modern MR-based techniques have been used toachieve a better in vivo picture of the underlying pathologicchanges of many neurologic conditions. Diffusion tensor MRIcan identify infarctions involving the MLF and also revealsdetailed information regarding white matter fibers tract anatomyand direction.40 Using line scan diffusion MRI, Mamata and colleaguesvisualized, in six healthy volunteers, the principal fiber tractsof white matter, including the MLF.41
Cerebrovascular disease.
The most common cause of INO in an older patient is ischemicinfarction. These patients are typically older than patientswith MS, with an average age of 62–66 years.42 In contrastto MS, most (87 to 93%) INO syndromes in this setting are unilateral.In a large case series of 410 cases of INO evaluated by thesame observer, stroke was the most common cause of INO (38%).42In this series, individual cases of INO are reported with variedstroke subtypes, including hemorrhage (hypertensive, vascularmalformation), vertebral artery dissection, temporal arteritis,and other vasculitides.
Multiple sclerosis.
MS constitutes the second most common cause of INO, representingapproximately one-third of cases (34%), and is the most commoncause in a young person (<45 years), where most are bilateral.42
Inflammation in MS is contingent upon trafficking of mononuclearcells across the cerebrovascular endothelium in a process mediatedby well-characterized adhesion molecules. Post-capillary venulesprovide the scaffolding for adhesion and trafficking into theCNS and have their greatest concentration in areas around theperiventricular zones.43,44 As such, the brainstem tegmentumis an area of high predilection for disease activity in MS.
Other etiologies.
A large number of causes make up the one-quarter to one-thirdof INO cases that are not due to MS or cerebrovascular disease(table). The most common of these are infection, trauma, andtumor. In some remarkable examples, mild head injury can producean isolated unilateral or bilateral INO.45,46 A partial thirdnerve palsy with prominent medial rectus weakness may be confusedwith an INO. Distinguishing features include other third nervedeficits (weakness of elevation, ptosis, pupil dilation), impairedconvergence, and absence of the contralateral abduction nystagmus,all of which point to a third nerve palsy rather than an INO.
Eye movement abnormalities including INO have been reportedin progressive supranuclear palsy (PSP).47 Parkinsonism andother features of PSP are present in these individuals, andmost eye movement abnormality can be overcome with oculocephalicmaneuvers (confirming its supranuclear character), but not inan INO (confirming its nuclear character).
A pseudo-INO is a well-described phenomenon in patients withmyasthenia gravis and Guillain-Barré syndrome.48,49 Thepresence of ptosis and lid fatigue will alert the clinicianto myasthenia, while areflexia, usually with ataxia or limbweakness, will suggest Guillain-Barré syndrome. The Miller-Fishersyndrome involves ocular motor dysfunction (potentially withINO), ataxia, and diminished or absent reflexes.49 Findingssuggestive of bilateral INO have also been reported in the settingof drug overdose; however, these individuals would be expectedto have severely impaired level of consciousness.50
The deficits associated with INO often resolve over a few weeksto months.51 In one series, patients with a cerebrovascularetiology were less likely to recover; 63% had persistent symptomsafter 3 years. However, others have observed a better prognosiswith INO due to brainstem infarction, with 79 to 87% recoveryin 2 to 3 months.52,53
Patients may be treated with patching of one eye for symptomaticrelief. Patching of the affected eye may be helpful for thosepersons who experience diplopia as a result of their INO. Whenthe syndrome is secondary to MS, corticosteroids can serve toaccelerate recovery, albeit limited in many. Since most patientsare well aligned in primary position of gaze (with good binocularfusion), and the double vision is typically provoked in eccentricgaze, the use of prisms is usually not helpful. However, a concomitantand stable skew deviation may be amenable to prismatic correctionto abolish the vertical misalignment (and consequent diplopia)of the eyes.
INO is one MLF-related syndrome that represents a useful modelby which to objectively characterize a distinctive neurologicsyndrome and its corresponding disability, with associated imagingmeasures of brain tissue injury. This strategy may representa useful proof of principle model of pathophysiology upon whichto test neuroprotective and neurorestorative therapies suchas promoters of axonal sprouting and stem cell remyelinationinitiatives. This is of particular interest given the periventricularlocation of the MLF and that stem cells may be effectively deliveredinto the ventricular system.
The authors thank Klara Zapotocka from the Graphic Design Departmentat Prague College in the Czech Republic for the concept, design,and rendering of the artwork for the illustrated figures inthis review.
elliot.frohman{at}utsouthwestern.edu
Supported by the National Multiple Sclerosis Society (Lone StarChapter), the "Once Upon A Time," the Cain/Denius ComprehensiveCenter for Mobility Research, the Irene Wadel and Robert Athafund, the Kenney Marie Dixon Pickens fund, and the Jean Annand Steve Brock Fund for Medical Sciences.
Disclosure: Teresa Frohman has no conflicts to declare. StevenGaletta has received lecture fees from Biogen Idec. Dr. Foxhas received grant or research support from Biogen Idec, Genentech,Merck, National Institutes of Health, and National MS Society.Bob Fox has served as a consultant for Biogen Idec, Genentech,Merck, Questcor, and Teva Neuroscience. David Solomon has noconflicts to declare. Dominik Straumann has no conflicts todeclare. Massimo Filippi has received grants/contracts and honoraria/consultationfees from TEVA Neuroscience, Dompè Biogen, Bayer-Shering,and Merck-Serono. David Zee has no conflicts to declare. ElliotFrohman has received lecture fees from Biogen Idec, TEVA, andSerono and consulting fees from Biogen Idec.
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MLF CIRCUITRY OF SACCADIC...
