Saccadic Palsy after Cardiac Surgery:Characteristics and Pathogenesis

David Solomon, MD, PhD,1 Stefano Ramat, PhD,2 Robert L. Tomsak, MD, PhD,3 Stephen G. Reich, MD,4

Robert K. Shin, MD,4 David S. Zee, MD,1 and R. John Leigh, MD3

Objective: To characterize the syndrome of saccadic palsy that may follow cardiac surgery, and to interpret the findings usingcurrent concepts of the neurobiology of fast eye movements.Methods: Using the magnetic search coil technique, we measured eye, eyelid, and head movements of 10 patients who devel-oped selective palsy of saccades after cardiac surgery.Results: Patients showed varying degrees of slowing and hypometria of saccades in the vertical plane or both horizontal andvertical planes, with complete loss of all saccades in one patient. Quick phases of nystagmus were also affected, but smoothpursuit, vergence, and the vestibuloocular reflex were usually spared. The smallest saccades were less slowed than larger saccades.Affected patients were visually disabled by loss of ability to voluntarily shift their direction of gaze. Blinks and head thrustsmodestly improved the range and speed of voluntary movement. The syndrome usually followed aortic valve replacement.Common accompanying features included dysarthria, labile emotions, and unsteady gait. The saccadic palsy either improvedduring the early part of the course or remained static.Interpretation: Selective loss of all forms of saccades, with sparing of other eye movements, indicates malfunction of thebrainstem machinery that generates saccades. A current model of brainstem circuits could account for both hypometria andslowing. This syndrome and the visual disability it causes often go unrecognized unless saccades are systematically tested at thebedside.

Ann Neurol 2008;63:355–365

Our best visual acuity depends on images being placedon the central part of the retina (fovea or macula).During visual search, saccades (rapid eye movements)point the fovea at features of interest.1 Thus, we usevoluntary saccades to move the eye rapidly from onepoint of visual fixation to the next. Loss of voluntarysaccades causes visual disability. Progressive palsy ofvoluntary saccades is well recognized as a feature of de-generative diseases such as progressive supranuclear pal-sy; in this disorder, affected patients cannot look downto eat or fasten their shoelaces.1 Palsy of voluntary sac-cades may also occur abruptly with brainstem strokes,although other types of eye movements are usually af-fected.2,3

A hitherto little-recognized cause of selective saccadicpalsy arises as a complication of cardiac surgery, espe-cially aortic valve replacement.4–8 In the postoperativeperiod, affected patients often have vague visual com-plaints that may be dismissed as either “functional” orcaused by the effects of sedation, unless the clinician

specifically examines saccades. Prior case reports havedescribed involvement of either vertical or horizontalsaccades, or both. When tested, reflexive quick phasesof nystagmus and voluntary saccades are reported asbeing impaired, whereas other eye movements (pursuit,vestibular, vergence) are preserved.4,5 The pathogenesisof the disorder is unclear and is complicated by reportsthat some affected patients appear to show progressionwith time.5,6 One patient who died of infection amonth after the onset of saccadic palsy showed neuro-nal loss and gliosis in the midline pons.4 Few reportshave contained reliable measurements of eye move-ments; thus, the nature of the deficit has not beenclearly defined. The purpose of this study was to char-acterize and quantify the defect of gaze control so thatit could be interpreted using modern concepts of thebiology of saccades, with the ultimate goal of develop-ing strategies to rehabilitate the enduring visual disabil-ity. Partial results from two patients have appeared pre-viously in a brief report.5

From the 1Departments of Neurology and Otolaryngology, JohnsHopkins University, Baltimore, MD; 2University of Pavia, Pavia,Italy; 3Department of Neurology, Veterans Affairs Medical Centerand University Hospitals, Case Western Reserve University, Cleve-land, OH; and 4Department of Neurology, University of Maryland,Baltimore, MD.

Received May 2, 2007, and in revised form Jun 23. Accepted forpublication Jun 29, 2007.

This article includes supplementary materials available via the Inter-net at http://www.interscience.wiley.com/jpages/0364-5134/supp-mat

Published online Aug 14, 2007, in Wiley InterScience(www.interscience.wiley.com). DOI: 10.1002/ana.21201

Address correspondence to Dr Leigh, Department of Neurology,University Hospitals, 11100 Euclid Avenue, Cleveland, OH 44106-5040. E-mail: rjl4@po.cwru.edu

ORIGINAL ARTICLE

© 2007 American Neurological Association 355Published by Wiley-Liss, Inc., through Wiley Subscription Services

Subjects and MethodsWe studied 10 patients (P1-P10; 4 female patients; agerange, 30–70 years; median, 48.5 years) who had been re-ferred because of visual complaints after cardiac or vascularsurgery; their clinical features are summarized in the Table.Some patients’ visual complaints were correctly identified asbeing due to voluntary saccadic palsy, but others were con-sidered to have psychogenic complaints, and a correct diag-nosis was sometimes not made for a year or more. Visualsystem examinations were always normal, and the complaintswere due to abnormal eye movements. All patients and con-trol subjects gave informed written consent, in accordancewith the Declaration of Helsinki and the Institutional Re-view Boards of the Cleveland Veterans Affairs Medical Cen-ter and Johns Hopkins University.

We recorded horizontal and vertical positions of each eyeusing the magnetic search coil technique,1 which allows pre-cise measurement even in saccadic palsy. Subjects viewed asmall target located centrally at a distance of 1.2 m with eacheye in turn. Head rotations were also monitored using asearch coil, and in P1 to P3 and P9, measurements weremade of eyelid movements (blinks) using a small coil tapedto the lateral border of the upper lid of one eye.9 Subjectsmade saccades in response to jumps of the visual targetthrough visual angles ranging from 5 to 30 degrees. Smooth-pursuit tracking was tested as the visual stimulus moved at0.3Hz through � 15 degrees, horizontally and vertically.Vergence was tested as patients shifted their point of fixationbetween the visual target at 1.2m and a second visual targetlocated at the near point of accommodation (typically15cm). Active head rotations in darkness, or passive impul-sive rotations during fixation of the visual target, were ap-plied to test the vestibuloocular reflex (VOR) in the horizon-tal and vertical planes; some patients were rotatedhorizontally en bloc in a chair. Optokinetic responses weremeasured as patients watched horizontally or vertically mov-ing stripes projected onto a tangent screen or motion of ahandheld optokinetic drum rotated by the examiner.

Coil signals were low-pass filtered (0–150Hz) before digi-tization at 500 or 1,000Hz, and eye velocity was computeddigitally.10 We defined saccade onset and ending by a veloc-ity threshold of 10 degrees/second11; no patient showed eyedrifts or nystagmus. We compared “main sequence” relationsbetween the amplitude and peak velocity or duration with 10healthy control subjects who we had previously studied (4female patients; age range, 24–64 years; median, 35 years).11

Because most patients made small saccades, we used a powerfunction to fit the data,12 which provides a more reliablemethod of detecting slowing of small movements than does anegative exponential:

Peakvelocity � K*Amplitudem (1)

Duration � L*Amplituden (2)

We estimated the total horizontal and vertical range ofmovements for each patient. Because some patients with lim-ited range of saccades were not able to direct their line ofsight at the visual target after it jumped to a new position,

we measured the relative gain of the initial saccade from sizeof initial saccade/size of total saccadic gaze shift in responseto target jump. The gain of smooth pursuit was calculatedfrom the slope of eye velocity/target velocity, and of theVOR from eye velocity/head velocity.

ResultsThe Disorder of SaccadesAll 10 patients showed abnormalities of saccades andquick phases of nystagmus (see the Table), but the ex-tent and nature of the deficits varied. Representativerecords of the range of disorders are shown in Figure 1in comparison with a saccade made by a control sub-ject. Thus, some patients (eg, P9) generated slow sac-cades that carried the eye almost all the way to thetarget (see Fig 1B). Conversely, other patients (eg, P4,P5, and P8) made a “staircase” of 10 or more smallsaccades to acquire the target (see Fig 1D); clinically,this appeared like a slow, smooth movement. Mostcommonly, hypometria was combined with slowing,but even when a single slow saccade was made to thetarget, careful examination of the velocity channel of-ten showed a transient slowing, suggesting closelyspaced saccadic pulses (see Fig 1C). The most extremeexample of saccadic palsy was P10, who had lost allability to make saccades and quick phases. Nine pa-tients showed slowing of both horizontal and verticalsaccades; slowing of vertical saccades occurred selec-tively in P2 and predominantly in P3. No patientshowed slowing of just horizontal saccades.

Examples of main sequence plots from P3 are shownin Figure 2; also shown are representative power-function fits of the patient’s data, providing the valuesof the power (m or n) and the scaling factors (K or L).Figure 3 summarizes power-function fits for all patientsand compares them with 95% prediction intervals forall healthy control subjects. What is notable is that allpatients (except P2 horizontally) showed abnormal val-ues of the power either for peak velocity (m) or dura-tion (n), but the values of scaling factors overlappedsubstantially with control subjects. This finding sug-gests that saccadic slowing was not due to a simplescaling of main-sequence curves compared with controlsubjects, but that some form of saturation (reflected bythe shape of the curve imposed by m or n) accountedfor predominant slowing of large saccades. (This find-ing is addressed further in the Discussion and Supple-mentary information, where we apply a model to ac-count for the responses of our patients.)

Measurements of the relative gain of saccades, to-gether with an estimate of the saccadic range, whichdepended on the patient’s effort, are summarized inSupplementary Table 1. In some patients (P2, P4, andP5), vertical saccades were small and accompanied bylarge blinks, which precluded reliable measurement.Most patients showed both hypometria and slowing of

356 Annals of Neurology Vol 63 No 3 March 2008

Table. Summary of Clinical Findings

PatientNo.

Age (yr)/Sex/

Examinationa

Cardiac Disorder Clinical OcularMotor Findings

OtherClinicalFeatures

Neuroimaging Medicines withCNS Effects

P1 64/M/2 moand 2 yr

Repair of ascendingaortic aneurysm;aortic valvereplacement

Slow and smallhorizontal andvertical saccades;developed blink-head-thruststrategy; othermovementsnormal

Mild difficultywithbalance;milddysarthria

CT: normal Procainamidehydrochloride,metoprolol

P2 41/F/5 moand 5 yr

Repair of patentductus arteriosis

Vertical saccadessmall and slow;horizontalsaccades and eyemovementsnormal; largehorizontal headmovementssometimes “reset”vertical gaze

Dysarthria;labile affect;progressivegait disorder

MRI: normal; MRA:narrow P1segment of leftPCA

P3 44/F/6 mo Several repairs ofaortic dissectionover 10 yearswith aortic valvereplacement

Transient verticaldeviation aftersurgery, withupgaze limitation;subsequently,slow and smallhorizontal andvertical saccades;frequent blinksneeded to shiftvertical gaze;other movementsnormal

Undiagnosedfamilialconnectivetissuedisease;labile affect,dysphagia

MRI: periventricularsmall-vessel signalchanges; MRA:narrow P1segment of PCA

Metoprolol

P4 46/M/4 mo Nephrectomy forcancer, withspread to rightatrium;cardiopulmonarybypass andhypothermia,with 3 minutescirculatory arrest

Horizontal andvertical saccadeshypometric,made withfrequent blinksand some headmovements;other movementsnormal

Incompleteremoval ofcancer;dysphagiaanddrooling

MRI of head normal Imatinibmesylate;erlotinib

P5 45/F/10mo

Aortic valvereplacement foridiopathichypertrophicsubaortic stenosis

Initial upward gazedeviation andpossible trochlearnerve palsy;vertical saccadicpalsy greater thanhorizontal;developed blink-induced vergenceused to assistgaze shifts; othermovementsnormal

Emotionallability

Normal CT Escitalopramoxalate,clonazepam,metoprolol

P6 40/M/10mo

Aortic dissection;prior left carotiddissection

Slow horizontal andvertical saccades;developed blink-head-thruststrategy; othermovementsnormal

Ehlers–Danlossyndrometype III

MRI: increasedsignal in leftposterior thalamusand left medialtemporal lobe

Labetalol,paroxetine

Solomon et al: Saccadic Palsy 357

saccades, but in those who made the smallest saccades(eg, P4; see Fig 1D), peak velocity was not greatly dif-ferent from similarly small saccades made by controlsubjects.

Quick phases were commensurately affected to vol-untary saccades and were often sparse or absent. Thus,optokinetic stimulation often caused a tonic deviationof the eyes in the direction of stimulus motion withsmall, quick phases that did not effectively reset eyestoward center (Fig 4A). In P10, rotation in a chair in-duced tonic deviation of the eyes at the extreme of gaze

(see video clip Quick_Phases_Absent in Supplementarydata).

Effects of Blinks and Head Movements on Saccades:Recovery and AdaptationFor the group of patients, if improvement occurred, itdid so during the acute period after surgery, as in P7.Nonetheless, within a few months of the onset of theirsaccadic palsy, all patients developed a strategy of usingblinks and head thrusts to shift their direction of gaze(see video clip Slow_Saccades in Supplementary data).

Table. Continued

PatientNo.

Age (yr)/Sex/

Examinationa

Cardiac Disorder Clinical OcularMotor Findings

OtherClinicalFeatures

Neuroimaging Medicines withCNS Effects

P7 52/F/6 mo Elective repair ofthoracoabdominalaneurysm;postoperativehypotensionfollowed byhypertension

Initially had rightoculomotor palsythat resolved;subsequentlyslow saccades,less evident fordownwardmovements;other movementsnormal

Systemic lupuserythematosus

MRI: diffuse signalchanges but noevidence ofinfarction

Mycophenolatemofetil,carvedilol

P8 59/M/3 mo Type A dissectionrepair, with somedifficulty weaningfromcardiopulmonarybypass

Transient diplopia(skew deviationand left headtilt); bothhorizontal andvertical saccadesslow and small,improved withblinks; othermovementsnormal

Initial rightlower facialweakness

MRI: nondiagnostic,diffusion negative

P9 70/M/18mo

Replacement of abicuspid aorticvalve and repairof aorticaneurysm

Slow and smallhorizontal andvertical saccades;developed blink-induced vergencewith headmovements toassist gaze shifts;other eyemovementsnormal

Postoperativepseudomonasseptic shock;somedifficultywalking,withoccasionalfalls;dysarthria

MRI: mild diffuseatrophy

Escitalopramoxalate

P10 56/M/4 mo Aortic valvereplacement andaortic aneurysmrepair

Total loss of allsaccades;impairedconvergence;other eyemovementsnormal

Dysarthria MRI: mildperiventricularwhite matterlesions

Metoprolol

aExamination denotes period after surgery that patient was evaluated.

CNS � central nervous system; CT � computed tomography; MRI � magnetic resonance imaging; MRA � magnetic resonanceangiography; PCA � posterior cerebral artery.

358 Annals of Neurology Vol 63 No 3 March 2008

In P1 to P3 and P9, we documented that blinks andhead thrusts tended to increase the size of the gazeshifts, with a smaller effect on speed (see Supplemen-tary Fig 1).

Because these self-developed strategies producedmodest improvement, we attempted formal rehabilita-tion in P1 and P2, but with little benefit.5 For exam-ple, P2 had noted that whenever her eyes became ver-tically “locked up,” if she made a large eye-head gazeshift in the horizontal plane, this would reset her eyesvertically. Accordingly, she made a 6-week rehabilita-tion effort, during which she wore glasses that wereopaque except for vertical slits (requiring her to makelarge, horizontal eye-head movements), but they in-duced no improvement of her voluntary control of ver-tical saccades. Thus, despite these and other attemptsat producing adaptation using physical therapy, whenreevaluated 5 years after her cardiac operation, she re-mained unable to look down to see her car keys in herpurse and, on one occasion, burned both of her fore-arms as she removed a hot dish from the oven. She hadgiven up her job as an evaluator of art because shecould no longer visually scan paintings.

Other Eye MovementsIn contrast with saccades, vergence (see Fig 4B), VOR(see Fig 4C), smooth pursuit (see Fig 4D), and theability to hold the eye in an eccentric position werepreserved. Only P10, with complete saccadic palsy,showed deficient vergence, although he was able tosmoothly pursuit targets (see Fig 4D) and could gen-erate smooth eye velocities exceeding 15 degrees/sec. InP2, smooth eye movements driven by the optic flowthat occurs during locomotion would drive her eyesinto downgaze, and she would then reset her positionof gaze by smoothly tracking an upward movement ofher own hand.

Other Neurological and Radiological FindingsSome patients (see the Table) showed other persistingsigns: dysarthria, emotional lability, and gait difficul-ties. The dysarthria was characteristically slow and“spastic,” sometimes being severe enough to precludetelephone conversation. Emotional lability was encoun-tered especially in P2; this improved somewhat withtime and was helped by selective serotonin reuptake in-hibitor agents. Several patients also reported gait insta-bility. P2 developed dystonic posturing of her toes.

Fig 1. Examples of horizontal saccadic abnormalities after cardiac surgery. (A) Accurate saccade made by a healthy subject. (B)Slow saccade made by Patient 9 (P9) that is slightly hypometric. (C) Slow saccade made by P1 that is hypometric; note that veloc-ity dips and then increases (arrow), suggesting more than one pulse of innervation. (D) Pronounced hypometria of saccades made byP4, with a staircase of small movements that take the eye to its target. Positive values indicate rightward movements. Note thatscales differ for each panel. Red lines designate eye position; dashed lines designate target position; blue lines designate eye velocity.

Solomon et al: Saccadic Palsy 359

All patients underwent either magnetic resonanceimaging or computed tomography scanning of thebrain; aside from evidence of small-vessel disease in thecorona radiata, no abnormalities were detected. In P2and P3, some narrowing of the proximal segment ofone posterior cerebral artery was noted on magneticresonance angiography. Clinical evidence suggestedbrainstem ischemia in several patients. Thus, P3 re-ported transient vertical diplopia soon after her surgery.P5 showed upward gaze deviation and right hyper-tropia that increased on right head tilt in the postop-erative period. Early in her course, P7 had unilateralptosis and diplopia, suggestive of oculomotor nervepalsy, which resolved, suggesting midbrain ischemia.P8 described transient diplopia caused by a concomi-tant right hypertropia (skew deviation) together with aleft head tilt.

DiscussionWe have characterized an uncommon disturbance ofgaze that followed cardiac or aortic surgery in 10 pa-tients. All patients had a selective defect of voluntaryand reflexive saccades, with preservation of smooth-pursuit, vestibular, and vergence eye movements. Thedisorder of saccades consisted of slowing, hypometria,and limited range of voluntary movement. In most pa-

tients, both horizontal and vertical saccades were af-fected, but in only one patient (P2), vertical saccadeswere selectively involved. Most patients used blinks,sometimes with head movements, to assist gaze shifts.These findings raise several points for discussion. First,what is the nature of the ocular motor defect? Second,in what ways could premotor circuits malfunction inaffected patients? Third, what do the other neurologi-cal abnormalities of affected patients tell us about thenature of the disorder? Finally, what visual disability iscaused by this form of saccadic palsy, and are any ther-apies helpful?

Nature of the Ocular Motor DefectIn each of our patients, and in prior cases in whom asystematic examination of eye movements, supple-mented with measurements, was reported, the deficitconsisted of a selective palsy of all forms of saccades.4,5

Thus, voluntary saccades were either slow or hypomet-ric, or both. Quick phases of nystagmus (reflexive sac-cades) were absent or reduced during optokinetic orvestibular stimulation. Other patients with saccadicpalsy after cardiac surgery have been reported to haveabsent or impaired smooth pursuit,6,8 although eyemovements were not recorded. In our patients, smoothpursuit was prominently preserved, even in P10, who

Fig 2. Representative plots of amplitude versus peak velocity (A) or duration (B) for horizontal saccades made by Patient 3 (P3),compared with 95% prediction intervals (PIs) for the group of 10 healthy subjects. Parameters for power-function fit of peak veloc-ity or duration versus amplitude are indicated.

360 Annals of Neurology Vol 63 No 3 March 2008

had complete saccadic palsy (see Fig 4D). Vergencewas also usually preserved and was sometimes en-hanced to promote gaze shifts (see SupplementaryFig 1).

This stereotypic presentation suggests that the com-mon mechanism for generating all types of fast eyemovements, which resides in the brainstem, was af-fected in these patients. This clinical picture is distinctfrom the disturbance of gaze that occurs with corticallesions, ocular motor apraxia. For example, with water-shed infarcts that involve bilateral frontal and parietaleye fields, patients lose the ability to generate all formsof voluntary eye movements (voluntary saccades,smooth-pursuit, and vergence), whereas reflexive eyemovements (vestibular and quick phases of nystagmus)

are preserved.1,13 A similar picture occurs with otherprocesses that bilaterally affect the cortical eye fields,and there are often other associated defects, such asconstitute Balint’s syndrome.14 Our patients had nor-mal vision and no disturbance of cortical functionssuch as neglect. This defect of saccades that followscardiac surgery has been likened to that occurring inprogressive supranuclear palsy.6 However, our patientsshowed a substantial defect of horizontal saccades, to-gether with preservation of smooth-pursuit and ver-gence movements; none of these findings is character-istic of progressive supranuclear palsy.1

Neuroimaging in P2 and P3 showed narrowing ofthe proximal posterior cerebral artery, from whicharises a small perforating vessel, the posterior thalamo-

Fig 3. Summary for nine patients able to make saccades of relations between amplitude and peak velocity (A) or duration (B), cor-responding to Equations 1 and 2 (see Subjects and Methods). The parameter values correspond to power-function fits similar tothose shown in Figure 2. NS 5% and NS 95% indicate prediction intervals for normal control subjects.

Solomon et al: Saccadic Palsy 361

subthalamic paramedian artery that supplies an area ofthe rostral midbrain important for the generation ofvertical saccades (see the following section). Severalother patients showed clinical evidence of brainstemdisturbance such as diplopia (see the Table). Only onewell-studied case has been reported in which autopsydata were available.4 In that patient, who died of in-fection several weeks after aortic valve replacement,neuronal loss and gliosis were confined to the parame-dian pons, an area important for generating saccades. Itremains possible that hypotension,15,16 or possibly in-traoperative hypothermia, contributed to the develop-ment of the syndrome.

Malfunction of Premotor Circuits ThatGenerate SaccadesThe reticular formation of the brainstem houses thevital machinery for generating saccades: premotor burstneurons and omnipause neurons (OPNs; Fig 5). Burstneurons show high-frequency discharge immediatelypreceding saccades, the pulse of innervation.17,18 Therate of burst neuron discharge is related to the peak

velocity of the saccade, whereas the total number ofspikes in the burst is related to the size of the saccade.Burst neurons are of two main types: excitatory andinhibitory. They both project monosynaptically to oc-ular motoneurons in such a way that Sherrington’s lawof reciprocal innervation is obeyed. Excitatory burstneurons generating horizontal saccades are located inthe paramedian pontine reticular formation, at the levelof the abducens nuclei, and extending rostrally.19 Theyare glutamatergic and project monosynaptically to theipsilateral abducens nucleus. Experimental bilateral le-sions in the paramedian pontine reticular formation se-lectively abolish horizontal saccades, leaving other eyemovements intact.20 Excitatory burst neurons generat-ing vertical and torsional saccades and quick phases arelocated in the midbrain, in the rostral interstitial nucleiof the median longitudinal fasciculus.21 They projectmonosynaptically to the vertical and torsional mo-toneurons. Bilateral chemical lesions of rostral intersti-tial nuclei of the median longitudinal fasciculus abolishvertical and torsional rapid eye movements.22

A second important component of the brainstem

Fig 4. Representative examples of preservation of other types of eye movements in Patient 3 (P3), who had both horizontal andvertical saccadic palsy, and P10, who had complete saccadic palsy. (A) Example of tonic deviation of the eyes in the direction ofupward optokinetic stimulus motion in P3; resetting quick phases are small. Red line indicates vertical gaze; blue line indicateshorizontal gaze. (B) Convergence movement of about 15 degrees (positive value) in P3, made with a small upward saccade. Redline indicates vertical gaze; blue line indicates vergence. (C) Horizontal vestibuloocular reflex during passive yaw head rotation asP3 looked toward a flashing light in a dark room; gain is about 1.0, so that gaze (eye position in space) remains almost constant.Green line indicates head; blue line indicates gaze; red line indicates eye in head. (D) Onset and subsequent horizontal smoothpursuit in P10; note how he generates smooth movements with little phase shift compared with the target (dashed line), despitecomplete absence of corrective saccades. Red line indicates horizontal gaze.

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saccade generator is OPNs, which lie close to the mid-line in the raphe interpositus nucleus.23 OPN are gly-cinergic24 and project to burst neurons in both thepons and midbrain. OPN are tonically active but pausebefore saccades in any direction; they resume firingwhen a motor error signal falls to near zero, signalingthat the saccade is complete. Electrical stimulation ofOPN arrests saccades in midflight.25 Initially, it wasproposed that OPNs prevent burst neurons from firingexcept when a saccade is initiated. However, chemicallesions of OPNs cause saccades to become slow, al-though they are initiated after a normal reactiontime.26 More recently, it has been proposed that, rather

than acting simply as a gate or switch, OPNs also havea neuromodulatory function, to increase the respon-siveness of saccade-related neurons when they receive atrigger signal.27,28 Thus, not only is glycine an inhibi-tory neurotransmitter at strychnine-sensitive channels,but it is also a neuromodulator at N-methyl-D-aspartatechannels.29 The effect of OPNs on burst neurons may,therefore, be twofold: inhibition when no saccade isplanned, but enhancement of glutamatergic mecha-nisms when a saccade is triggered (see Fig 5). The trig-ger signal for a saccade arises from the superior collicu-lus, which, in turn, receives inputs from the corticaleye fields.30 The superior colliculus projects directly toOPN and indirectly to burst neurons via long-leadburst neurons, which are distributed throughout thebrainstem reticulum.31,32

Several distinct mechanisms that could have causedslow saccades in our patients are schematized in Figure5. First, the burst neurons themselves could be dam-aged during cardiac surgery, whether by local ischemia,microemboli, or some other process (see Fig 5, site 1).Burst neurons for horizontal saccades and OPN (forboth horizontal and vertical saccades) lie in close prox-imity in the pons. Thus, it follows that selective deficitsof horizontal saccades are unlikely, and they were notobserved in this study. Selective involvement of rostralinterstitial nuclei of the median longitudinal fasciculuscould account for the predominantly vertical saccadicdefect in P2. Second, OPNs might be damaged, inwhich case both horizontal and vertical saccades wouldbe expected to be slow (see Fig 5, site 2). Less severedamage to OPN could change their discharge proper-ties such that they resumed firing before the eyereached the target. Thus, the threshold at which themotor error signal causes OPN to resume dischargecould be increased (see Fig 5, site 4), causing saccadesto become hypometric. Third, the trigger signal fromthe superior colliculus, which is normally relayed vialong-lead burst neurons, might be disrupted so that itwas not synchronized with the cessation of OPN firing(see Fig 5, site 3). Because the superior colliculus en-codes saccades in polar coordinates, a disturbance ofthe transformation of the trigger signal into the Carte-sian coordinates of burst neurons might be expected toaffect both horizontal and vertical movements. Finally,it is also possible that cerebellar damage contributes tothe saccadic abnormalities. Acceleration and decelera-tion of saccades, as well as accuracy, are under controlof the midline cerebellum: the ocular motor vermis andfastigial ocular motor regions.33 A selective cortical cer-ebellar lesion affecting the ocular motor vermis resultsin hypometria and decreased saccade acceleration anddeceleration.34 Purkinje cells in the cerebellum are se-lectively damaged by global ischemic conditions.35 Pur-kinje cells normally inhibit fastigial nuclear outputneurons, many of which, in turn, project to contralat-

Fig 5. Schematic of brainstem components of saccade-generating mechanism, with hypothetical sites at which slow orhypometric saccades might arise. Excitatory burst neurons(EBNs) receive a trigger signal from the superior colliculus(not shown), which is relayed by long-lead burst neurons(LLBNs) and uses glutamatergic mechanisms. The second ma-jor projection to burst neurons is from omnipause neurons(OPNs), which are tonically active but are inhibited by thesuperior colliculus when a saccade is to be generated. OPNsinhibit burst neurons via glycine. When a saccade is to betriggered, OPNs cease discharge, releasing burst neurons frominhibition. The trigger signal is amplified by glycine, whichalso acts as a neuromodulator at glutamatergic receptors. OPNneurons cease firing during the saccade but resume when amotor error signal falls to near zero, signaling that the saccadeis complete. Slow saccades could be caused by (1) lesions affect-ing EBN, (2) lesions affecting OPNs, or (3) an abnormaltrigger signal. Hypometric saccades might arise if the thresholdat which the motor error signal allows OPNs to resume dis-charge is increased (4). MN � motoneuron.

Solomon et al: Saccadic Palsy 363

eral inhibitory burst neurons.36 Thus, loss of vermisinhibition of fastigial neurons might result in excessiveor premature excitation of inhibitory burst neurons,thereby slowing saccades, and even cause the staircaseof small saccades seen in some patients.

Several lines of evidence support the hypothesis thata disturbance of the brainstem reticular formation wasresponsible for saccadic palsy in our patients. First, onewell-studied case of saccadic palsy had lesions limitedto the paramedian pons.4 Second, the stereotypicalfindings, described in the previous section, bespeakbrainstem reticular disease, not cerebral or cerebellardysfunction. Third, P2, P3, P5, P7, and P8 showedother evidence of brainstem damage. Fourth, clinicalevidence of cortical or cerebellar damage was lacking.Fifth, we tested a current model for the brainstem gen-eration of saccades28 and found that it could accountfor the eye movement disorder in our patients if om-nipause and, to some extent, premotor burst neuronsmalfunctioned (see Supplementary Data and Supple-mentary Fig 2). Nonetheless, other mechanisms causedby damage involving the cerebral hemispheres or cere-bellum remain possible, and functional imaging mayhelp clarify whether more than one mechanism is in-volved.

Insights from Other Neurological ManifestationsBesides saccadic gaze palsy, our patients showed otherneurological abnormalities. These included a spasticdysarthria and emotional lability, which have been at-tributed to lesions in the periaqueductal gray matter ofthe midbrain,37 although lesions at other sites are pos-sible. Some of our patients also reported instability ofgait, and P2 also suffered uncomfortable dystonic pos-turing of her toes and a mild gait ataxia. The patho-genesis of these complaints remains unclear. Prior re-ports have suggested that some of these deficits, andperhaps the gaze disturbance, get worse with time.6 P1and P2, whom we have followed the longest, reportsome minor progression of gait difficulties. Such a pro-gression might be viewed as evidence against amonophasic ischemic insult. However, some brainstemstrokes can cause progressive disorders, the best knownbeing the syndrome of oculopalatal tremor associatedwith hypertrophic degeneration of the inferior olivarynucleus.1 It appears possible that disruption of otherbrainstem circuits could cause persisting or progressivesymptoms.

Recovery Mechanisms and Rehabilitation of theVisual DisabilityBecause our patients had preservation of their VOR,head movements usually did not aid efforts to changethe direction of gaze. Nevertheless, many of our pa-tients spontaneously developed mechanisms to attemptto improve their ability to voluntarily shift gaze, such

as blinks and head thrusts. Blinks are known to facili-tate saccades, possibly by inhibiting OPN.38 Headmovements may also improve gaze shifts, perhaps byproviding a stronger signal to the brainstem mecha-nisms that trigger saccades with head movements.39

However, even in those patients who were specificallytrained to use head thrusts and blinks, these mecha-nisms produced only modest improvements in rangewithout any substantial effect on the speed of the gazeshift (see Supplementary Fig 1). Thus, our patients re-mained visually disabled several years after cardiac sur-gery.

Could pharmacological interventions restore controlof voluntary gaze in such patients? This question is in-triguing if, indeed, burst neurons may be spared insome cases, and if the control of their discharge is atfault. More information is needed about the mem-branes and channels on saccadic burst neurons, andhow these mechanisms lead to firing rates that areamong the highest in the nervous system. Additionalclues may come from the pharmacology of medicationsthat slow saccades, such as benzodiazepines.40 Armedwith such knowledge, it may become possible to sub-ject agents with known effects on channels and neuro-transmitters to a clinical trial.

This work was supported by the NIH (EY06717, R.J.L.; EY01849,D.S.Z.), Department of Veterans Affairs (R.J.L.), and Evenor Arm-ington Fund (R.J.L.).

We thank Drs J. Posner, G. Kosmorsky, P. Savino, and S. Galettafor referring patients, and Dr B. Volpe for advice and assistancewith rehabilitative efforts. We are grateful to Dr L. Optican forproviding us with insights into the brainstem generation of saccades.

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