Journal ofNeurology, Neurosurgery, and Psychiatry, 1978, 41, 1084-1091

Reflex vertical gaze and the medial longitudinalfasciculusL. R. JENKYN, G. MARGOLIS, AND A. G. REEVES

From the David Prosser Neurology Research Laboratory, Division of Neurology, Departmentof Medicine, Dartmouth-Hitchcock Medical Center, and the Department of Pathology,Dartmouth Medical School, Hanover, New Hampshire, USA

S U M MARRY Extraocular movements were investigated in a patient with bilateral vascularlesions of the medial longitudinal fasciculus. The patient showed voluntary and reflex horizontalgaze consistent with his lesion, but had absent reflex vertical gaze. Voluntary vertical gaze was

present. Necropsy was performed, and the findings suggest that the medial longitudinal fasciculiin the pons convey impulses for reflex vertical gaze, but are not required for voluntary verticalgaze.

Lesions of the medial longitudinal fasciculus(MLF) produce characteristic neuro-ophthalmo-logical findings. Bilateral lesions are most commonin demyelinating processes but are also observedwith occlusive vascular disease and neoplasm(Smith and Cogan, 1959; Christoff et al., 1960;Cogan, 1970; Gonyea, 1974). With completebilateral involvement, there is paralysis of adduc-tion of both eyes with nystagmus in the abductingeye. Vertical nystagmus is usually present onupgaze, and convergence may or may not be pre-served. Skew deviation is rarely observed (Smithand Cogan, 1959). In less complete lesions, theremay be only paresis of adduction with nystagmusof both eyes in the direction of gaze (Christoffet al., 1960). Unilateral lesions are caused morecommonly by occlusive vascular disease than bydemyelinating processes (Cogan et al., 1950; Fineand MacGlashan, 1956; Harrington et al., 1966;Kupfer and Cogan, 1966; Ross and DeMyer, 1966).The paresis or paralysis of adduction is seenipsilateral to the side of the lesion. Abductionnystagmus is usually present contralateral to theand vertical nystagmus occurs frequently. Con-vergence is preserved. Skew deviation is commonwith the elevated eye usually on the side of thelesion (Smith and Cogan, 1959; Cogan, 1970;side of the lesion. Vertical gaze is usually intact,

This study was supported in part by the Hitchcock Foundation.Address for reprint requests: Dr Lawrence R. Jenkyn, David ProsserNeurology Research Laboratory, Division of Neurology, Departmentof Medicine, Dartmouth-Hitchcock Medical Center, Hanover, NewHampshire 03755, USA.

Accepted 27 June 1978

Keane, 1975). A mechanism for the eye move-ments seen in internuclear ophthalmoplegia hasbeen postulated by Pola and Robinson (1976), andrecently confirmed by electro-oculographic analysisof 25 patients (Kirkham and Katsarkas, 1977).

Unilateral hot or cold caloric stimulation of thesemicircular canals results in reflex conjugatehorizontal gaze (Bender, 1959; Shanzer andBender, 1959). The reflex response, also known asthe slow component of nystagmus, is thought tooriginate in the hair cells of the horizontal semi-circular canals and to follow a path to the contra-lateral paramedian pontine reticular formation viathe vestibular nuclei of the side stimulated. Thisarea of the reticular formation is thought to bethe source of integration of both voluntary andreflex conjugate horizontal eye movements(Bender and Shanzer, 1964; Cohen, 1971; Sharpeet al., 1974). With the subject in the supine posi-tion, unilateral cold stimulation results in reflexgaze toward the side irrigated, while warm stimula-tion directs gaze to the opposite side. The cerebralhemispheres are thought to generate a checking orfast component in the direction opposite to theslow component that determines the direction ofthe specified nystagmus-that is, nystagmus to theleft means fast component to the left (Bender,1955; Pasik et al., 1960). While some authors citethe usefulness of double simultaneous caloricirrigation in eliciting reflex vertical gaze, we havefound few reports investigating the neural connec-tions of this mechanism in man (Bender, 1959,1960; Shanzer and Bender, 1959; Shanzer, 1964;Shanzer et al., 1964).

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In primates, including man, voluntary verticalgaze is thought to be mediated in the pretectalregion of the midbrain (Bender and Shanzer, 1960;Christoff et al., 1962; Shanzer et al., 1964). Volun-tary upgaze is thought to require an intact pre-tectum and posterior commissure (Bender, 1959;Christoff et al., 1962; Pasik et al., 1969a, b), whileintact structures dorsomedial to the red nuclei areconsidered necessary for voluntary downgaze(Bender, 1959; Christoff et al., 1962; Jacobs et al.,1973; Cogan, 1974; Halmagyi et al., 1978). Recentstudies in monkeys have confirmed that bilaterallesions of the MLF eliminate reflex vertical eyemovements and impair fixation in extremes ofvertical gaze while not affecting voluntary verticalsaccades (King et al., 1976; Evinger et al., 1977).We report a case of bilateral MLF involvementand impaired reflex vertical gaze with preservedvoluntary vertical gaze which suggest that thepathway mediating reflex vertical gaze in manincludes the medial longitudinal fasciculi.

Case report

A 63 year old white man was transferred on 30October 1974 to the White River JunctionVeterans Administration Hospital with the chiefcomplaint of increasing lethargy and confusionover four days. He had a longstanding history ofdiabetes mellitus and severe peripheral vasculardisease. Abnormal general findings included asoft mid-systolic murmur and a fourth heartsound. The left leg had no pulses, and the rightleg had been amputated above the knee forocclusive vascular disease. On neurological ex-amination the patient was arousable and oriented.He had a Cheyne-Stokes pattern of respirationwhile sleeping. He had no visual field defect, equalpupils with normal direct and consensual lightreflexes bilaterally, normal direct and consensualcorneal reflexes bilaterally, decreased gag reflexesbilaterally, and dysarthria with slight deviation ofthe tongue to the left. Eye movement abnormalitiesare described below. He was able to move allextremities to command. Paratonia (resistance tomovements in all directions) was present diffusely,and there was a slight drift with pronation of hisright upper extremity. Biceps and triceps reflexeswere normal bilaterally. Knee and ankle jerkswere absent in the left leg, and the left plantarresponse was flexor. Sucking, forced biting, androoting reflexes were present. Abnormal laboratoryvalues were blood glucose of 19.4 mmol/l andblood urea nitrogen of 10 mmol/l. An old septalmyocardial infarct was detected on electro-cardiography. Skull radiography showed calcifica-

tion in the carotid arteries. Cerebrospinal fluidstudy revealed protein of 1.12 g/l and glucose of8.2 mmol/l with all other parameters withinnormal limits. EEG and brain scan were normal.

NEURO-OPHTHALMOLOGICAL FINDINGS (Fig. 1)At rest a skew deviation was present with the lefteye 3 mm above the right. Attempts to convergeafter instruction without fixating on a visual targetyielded no eye movements. With tracking of avisual target, 2 mm of adduction of the right eyeand 1 mm of adduction of the left eye were seen.An incomplete bilateral MLF syndrome was

present. On voluntary gaze to the right, the righteye abducted 7 mm with nystagmus to the right,while the left eye came to the midline withoutnystagmus. On left lateral gaze, the left eyeabducted 7 mm with nystagmus to the left, whilethe right eye adducted 2 mm past the midline

3rr- 2rnm mm

(~ <g> < <D\bluntary non-target Tracking

AT REST CONVERGENCE

7mm 62rn4t2mm

To right Up2mm m

To left 7mm Down 5mmVOLUNTARY GAZE

7mm '*2mm 7mm'2D~ ,> <W)' C4f 4m9 :Presented left to right Presented upwards Presented right to left

OPTOKINETIC STIMULATION

7mm

Head rotated right to left Head extended

7mm 2mm 2mm

Head rotated left to right Head flexed

OCULOCEPHALIC STIMULATION

7mm 4mm

Right: ice water irrigation Bilaterol ice water irrigation

~2mm 7mm

<:ED <D~ doLeft: ice water irrigation Biloteral worm water irrigation

CALORIC STIMULATION

Fig. 1 Schematic presentation of neuro-ophthalmological findings. A large arrow indicates thedirection of active checking. A small arrow indicatesthe direction of minimal intermittent checking.Absence of arrow indicates no checking. Nomeasurement indicates no change from midposition.

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without nystagmus. Vertical tracking of an objectresulted in 2 mm upgaze bilaterally with discon-jugate nystagmus upwards, and in 7 mm downgazein the right eye and 5 mm downgaze in the lefteye without nystagmus.

Optokinetic responses were elicited by use of anoptokinetic drum while the patient was alert.Optokinetic nystagmus was seen in the right eye,greater on movement of the stimulus from left toright than on right to left. In the left eye, therewas full abduction with the stimulus moving tothe patient's left and absent adduction with itmoving to the right and no nystagmus in eitherdirection. Vertical presentation of the optokineticstimulus produced no change in the eyes frommidposition.

Horizontal oculocephalic reflex evaluationshowed only abduction without nystagmusbilaterally.

Vertical oculocephalic testing revealed a 2 mmdeviation of the eyes upward when the chin wasflexed toward the chest. Frenzel glasses were notused, and visual fixation was not controlled withthis manoeuvre. With brisk extension of the headthe eyes remained in midposition.With the head raised 30 degrees above the

horizontal, caloric irrigation was performed with60 ml of ice water both unilaterally and bilaterallyand hot tap water bilaterally, with five minutesbetween irrigations. Cold stimulation on the rightelicited 7 mm abduction of the right eye withoutnystagmus and no adduction or nystagmus of theleft eye. Cold stimulation on the left elicited 7 mmabduction of the left eye with depressed, inter-mittent checking and 2 mm adduction of the righteye with active checking. Double simultaneous icewater stimulation resulted in a 4 mm depressionof the right eye with a variable nystagmus some-times to the right and sometimes vertically, andno depression or nystagmus of the left eye. Doublesimultaneous hot stimulation resulted in no re-sponse from the midposition in either eye. Upwardand outward deviation of both eyes on forcedclosure of the lids (Bell's phenomenon) wasobserved.

COURSEThe patient developed gangrene of the left lowerextremity, and died two months later with nochange in his neurological status.

PATHOLOGYGross findings included a recent focal infarct ofthe myocardial septum and an old extensiveantero- and posteroseptal infarct. The heart wasenlarged with left ventricular hypertrophy and

L. R. Jenkyn, G. Margolis, and A. G. Reeves

dilatation. There was pulmonary congestion andoedema. Atherosclerosis was severe in the aortaand moderate in the coronary arteries. Thecerebral circulation exhibited mild atherosclerosiswithout significant narrowing.The brain showed a 2 mm cystic infarct in theright cerebral peduncle at the junction of themedial and lateral portions. The peduncle medialto this zone was palpably softened. In the rostralpons, a vertically oriented zone of softening in-volved the tegmentum on the left side from the ven-tricular surface to the pars basalis. At this point,it forked into a Y that extended diagonally acrossinto the pars basalis of the contralateral side (Fig.2). The lesion extended caudally 5 mm from theuninvolved left fourth nucleus. The remainder ofthe brainstem was normal. There was also a 30 mminfarct of the left frontal operculum. There wasno involvement of the midbrain tectum, teg-mentum, or periaqueductal region. The mamillarybodies appeared normal, and there was no atrophyof the substantia nigra. The cerebral cortex showedmild generalised atrophy, with moderate dilatationof the ventricular system.

Microscopic analysis of the lesion in the mid-pons showed a malacic zone in the left tegmentuminvolving the anatomical regions formerlyoccupied by the medial longitudinal fasciculus,and the dorsal, ventral, and superior tegmentalnuclei (Fig. 3, top). The lesion extended to thepars basalis of the pons where it crossed the mid-line. The cystic area was partially occupied by

Fig. 2 Transverse gross section through rostral ponsshowing destruction of left medial longitudinalfasciculus and underlying tegmentum, now evidentas a sharply defined cystic zone. No gross alterationsof the right medial longitudinal fasciculus arerecognisable.

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foamy macrophages and remnants of blood vessels.There was a diffuse astroglial reaction in thesurrounding tissues. Throughout the right mediallongitudinal fasciculus there was a scattered lossof myelinated fibres producing a moth-eaten ap-pearance (Fig. 3, bottom). There were alsoscattered, swollen, degenerating axons spreadthroughout the fasciculus. In the surroundingtissues, there was an astroglial reaction involvingthe dorsal and superior tegmental nuclei. The re-mainder of the brainstem, including the pretectum,was normal.

Discussion

The patient showed signs of diffuse bilateral cere-bral dysfunction and bilateral involvement of the

V.

:-:. .

* **'.

MLF. There was no reflex upgaze in either eye andminimal reflex downgaze on the side of the in-completely involved MLF during double simul-taneous caloric stimulation. The presence of upgazeon oculocephalic testing suggests either that thepatient was fixating visually during the head flexionmanoeuvre (which obscured the reflex component),or that the bilateral hot caloric stimulation was notsufficient to elicit the response. It must be con-sidered that the pathway for reflex upgaze maydiffer from that of reflex downgaze. The post-mortem findings, and the presence of a bilateralMLF syndrome response on caloric stimulation ofeach side, imply that the vestibular connectionsto the paramedian pontine reticular formation wereintact bilaterally. There was complete destructionof the paramedian pontine reticular formation

Fig. 3 Top: transverse microscopicsection through rostral pons. The absenceof parenchyma on the left demarcatesthe cystic lesion which lha-s effaced theleft medial longitudinal fasciculus. Atthis low magnification, the right mediallongitudinal fasciculus appearsapproximately normal, except for a fewvacuolar zones (Luxol fast blue-haematoxylin eosin, original magnificationX45). Bottom: detail of enclosed areafrom top of figure showing subtlestructural lesions iwhich are compatiblewith functional defects in right mediallongitudinal fasciculus. These consist ofproliferation of aFtrocytes (A), vacuolesindicating loss of individual myelinatedfibres (B), and swollen degenerating axons(C) (original magnification X250).

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only in the rostral pons on the left as well as ofthe left MLF, while the right paramedian pontinereticular formation was not involved at all, andthe right MLF only partially so. This suggests thatthe absence of reflex vertical gaze in the left eyemay have been caused by reticular formation in-volvement as well as MLF destruction, while im-paired but detectable reflex downgaze of the righteye was a function of the intact reticular forma-tion on the right or only partial involvement ofthe right MLF. Despite these hypothetical objec-tions, it seems that bilateral lesions in the MLFwere the major factor contributing to impairmentof reflex vertical eye movements in this patient.A recent report of seven cases of the "locked-

in" syndrome described one patient with bilateralreflex downgaze on double simultaneous ice watercaloric stimulation. Postmortem findings showedbilaterally intact medial longitudinal fasciculi,while the basis pontis and both paramedian reticu-lar formations were destroyed. The author doesnot comment on the basis for the preserved reflexresponse (Hawkes, 1974). On double simultaneouscaloric stimulation, the observed vertical conjugatedeviation of the eyes results from thermally-induced currents in the endolymph of either theunopposed anterior (resulting in reflex upgaze) or

posterior (resulting in reflex downgaze) semi-circular canals after antagonistic reflex gaze signalsfrom the horizontal semicircular canals neutraliseeach other (Szentagothai, 1950; McMasters et al.,1966; Pasik et al., 1969a). It has been shownexperimentally in monkeys that ascending fibresfrom the vestibular nuclei project to the extra-ocular motor nuclei primarily via the mediallongitudinal fasciculi, and that most axons in theMLF rostral to the abducens nuclei arise fromboth vestibular nuclear complexes (Carpenteret al., 1963; Carpenter and McMasters, 1963;Carpenter and Strominger, 1965; McMasters et al.,1966). Vertical vestibulo-ocular responses havebeen abolished by sectioning the MLF in primates(Evinger et al., 1977). Thus the clinical and experi-mental evidence support the concept that themedial longitudinal fasciculi carry the innervationfor reflex vertical gaze from the vestibular nucleito the oculomotor and trochlear nuclei.Our patient demonstrated voluntary vertical

gaze, although the range of movement of upgazewas limited. This observation has been made inother patients with diffuse cortical dysfunction(Critchley, 1956; Hurwitz, 1968; Adams andHurwitz, 1974; Jenkyn et al., 1977). Additionally,it has been suggested that the neuronal pathwaysfor vertical gaze are not direct, but proceed fromthe pretectum to the rostral paramedian pontine

L. R. Jenkyn, G. Margolis, and A. G. Reeves

reticular formation before turning cephalad toenter the oculomotor and trochlear nuclei(Christoff, 1974). This conclusion was based on theabsence of vertical gaze observed in three patientswith infiltrating gliomas of the pons which did notextend into the midbrain, and four patients withfocal infarctions of the pontine tegmentum whichextended across the midline. The pathology re-ported in the "locked-in" syndrome demonstratespreserved voluntary vertical gaze in cases withbilateral destruction of the caudal paramedianpontine reticular formation (Halsey et al., 1967;Kemper and Romanul, 1967; Chase et al., 1968;Nordgren et al., 1971; Hawkes, 1974). No reportscould be found describing vertical eye movementsin patients with bilateral destruction of the rostralparamedian pontine reticular formation. Theabove observations suggest that cortical innerva-tion of vertical eye movements in man is mediatedby structures caudal to the midbrain in the rostralpons, and this is supported by the experimentalevidence in monkeys (Bender and Shanzer, 1964).Skew deviation was observed in our patient. The

hypertropic eye was ipsilateral to the completelydestroyed MLF. A review of the subject docu-ments the observation that the elevated eye isipsilateral to the lesion in unilateral internuclearophthalmoplegia (Keane, 1975). It is possible thathypertropia on the side of the lesion results fromloss of a tonic downward component originatingin the vestibular nuclei and carried by a disruptedMLF. The release of a tonic upward component,possibly of vestibular origin and conveyed by thecontralateral MLF, may also explain the origin ofthe upward deviation of the eye in unilateral orincomplete bilateral MLF syndromes. It wouldfollow that the relatively infrequent occurrence ofskew deviation with complete bilateral MLFlesions results from a balanced loss of upward anddownward tonic influences.Other lesions abolishing reflex vertical gaze

would include labyrinthine, eighth nerve, andvestibular nuclear involvement bilaterally. Recentreports suggest that pretectal lesions may also im-pair reflex vertical gaze in the absence of completethird and fourth nerve nuclear destruction(Halmagyi et al., 1978; Reagan and Trautmann,1978). In these syndromes, however, voluntaryvertical gaze is also significantly impaired.We have reported a case of bilateral MLF in-

volvement and impaired reflex vertical gaze withpreserved voluntary vertical gaze. In addition, wehave noted a case in the literature of intact reflexdowngaze with the medial longitudinal fasciculias the only preserved ascending extraocular motorpathways. We conclude that the major pathways

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for reflex vertical gaze in man are the mediallongitudinal fasciculi. These observations do notimply a centre for reflex vertical gaze. Rather,they stress the importance of separate pathways(Fig. 4) for voluntary and reflex vertical conjugateeye movements and the probable role played by

DORSAL VIEW

N -_ PC

MIDBRAIN

PONS

the medial longitudinal fasciculi in mediating reflexvertical gaze.

We wish to thank Judy Murphy for her efforts inpreparation of the manuscript, and Val Page forthe medical illustrations.

DORSAL VIEW

MIDBRAIN

PON S

MEDULLA\IHWXAS

\-- |CORTICA\ I--- IErLEX\ 1..... POS3WLE WECUSWIW.\I OOTICAL MHS )

Innervation of voluntary and reflex horizontal gaze

(a)

PATHWAYS

--- REFLEX \(.I I I ..POSSIBLE DECUSSATING |

REFLEX PATHWAYSI

Innervation of voluntary

MEDULLA

and reflex vertical gaze

LATERAL VIEWMIDBRAIN PONS

PATHWAYS

CORTICAL

--- REFLEX(...... POSSIBLE DECUSSATING

CORTICAL PATHWAYS)Innervation of voluntary and reflex horizontal gaze

(b)

PATHWAYS

___ REFLEX

Innervation of voluntary and reflex vertical gaze

(d)Fig. 4 (a and b) Dorsal and lateral schematic representations of the presumed pathways of voluntary andreflex horizontal gaze. The exact level of decussation of the corticobulbar axons into the contralateralPPRF is not known and may take place at multiple levels. (c and d) Dorsal and lateral schematicrepresentations of the presumed pathways of reflex vertical gaze. Innervation of voluntary vertical gaze

requires an intact pretectal region, posterior commissure, and rostral pontine paramedian reticular formation(stippled area). The exact neuronal pathways within this area are not known.PC=posterior commissure; SC=superior colliculus; IC=inferior colliculus; III N=oculomotor nucleus;IV N=trochlear nucleus; VI N=abducens nucleus; MLF-medial longitudinal fasciculus; PPRF=paramedianpontine reticular formation; VEST N=vestibular nucleus; RN=red nucleus.

MEDULLA

(c)

MIDBRAIN

LATERAL VIEWPONS MEDULLA

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