SURVEY OF OPHTHALMOLOGY VOLUME 51 � NUMBER 1 � JANUARY–FEBRUARY 2006

CLINICAL CHALLENGESPETER SAVINO AND HELEN DANESH-MEYER, EDITORS

A Diplopia DilemmaMark Saunders, FRANZCO,1 Celeste Guinane, BAS,1 Martin MacFarlane, FRACS,2

Ken Tarr, FRANZCO,2 M. Tariq Bhatti, MD,3,4,5 and David W. Pincus, MD, PhD5

Departments of 1Ophthalmology and 2Neurosurgery, Christchurch Hospital, Christchurch, New Zealand; Departmentsof 3Ophthalmology, 4Neurology, and 5Neurological Surgery, University of Florida College of Medicine, Gainesville, FloridaUSA

(In keeping with the format of a clinical pathologic conference,the abstract and key words appear at the end of the article.)

[A video presentation that helps illustrate the concepts discussed in this paper has been created.Please log on to Survey of Ophthalmology’s Web page (www.Elsevier.com/locate/survophthal) to view the video.]

Case Report. A 38-year-old healthy man awoke onemorning with diplopia. He had seen an optometristwho prescribed new spectacles, which did not help.The patient has subsequently seen an ophthalmol-ogist and a neurologist. The neurologist madea diagnosis of a presumed right fourth nerve palsy.Magnetic resonance imaging (MRI) showed a slight-ly irregular lesion in the tectum of the midbrainwith marginal patchy gadolinium enhancement.There was mild compression and stenosis of theaqueduct and mild ventricular enlargement (Fig. 1).This did not change over a 5-month period. Notreatment was undertaken. A repeat MRI scan 5months later confirmed that there was no change inthe size of the lesion. The diplopia had not changedover the 5-month period. He was then referred toa neuro-ophthalmologist because of the persistentdiplopia.

The patient had difficulty explaining the featuresof his diplopia. The double vision disappeared if

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� 2006 by Elsevier Inc.All rights reserved.

either eye was covered. It was not gaze-dependent.Both reading and driving were difficult. At times hewould fall when he walked down stairs but he rarelyhad any problem when he walked up stairs. He haddifficulty fixing from near to far and back again. Thediplopia had not varied from the onset. Headacheswhen present were of a fleeting nature that lasted upto 10 minutes, occurring sporadically every 1 or 2days. There was occasional postural vertigo andunsteadiness. The patient was otherwise healthy andon no medications.

The corrected visual acuity was 20/20 OU.Binocular vision was present including stereopsisto 60 seconds of arc. His current glasses had anappropriate prescription and incorporated 3 prismdiopters (PD) of base-out prism. The visual fieldswere normal. The ocular media were clear. Thefundi were normal with pink healthy optic disks.There were no focal neurological signs or abnormallong track signs.

0039-6257/06/$--see front matterdoi:10.1016/j.survophthal.2005.11.004

DIPLOPIA DILEMMA 69

The range of ocular movement was normal. Covertest demonstrated 2 PD of right hyperphoria inprimary position, which increased slightly on rightand down gaze. A Bielschowski head tilt test wasnegative for a fourth nerve palsy. The nine positionsof gaze are shown in Fig. 2.

How do you explain the presenting symptom of diplopia?

What further office examinations would you performgiven the site of the lesion?

Comments

Comments by M. Tariq Bhatti, MD, and David W.Pincus MD, PhD

We are presented with a previously healthy manwith a 5-month history of a poorly characterizedcomplaint of binocular double vision and a myriadof other symptoms presumably due to a right fourth

Fig. 1. Saggital MRI showing tectal lesion (*).

cranial nerve palsy. A detailed history obtained froma patient with binocular double vision can providevaluable assistance to the examiner in formulatingan initial list of possible diagnoses. Double visionthat is dependent upon head or eye positioning,distance or near viewing, as well as symptomsprecipitated by environmental conditions, cansuggest a particular ocular motility problem. Ifa patient does not spontaneously offer such details,it is important to inquire specifically about themduring the interview phase of the examination ordemonstrate these features during the physicalexamination. In this particular case it appears,based on the initial examination findings, that notall of the patient’s symptoms can be readilyattributed to the double vision. Certainly, patientswith double vision may complain of difficultyreading or driving, but these problems are oftencorrected with monocular occlusion or prismtherapy. In addition, the patient’s difficulties withalternating between near and distance fixation, andwalking down stairs may be indicative of more thanjust a primary position misalignment of the eyes, buta dysfunction of the ‘‘dynamic’’ aspects of eyemovement.

We are told the neuro-ophthalmologic examina-tion is essentially normal aside from a slight verticalmisalignment of the eyes. The range of ocularmovement is noted to be normal with a 2-PD righthyperphoria in primary gaze. An important piece ofinformation provided is the finding of a negativeBielschowski head tilt test. The result of the three-step test indicates the pattern of the verticalmisalignment is not consistent with a fourth cranialnerve palsy, but more likely a skew deviation, whichis a supranuclear ocular motility disorder resulting

Fig. 2. Composite of eye movements.

70 Surv Ophthalmol 51 (1) January--February 2006 SAUNDERS ET AL

from disruption of the otolithic-ocular pathwayswithin the brainstem.5 The vertical misalignment ofa skew deviation may be comitant or incomitant andin some patients the hypertropia may alternatebetween eyes in right and left gazes (alternatingskew deviation). There may be associated oculartorsion (incyclotorsion of the hypertropic eye) bestdetected by the double Maddox rod test or indirectfunduscopy. The ocular misalignment of skewdeviation is often constant, but periodic andparoxysmal forms have also been described.6

To determine what office examination test will beuseful in determining this patient’s symptoms it isimportant to appreciate the concept that function-ally, the ocular motor system can be divided into sixsystems:7

1. Vestibulo-ocular2. Fixation or gaze holding3. Optokinetic4. Vergence5. Smooth pursuit6. Saccadic

Each system operates relatively independentlythrough a set of premotor neurons that project tothe three ocular motor cranial nerves (third, fourth,and sixth cranial nerves) with the ultimate goal ofestablishing clear, stable, and single binocular vision.In order to coordinate the precise combinedmovement between the eyes there exist multipleparallel descending supranuclear pathways from thecerebral cortex, relaying through the basal ganglion,thalamus, superior colliculus, and cerebellum, ulti-mately synapsing onto the premotor and ocularmotor cranial nuclei in the brainstem. Therefore,

any patient with a suspected ocular motility abnor-mality should undergo clinical assessment of each ofthese functional systems (Table 1). As in thisparticular case, it is not sufficient to measure theocular misalignment and assess the symmetry andrange of ocular movements. The dynamic quality,speed, and extent of eye motion during saccadic andsmooth pursuit eye movements need to be evaluated.

Case Report (Continued)

What additional clinical sign would you look for?

Comments (Continued)

Comments by Drs. Bhatti and Pincus

The patient demonstrates normal horizontal eyemovements during both smooth pursuits andsaccades. Upgaze and downgaze smooth pursuitmovements are also normal, but in striking contrastthere is dysfunction of vertical saccadic movementson attempted upgaze as manifested by decreasedamplitude (hypometria) and decreased velocity ofthe eye movements. It is also noted that onattempted upward saccades there are small converg-ing and retracting movements of the eyes, known asconvergence-retraction nystagmus (the use of the termnystagmus for this condition is a misnomer becausethe eye movements are not a true form of nystagmusbut rather a saccadic disorder). The findings of anupgaze saccadic palsy and convergence-retractionnystagmus may explain the patients’ difficulties withvisually oriented tasks because objects of concerncannot be fixated and maintained on the fovea.

TABLE 1

Eye Movement Systems

Eye Movement System Function Clinical Assessment

Vestibulo-ocular (VOR) Stabilize image during brief headrotations

Doll’s eye maneuverCaloric testingHead rotation during Snellen visualacuity testing

Optokinetic (OKN) Stabilize retinal image duringsustained head rotation

Large field stimulus

Smooth pursuit Maintain stable eye tracking orcombined eye--head tracking ofslowly moving object

Present slowly moving small targetOptokinetic drum

Vergence Maintain foveal fixation of objectduring movement of eyes inopposite direction

Near rule: measure near point ofconvergence and accommodationPrism bar: measure fusionalamplitudes

Saccades Rapid change of fixation to foveaof objects of interest

Present two objects separated by distanceOptokinetic drum

Fixation Maintain image on foveaof stationary image

Observe eyes during fixation ofstationary target

DIPLOPIA DILEMMA 71

The constellation of skew deviation, upgazesaccadic palsy and convergence-retraction nystag-mus is indicative of the dorsal midbrain syndromealso known as pretectal or Parinaud syndrome.1

Other clinical findings that may be encounteredwith this syndrome include a downgaze preference(‘‘sun setting’’ sign in children), upper eyelidretraction (Collier sign), convergence or divergenceinsufficiency, convergence spasm, pseudoabducenspalsy, and square wave jerks. In the majority ofpatients with the dorsal midbrain syndrome, thepupils will be in a mid-dilated position with light-near dissociation (pupil response to near effort isstronger than the direct light reflex). In this patient,the pupillary light reflex should be evaluated and iffound to be absent or sluggish then the pupillaryresponse to near effort assessed.

Case Report (Continued)

What are your differential diagnosis and your manage-ment plan for the diplopia?

Comments (Continued)

Comments by Drs. Bhatti and Pincus

Before we discuss the differential diagnosis of thedorsal midbrain syndrome and the managementoptions for this patient, it may be instructive todiscuss in some detail one of the cardinal features ofthe dorsal midbrain syndrome, the vertical gazepalsy and the neural control of vertical eye move-ments (Fig. 3). The current understanding of thecomplex anatomical, physiologic, pathologic, andbehavioral aspects of human eye movements isincomplete and much of our knowledge is basedon experimental primate studies, clinical observa-tion with radiologic, and occasionally postmortem,correlation and more recently functional neuro-imaging techniques.6

Vertical saccadic and torsional eye movements aregenerated by premotor nuclei located within therostral midbrain (mesencephalon) that relay signalsto the third and fourth cranial nuclei. In addition,the pathways for vertical smooth pursuit and verticalvestibular generated eye movements ultimatelysynapse onto the third and fourth cranial nuclei.Therefore, a variety of supranuclear vertical eyemovement disorders may be encountered fromlesions in the midbrain including upgaze palsy,downgaze palsy, or combination of both, doubleelevator palsy, vertical one-and-one- half syndrome,and skew deviation.4 There appears to be three mainstructures within the rostral midbrain tegmentum

critical in the generation and maintenance ofsupraversion (upgaze) and infraversion (downgaze)(Fig. 4):

� Rostral interstitial nucleus of the mediallongitudinal fasciculus (riMLF)

� Interstitial nucleus of Cajal (INC)� Posterior commissure (PC)

Fig. 3. Diagram of vertical eye movement pathways.riMLF 5 rostral interstitial nucleus of the mediallongitudinal fasciculus; INC 5 interstitial nucleus of Cajal;PC 5 posterior commissure; MLF 5 medial longitudinalfasciculus; SR 5 superior rectus muscle; IR 5 inferiorrectus muscle; IO 5 inferior oblique muscle; SO 5superior oblique muscle.

Fig. 4. Saggital view of brainstem illustrating the relativeposition of the important structures for vertical eyemovements.

72 Surv Ophthalmol 51 (1) January--February 2006 SAUNDERS ET AL

We will briefly discuss the role of each structureseparately.

The riMLF is considered the neural substrate forvertical saccades. It contains excitatory and inhibi-tory burst cells for upward and downward saccadiceye movements. The primary projection of thesecells is to the elevators (superior rectus and inferioroblique muscles) and depressors (inferior rectusand superior oblique muscles) of the eyes. TheriMLF projects ipsilaterally to the subnuclei of theinferior rectus and fourth nuclei and bilaterally tothe superior and inferior oblique subnuclei. Clini-cally, lesions of the riMLF result in either a down-ward saccadic palsy or a combined upward anddownward saccadic palsy. In addition, unilaterallesions lead to a contralateral ocular rotation andtorsional nystagmus of both eyes.2

The INC is the primary neural integrator forvertical gaze-holding and contributes to eye-headcoordination. As a neural integrator, the INCintegrates velocity-coded signals into position-codedsignals of all eye movements to overcome thenatural elastic properties of the orbital tissues bydelivering impulses to the yoke extraocular musclesfor constant contraction during eccentric fixation.6

Unilateral lesions of the INC can result in the oculartilt reaction (manifested by contralateral head tilt,ipsilateral hypertropia with intorsion, and contralat-eral hypotropia with extorsion) and ipsilesionaltorsional nystgmus. Bilateral lesions can result ina vertical gaze palsy with sparing of vertical saccadiceye movements and upbeat nystagmus.

The PC is comprised of a group of nuclei as wellas axons from the INC projecting to the contralat-eral INC, third nerve nuclear complex, and fourthnuclei. In addition, the PC contains fibers from thenucleus of the PC projecting to the contralateralriMLF and INC that are important for verticalupward eye movements. An insult to the PC canresult in impaired vertical eye movements, inparticular upward saccades, and other manifesta-tions of the dorsal midbrain syndrome (see above).

Additional structures and cells involved in verticaleye movements include the medial longitudinalfasciculus (for vertical gaze holding, vertical vestib-ular, and vertical smooth pursuit eye movements),periaqueductal grey matter, M-group cells, y-groupcells of the inferior cerebellar peduncle, vestibularnucleus and the central mesencephalic reticularformation. Because some of these pathways arelocated in the pons and medulla, lesions in theseareas can result in pathologic vertical eye move-ments. In addition, horizontal eye movementabnormalities have been described from lesions ofthe mesencephalic reticular formation within themidbrain.8

There are a variety of voluntary and reflexivesaccadic eye movements (Table 2). Saccadic eyemovements can reach velocities of 600 �/sec. Thespeed of the saccade is dependent on its amplitude,with larger amplitudes generating increasingly fastersaccades. There is often a latency period of 200 msecprior to the development of the movement andonce a saccade begins no changes can be made untilthe end of its determined position. However, visualinformation is continually being processed duringthe saccade and can be used to influence the timing,size and direction of the next saccade. Severalcortical and subcortical regions are involved in thedevelopment of saccadic eye movements. Theseregions are interconnected to one another andform parallel descending pathways to the premotornuclei for vertical eye movement. Some of theimportant structures and their functions are thefollowing:

Frontal eye fields: Contribute to the generation ofvoluntary saccadesParietal eye fields: Influence programming ofsaccades to visual targets and shifts of visualattentionBasal ganglion: Inhibit reflexive saccades duringfixation and assist in voluntary saccadesThalamus: Contribute to the programming ofsaccadesSuperior colliculus: Involved in visually drivenreflexive saccadesCerebellum: Influence the latency and amplitudeof saccades

In contrast to saccades, smooth pursuit eyemovements travel at speeds no faster than 30 �/secwith a latency period of 100 msec. Their movementdepends on small central moving targets. The size,location, and dynamic properties of the target arecarried by the afferent visual system via themagnocellular and parvocellular pathways to corti-cal structures. The generation of smooth pursuitmovement relies on the processing of the visualtarget by the primary visual (striate) cortex andextrastriate cortical regions within the temporal-parietal-occipital junction. Additional areas involvedin smooth pursuit eye movements include thefrontal eye fields and cerebellum. Descendingvertical smooth pursuit pathways are relayed to thepons (y-group cells) reaching the midbrain throughthe medial longitudinal fasciculus.

As mentioned above, there are several clinicalfindings that characterize the dorsal midbrainsyndrome, not all of which may be present ina single patient. As the name suggests, the syndromeoccurs from an insult to the structures within therostral dorsal midbrain, including the tectal plate

DIPLOPIA DILEMMA 73

TABLE 2

Classification of Saccades

Classification Definition

Volitional saccades Elective saccades made as part of purposeful behaviorPredictive, anticipatory Saccades generated in anticipation of or in search of the appearance of a target at a

particular locationMemory-guided Saccades generated to a location in which a target has been previously presentAntisaccades Saccades generated in the opposite direction to the sudden appearance of a target

(after being instructed to do so)To command Saccades generated on cue

Reflexive saccades Saccades generated to novel stimuli (visual, auditory or tactile) that unexpectedly occurwithin the environment

Express saccades Very short latency saccades that can be elicited when the novel stimulation is presentedafter the fixation stimulus has disappeared (gap stimulus)

Spontaneoussaccades

Seemingly random saccades that occur when the subject is not required to perform anyparticular behavioral task

Quick phases Quick phases of nystagmus generated during vestibular or optokinetic stimulation or asautomatic resetting movements in the presence of spontaneous drift of the yes

Reprinted from Leigh and Zee6 with permission of Oxford University Press, Inc.

(roof of the midbrain). Although all vertical eyemovements (upgaze, downgaze, reflexive, and vol-untary) can be affected in the dorsal midbrainsyndrome, an upgaze saccadic palsy is most frequentdue to interruption of the fibers of the PC.9 Thedorsal midbrain syndrome can occur from a varietyof causes with the most common being midbraincerebrovascular accidents, tumors involving thepineal gland or tectal plate and hydrocephalus.

In this case the MRI demonstrates a posteriorthird ventricular-pineal region mass, which may bedirectly compressing the PC. Alternatively, tumors inthis region may cause indirect pressure on the PCresulting from tumor obstruction of the aqueduct ofSylvius leading to hydrocephalus. At this stage wewould suggest performing an endoscopic thirdventriculostomy (ETV) with endoscopic or stereo-tatic biopsy. Alternatively, ETV could be performedand the biopsy postponed until serum and cerebro-spinal fluid markers for beta-HCG and alpha-fetoprotein are measured.

Case Report (Continued)

Three months later the patient was readmittedsemi-acutely with raised intracranial pressure con-firmed by intracranial pressure monitoring. A rightfrontal burr hole and an endoscopic third ventricu-lostomy performed. Two slight protuberances werenoted on the upper posterior aspect of the thirdventricle, these were slightly pink in color andpresumably represented the tumor in the upperpart of the tectum. To avoid bleeding the lesion wasnot biopsied. A third ventriculostomy hole wascreated in the floor of the third ventricle through

into the interpeduncular cistern and enlarged to6--8 mm in diameter. CSF was taken for cytology.There were no abnormal cells and no malignantcells. The tumor markers of alphafeta protein andHCG were negative.

Six days postoperatively a follow-up MRI showedreduction in the size of the lateral ventricles. Themidline CSF flow study indicated a patent thirdventriculostomy endoscopic hole.

A follow-up MRI scan performed 3 months latershowed an unequivocal enlargement of the tumorwith complete obliteration of the aqueduct. Thetumor extended from the level of the upper part ofthe inferior colliculi to occupy the posterior end ofthe third ventricle. It measured 2.75 cm in maxi-mum length and 1.5 cm in vertical height. There wasno change in the clinical findings. A decision toproceed with conventional radiotherapy was un-dertaken.

Six months later a follow-up MRI scan showeda very good appearance compared to the earlierstudies. There was almost complete disappearanceof the tectal plate mass.

There was no abnormal enhancement. The CSFflow studies indicated that there was still no flowdown the aqueduct and the third ventriculostomywas widely patent.

The rapid response of the tectal plate tumor toradiotherapy would strongly suggest that the tumorwas a germinoma. Germinomas are extremelysensitive to radiotherapy and are usually cured bythis treatment.

The patient continues to need to patch one eyebecause of the lack of vertical saccades and theocular instability due to convergence-retraction.

74 Surv Ophthalmol 51 (1) January--February 2006 SAUNDERS ET AL

Concluding Comments

Comments by Drs. Bhatti and Pincus

With recent advances in instrumentation, fiber-optic technology, and endoscopic technique, ETVhas evolved into an excellent option in themanagement of patients with hydrocephalus dueto third ventricular outflow obstruction. ETV createsan opening in the floor of the third ventricle,proximal to site of obstruction, to allow cerebrospi-nal fluid to enter the basal cistern system andabsorption through normal cerebrospinal fluidpathways.

The technical details of ETV are not pertinent tothis discussion, but it should be noted that thecomplication rate is less than 5% with adverse eventsincluding arterial hemorrhage due to basilar arteryinjury, third cranial nerve palsy, meningitis, hemi-paresis, delayed closure of the fistula, and hypotha-lamic dysfunction.3 ETV is not performed by allneurosurgeons and traditional cerebrospinal fluidshunting procedures remain an alternative option.At the University of Florida, patients do not undergoradiation therapy of pineal region lesions withouta tissue diagnosis. We believe—due to the highdegree of safety and accuracy of stereotactic orendoscopic biopsy, and the potential for lesions tobenefit from chemotherapy with or without surgeryin addition to radiotherapy—biopsy is appropriatein most cases.

References

1. Baloh RW, Furman JM, Yee RD: Dorsal midbrain syndrome:clinical and oculographic findings. Neurology 35:54--60, 1985

2. Buttner U, Buttner-Ennever JA, Rambold H, Helmchen C:The contribution of midbrain circuits in the control of gaze.Ann NY Acad Sci 956:99--110, 2002

3. Cohen AR: Endoscopic neurosurgery, in Wilkins RH andRengachary SS (eds): Neurosurgery. Vol 1. New York,McGraw-Hill, 1996, ed 2, pp 539-46

4. Hommel M, Bogousslavsky J: The spectrum of vertical gazepalsy following unilateral brainstem stroke. Neurology 41:1229--34, 1991

5. Keane JR: Ocular skew deviation. Analysis of 100 cases. ArchNeurol 32:185--90, 1975

6. Leigh RJ, Zee DS: The neurology of eye movements, in TheContemporary Neurology Series. Oxford, Oxford UniversityPress, 1999, ed 3

7. Sharpe JA: Neural control of ocular motor systems, in MillerNR and Newman NJ (eds): Walsh & Hoyt’s Clinical Neuro-Ophthalmology, Vol 1. Baltimore, Williams & Wilkins, 1998,ed 5, pp 1101-67

8. Zackon DH, Sharpe JA: Midbrain paresis of horizontal gaze.Ann Neurol 16:495--504, 1984

9. Zee DS: Supranuclear and internuclear ocular motordisorders, in Miller NR and Newman NJ (eds): Walsh &Hoyt’s Clinical Neuro-Ophthalmololgy, Vol 1. Baltimore,Williams & Wilkins, 1998, ed 5, pp 1283-349

The authors reported no proprietary or commercial interest inany product mentioned or concept discussed in this article. Drs.Bhatti and Pincus gratefully acknowledge the assistance of DavidPeace, MS, Medical Illustrator, University of Florida BrainInstitute, Department of Neurological Surgery. We also wish toexpress appreciation for the editorial assistance of Mabel Wilson.This mansucript was supported by an unrestricted departmentalgrant from Research to Prevent Blindness, Inc., New York, NY.

Reprint address: M. Tariq Bhatti, MD, College of Medicine,University of Florida, Department of Ophthalmology, PO Box100284, Gainesville, FL 32610-0284.

Abstract. A 38-year-old man experienced double vision with pupillary abnormalities and convergenceretraction nystagmus. A mass, which responded to radiation therapy, was seen as the cause of his dorsalmidbrain syndrome. The neural control of vertical eye movements is reviewed and the management ofa third ventricular-pineal region mass discussed. (Surv Ophthalmol 51:68--74, 2006. � 2006 ElsevierInc. All rights reserved.)

Key words. convergence retraction nystagmus � diplopia � dorsal midbrain syndrome � skewdeviation � third ventricular tumor � vertical eye movement control