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Show Journal of Nemo- Ophthalmology 19( 1): 34- 38, 1999. © 1999 Lippincotl Williams & Wilkins, Inc., Philadelphia Acquired Convergence- Evoked Pendular Nystagmus in Multiple Sclerosis Jason J. S. Barton, M. D., Ph. D., F. R. C. P.( C)., Terry A. Cox, M. D., F. R. C. S.( C)., and Kathleen B. Digre, M. D. Nystagmus seen only with convergence is unusual. We describe four cases of acquired convergence- evoked pendular nystagmus in patients with multiple sclerosis. The nystagmus was horizontal and asymmetric in all patients. Eye movement recordings in one subject showed a conjugate rather than a convergent- divergent relationship of the phase of movement between the two eyes. All patients had evidence of optic neuropathy and cerebellar dysfunction. Occlusion of cither eye during fixation of near targets led to divergent drift of the covered eye and a decrease in nystagmus. Intravenous scopolamine reduced nystagmus in one patient. Base- in prisms alleviated symptoms of oscillopsia at near and improving reading visual acuity. Convergence- evoked pendular nystagmus may be more common than currently appreciated, particularly among patients with multiple sclerosis. Key Words: Pendular nystagmus- Convergence- Fusion- Multiple sclerosis. Convergence modulates many types of congenital and acquired nystagmus, in varying fashion. Acquired pendular nystagmus, for example, can increase, decrease, or be unchanged by convergence ( 1). Nystagmus that appears only with convergence is uncommon. The most frequent convergence- evoked nystagmus is an upbeat jerk type ( 2). Convergence- evoked pendular nystagmus seems exceedingly rare, with only four cases reported ( 3- 5). Three were congenital and only one was acquired, from multiple sclerosis ( MS). We describe four more patients with an acquired convergence- evoked pendular nystagmus due to MS, suggesting that this abnormality may be more common than we think. Manuscript received November 4, 1997; accepted December 20, 1997. From the Department of Neurology and Division of Ophthalmology ( J. J. S. B.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, U. S. A., Department of Ophthalmology ( T. A. C.), University of British Columbia, Vancouver, British Columbia, Canada, and Departments of Neurology and Ophthalmology ( K. B. D.), University of Utah, Salt Lake City, Utah, U. S. A. Address correspondence and reprint requests to Dr. Jason J. S. Barton, Department of Neurology, KS 446, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215, U. S. A. CASE REPORTS Patient 1 A 29- year- old woman had relapsing progressive MS. She had numbness in her arms at 19, followed 2 years later by balance problems. At age 22, she developed an Uhthoff s phenomenon causing transient decreases in color and visual acuity in her right eye, which persisted. The next year she developed gait and limb ataxia, urinary incontinence, and a spastic paraparesis that gradually worsened to paraplegia at age 25. Neuro- ophthalmologic examination showed visual acuity of 20/ 30 with the right eye and 20/ 20 with the left. With pseudoisochromatic plates, she scored 12/ 16 with the right eye and 16/ 16 with the left. There was no relative afferent pupil defect ( RAPD). She had marked optic atrophy, which was worse on the right. Pursuit and ves-tibulo- ocular response-( VOR)- suppression were mildly abnormal. Saccades were normal and there was no inter-nuclear ophthalmoplegia ( INO). Gaze- evoked nystagmus was present in right, left, and upgaze, and pendular nystagmus emerged with convergence. Her disease was stable during the next 3 years. Her distance vision was good, but near- vision was consistently blurred, which was improved by covering her right eye when reading. She denied oscillopsia. She was reexamined at age 29. Distant acuity had deteriorated to 20/ 100 with the right eye and 20/ 30 with the left. Near- vision was J8 with the right eye and J3 with the left. Reading acuity with both eyes open was J4. Color vision was 15/ 16 with either eye. There was no RAPD. Optic atrophy was pronounced bilaterally. Pursuit and VOR- suppression remained abnormal. Saccades were hypermetric. Gaze- evoked nystagmus was present on left and upgaze. In convergence, she had both an upbeat ocular and lid nystagmus and a horizontal pendular nystagmus, greater in the left eye. No pupillary oscillations occurred during pendular nystagmus. Pendular nystagmus dampened when either eye was occluded, or with a 20- diopter base- in prism before one eye. Intravenous scopolamine 0.4 mg reduced pendular nystagmus, improved near- vision with both eyes open to 34 ACQUIRED CONVERGENCE- EVOKED PENDULAR NYSTAGMUS IN MS 35 J2, but did not affect upbeat nystagmus or limb dysme-tria. Visual- evoked potentials ( VEP) were normal with PI00 values at 105 ms bilaterally. Magnetic resonance ( MR) imaging showed multiple lesions in the cerebral white matter, the left pons, and the region of the superior colliculi bilaterally ( Fig. 1). EOG Recording, Patient 1 Binocular direct current electrooculography ( EOG) was performed ( Fig. 2). Horizontal electrodes were placed at the lateral canthi and nose and vertical electrodes above and below the center of the right eye. Recordings were made in steady ambient lighting with periodic recalibrations. The pendular nystagmus had a frequency of 6 Hz, and was horizontal and conjugate. It began on EOG with fixation at a point 35 cm from her eyes, but was not visible clinically until fixating at a point 20 cm away. It was present in all gaze positions during convergence. It occurred when convergence was increasing or maintained at a fixation point closer than 35 cm. Amplitudes in the left eye increased from 1° to 3° in moving the fixation target from 30 cm to 10 cm, whereas frequency remained the same. Amplitudes in the right eye were small, < 1°. During divergence the nystagmus disappeared, reappearing if divergence stopped when the fixation target was within 35 cm of the patient. Closing either eye was followed by marked divergent drift and decrease in the amplitude of nystagmus. Convergence- evoked upbeat nystagmus also increased in frequency with increasing convergence. Optokinetic responses ( OKN) and VOR were normal, but VOR suppression was impaired and saccades were hypermetric. Patient 2 A 42- year- old woman had recurrent bouts of numbness in various limbs from age 19 to age 26. At age 27, she developed right optic neuritis and diplopia on right gaze. At age 32, she had a relapse with fatigue, leg numbness, urinary hesitancy, and depression. Examination then showed bilateral optic neuropathy and a left INO. During the next 10 years she remained stable, with persisting fatigue and poor balance, and had at least seven relapses with worsening balance and fatigue and either blurred vision or oscillopsia on right gaze. At age 36, she had transient right hemifacial spasm. Magnetic resonance imaging showed extensive multiple high-intensity lesions in the periventricular white matter of the cerebral hemispheres, consistent with MS. At age 40, she developed depression and oscillopsia while reading, which persisted. Examination showed cerebellar dysmetria in all limbs, legs worse than arms, and an ataxic- spastic gait. Prednisone was ineffective. Scopolamine patches were tried and discontinued because of blurred vision. She was treated with antidepressant drugs. At age 41, numbness and reading oscillopsia worsened, and she had startle myoclonus. Azathioprine was started 6 months later. When examined, she was taking lorazepam, amitrip-tyline, and azathioprine. Visual acuity at far was 20/ 25 + 2 with the right eye and 20/ 20 - 2 with the left. Near vision was J7 with both eyes open. Color vision was 11.5/ 16 with the right eye and 12/ 16 with the left. There was no RAPD. Automated perimetry showed paracentral scotomata in both eyes. Optic atrophy was present in both eyes, worse in the right, with retinal venous sheathing in the right also. There were frequent square- wave jerks and reduced smooth pursuit gain. Optokinetic responses and VOR suppression were abnormal. There was a left INO and ocular flutter. She had a primary position down- beating nystagmus with additional horizontal gaze- evoked nystagmus. With convergence she noted horizontal oscillopsia with the fixation target 70 cm away from her eyes, but horizontal pendular nystagmus was not clinically visible until the target was 25 cm to 30 cm away. It was larger in the right eye, increased with increasing convergence, and disappeared during divergence. Occluding either eye caused a divergent drift of the covered eye and abolished both nystagmus and os- FIG 1. Magnetic resonance imaging of patient 1. T2- weighted axial images show ( A) left- sided pontine lesion and ( B) left- sided midbrain tegmental lesion. J Nmim- Ophlhalmol, Vol. 19, No. I, 1999 36 J. J. S. BARTON ET Ah. right eye horizontal position ~ left eye horizontal position ~ fixation at far (> 100cm) vertical position JL right eye horizontal position-left eye horizontal position^ _ A_... fixation point 30cm fixation point 20cm fixation point 10cm r~ JX* r*~~ ™ -~ l*, r onset of divergence FIG. 2. Electrooculography ( EOG) eye movement recordings of patient 1. Each set of three traces shows horizontal positions of right eye ( top) and left eye ( middle) and vertical EOG ( bottom). Top left corner trace shows no nystagmus during fixation of a far target. Bottom trace shows asymmetric nystagmus during fixation of near targets, with nystagmus of the left eye increasing in amplitude with progressively nearer targets. With the onset of divergence, the nystagmus is immediately reduced ( arrow). Top right corner trace shows effect of covering left eye during viewing of a near target 20 cm away ( interval between long arrows). Covering results in reduction of nystagmus and divergent drift of the covered eye ( short arrow). Note convergence- evoked upbeat nystagmus in vertical trace ( open arrowhead). cillopsia, with improvement of near vision from J7 with both eyes open to J2 with monocular viewing using either eye. An 8- diopter base- in prism also improved near vision to J2 and stopped oscillopsia. Patient 3 A 33- year- old man had transient left arm weakness at age 19. Six years later, he developed right leg weakness, right- sided numbness, and balance problems after a cold. Tinnitus, intention tremor, and clumsiness of the hands followed after a few months, and the next year brought worsening of his balance and urinary urgency, which improved with prednisone. A computed tomography ( CT) scan showed bilateral hemispheric enhancing lesions consistent with MS. Visual evoked potentials ( VEPs) were prolonged with PI00 peaks at 141 ms in the right eye and 121 ms in the left eye. At age 30, he had blurred vision in the left eye for 3 weeks. Six months later, he had diplopia for 2 weeks. When seen at age 31, he had cerebellar dysarthria, intention tremor, and dys-metria in all extremities, left worse than right, and a spastic- ataxic gait. He had generalized hyperreflexia and pseudoathetosis of the left hand. Neuro- ophthalmologic examination showed severe bilateral INO. Magnetic resonance imaging showed high- signal- intensity lesions throughout the cerebral and cerebellar white matter, particularly in periventricular regions. At age 32, treatment with ( 3- interferon began. Fourteen months later, the neuro- ophthalmologic examination was repeated. He had noted blurred vision in the right eye for 4 months, but denied oscillopsia. Visual acuity at far was 20/ 200 with the right eye and 20/ 20 with the left. He saw 4/ 16 color plates with the right eye and 15.5/ 16 with the left. He had a 0.6 log unit RAPD in the right eye. There was optic atrophy in both eyes, worse in the right eye. He had square- wave jerks but normal pursuit and saccades. Optokinetic responses and VOR suppression were normal. A moderate bilateral INO was seen. He had gaze- evoked nystagmus in right, left, and downgaze. In convergence, a horizontal pendular nystagmus emerged in the right eye with the fixation target 30 cm away from the patient and also in the left when the fixation target approached within 20 cm. Covering either eye was followed by divergent drift of the covered eye and elimination of nystagmus. The nystagmus dampened during divergence and was suppressed by viewing with an 8- diopter base- in prism. Magnetic resonance imaging that day showed multiple hemispheric periventricular lesions, several lesions in the cerebellar hemispheres, the left middle cerebellar peduncle, and the midline tegmentum at the pontomesencephalic junction. Patient 4 A 62- year- old woman had " shimmering vision" when reading, present and unchanged for 2 years. She noted poor balance for 5 years and deteriorating handwriting over 1 year. She had had an episode of slurred speech and fatigue lasting several weeks at age 29 and a brief spell of vertigo at age 42. She had had a transient ischemic attack with left hand numbness and weakness 6 years earlier, leading to discovery of 98% stenosis of the internal carotid artery, treated with an endarterectomy. She had had a femoral bypass. She had been treated for hypertension and hypercholesterolemia for 10 years and had smoked for 40 years before 1982. She was taking hydrochlorothiazide 50 mg daily and niacin 250 mg three times a day. Her blood pressure was 150/ 100 mm Hg, and there was a left carotid bruit. Neurologic examination showed hyperreflexia bilaterally with extensor plantar responses and mild ataxia of gait. Her speech was normal and there were no cerebellar signs in the arms. Neuro-ophthalmologic examination showed acuity at far of 20/ 20 with either eye. Visual fields were normal to confrontation and there was no RAPD. Optic discs were normal. Pursuit and VOR suppression were impaired, but sac-cades were normal. There was mild gaze- evoked nystagmus on right and left gaze. Convergence produced a ./ Neuro- Ophtlmtmol, Vol. 19. No. I. 1999 ACQUIRED CONVERGENCE- EVOKED PENDULAR NYSTAGMUS IN MS 37 horizontal pendular nystagmus with larger amplitude in the left eye. Her cerebrospinal fluid contained elevated IgG and oligoclonal bands. VEPs showed markedly delayed PI00 values at 170 ms bilaterally. Magnetic resonance imaging showed multifocal periventricular lesions and atrophy of the posterior one third of the corpus callosum. She was diagnosed with MS. DISCUSSION Four cases of convergence- evoked pendular nystagmus have been reported previously. Three were presumed congenital, based on a lack of oscillopsia and normal ophthalmologic and neurologic examinations. One was a 55- year- old man with conjugate convergence-evoked pendular nystagmus and an unrelated cervical radiculopathy ( 4). Autopsy showed a few neurofibrillary tangles in the periaqueductal gray matter of the caudal midbrain, but the rostral midbrain had been discarded accidentally. The second was a 15- month- old boy with congenital convergence- evoked nystagmus ( 5). Inverted OKN was the only other finding, and flash VEPs were minimally delayed. The third was an 18- year- old girl with conjugate convergence- evoked pendular nystagmus ( 3). Clinical examination, flash VEPs, ERG, and CT scan were otherwise normal. One previous case of acquired convergence- evoked pendular nystagmus was a 38- year- old woman with MS and oscillopsia on near vision ( 4). She had mild ataxia of the left arm and leg and prolonged VEPs. Visual acuity and eye movements were otherwise normal. The nystagmus was convergent/ divergent. One other related case had convergent/ divergent pendular nystagmus apparent only with convergence clinically, but eye movement recordings showed that there was a small- amplitude nystagmus during fixation of a far target ( 6). This 41- year- old woman with MS also complained of oscillopsia while reading. She had decreased acuity in both eyes, bilateral INO, mild gait and limb ataxia, and pyramidal signs in the legs. Neurologic findings in our patients with acquired nystagmus included varying degrees of hyperreflexia and spasticity as well as cerebellar ataxia and dysmetria. Various cerebellar defects in ocular motility were present also, including gaze- evoked nystagmus, downbeat nystagmus, ocular flutter, and saccadic hypermetria. This is consistent with reports of a high correlation of cerebellar signs with other acquired pendular nystagmus ( 1,7). On the other hand, two of our cases also had INOs, and the MR scan in patient 1 showed pontine and midbrain lesions, consistent with a hypothesized brainstem site of dysfunction in acquired pendular nystagmus ( 8,9). Optic neuropathy may contribute to the expression of other acquired pendular nystagmus ( 1). This is not likely a simple effect of delay in negative visual feedback about eye position ( 10), but may reflect abnormal long- term calibration of internal ocular feedback circuits by visual factors ( 1 1,12). Some evidence of optic neuropathy was also evident in all six patients with acquired convergence- evoked pendular nystagmus. Visual evoked potentials were markedly abnormal in the patient of Sharpe et al. ( 4) and in two of the three who had VEPs performed in this report. Patient 1 had normal VEPs but had clinical evidence of optic atrophy and Uhthoff's phenomenon affecting vision, and patient 2, who did not have VEPS, had optic atrophy, paracentral scotomata, decreased color vision, and a history of optic neuritis. The patient of Averbuch- Heller et al. ( 6) had slight color desatura-tion in the eye with larger amplitude nystagmus. Another shared feature with other acquired pendular nystagmus is the good response to intravenous scopolamine in our patient 1 ( 8,13). Although there are shared features, convergence-evoked pendular nystagmus differs from other acquired pendular nystagmus in distinct ways. Convergence-evoked pendular nystagmus is always horizontal. In other acquired pendular nystagmus, any trajectory is possible, with various mixtures of vertical, horizontal, and torsional components in either eye ( 7,8). Although the two eyes in other acquired pendular nystagmus are phase- locked, even in the rare exception of differing frequencies ( 14), the phase relationship of one eye to the other is very variable. Although we only have eye movement recordings on patient 1, her data and that of the others in the literature suggest that convergence- evoked pendular nystagmus is restricted to one of two phase relationships, either in- phase ( conjugate) ( 4) or 180° out-of- phase ( convergent- divergent) ( 4,6). Thus, some forms of convergence- evoked pendular nystagmus are also convergent- divergent, but others are not, and similarly, convergent- divergent nystagmus is sometimes convergence- evoked, but not always: the two phenomena are dissociable. The initial descriptions of convergence- evoked pendular nystagmus found symmetric amplitudes ( 3- 5). However, asymmetry was the rule in all our cases with acquired convergence- evoked pendular nystagmus, and in that of Averbuch- Heller et al. ( 6). Asymmetry is not unusual in other acquired pendular nystagmus, occurring in nearly half of the cases ( 1,7). This asymmetry has been correlated with asymmetric indices of optic neuropathy ( 1). Evidence of a similar asymmetry in visual afferent function was present in patients 2 and 3 and the patient of Averbuch- Heller et al. ( 6), with worse function correlating with the side with larger nystagmus. Both accommodative stimuli ( the blurred retinal image of a near object) and fusional stimuli ( the disparate positions of the image of a near object on the two retinae) can prompt convergence. The role of fusional stimuli has been examined in six subjects: in all but one ( 3) the nystagmus did not occur with monocular viewing. However, the eyes of our patients did not maintain their converged position when one eye was covered ( suggesting an inadequate vergence response to accommodative stimuli). Thus, the decrease in nystagmus could represent a " gaze- position- dependency" as much as a " fusional dependency." Abnormal internal feedback circuits for vergence re- ./ Neiiro- Oplilluilmol. Vol. 19, No. I, 1999 38 J. J. S. BARTON ETAL. sponses to fusional stimuli may underlie convergent-divergent forms of pendular nystagmus ( 6). Excessively high gain in a negative feedback loop for vergence has been suggested ( 4,15). This would require an additional pathologic shortening of time delays within the vergence system to produce oscillations more rapid than 2.5 Hz ( 6). Conjugate forms of nystagmus, as in our patient 1, are not vergence oscillations, however, unless one proposes an additional 180° phase shift as part of the disease. These may represent oscillations of other conjugate ocular motor systems, such as that for smooth pursuit, somehow triggered by the act of convergence ( 4). Oscillations in the saccadic system are thought to produce the intermittent bursts of rapid oscillations in " voluntary nystagmus" ( 16,17), which often emerge with convergent effort ( 16). Voluntary nystagmus is usually accompanied by an effortful facial expression ( 18) and asynchronous flutter of the eyelids ( 19), is difficult to sustain for more than several seconds ( 16- 19), and is extremely rapid: - 15- 25 Hz ( 17); hence, it appears quite different from convergence- evoked pendular nystagmus. Alternatively, oscillators projecting to but external to brainstem ocular motor systems may be involved ( 6): the high frequency of ataxia and dysmetria in these patients suggests that these may be located in the cerebellum. The means by which convergence might modulate the activity of such cerebellar oscillators remains uncertain. Acknowledgment: J. B. was supported by National Institute of Neurological Diseases and Stroke grant no. NSO1920- 01 Al. A. Mallinson provided valuable assistance with the eye movement recording. REFERENCES 1. Barton . US, Cox TA. Acquired pendular nystagmus in multiple sclerosis: clinical observations and the role of optic neuropathy. J Neurol Neurosurg Psychiatry 1993; 56: 262- 7. 2. Oliva A, Rosenberg M. Convergence- evoked nystagmus. Neurology 1990; 40: 161- 2. 3. Hara T, Kawazawa S, Abe Y, Hiyoshi M, Mizuki Y, Yamada M. Conjugate pendular nystagmus evoked by accommodative vergence. Eur Neurol 1986; 25: 369- 72. 4. Sharpe J, Hoyt WF, Rosenberg MA. Convergence- evoked nystagmus: congenital and acquired forms. Arch Neurol 1975; 32: 191- 4. 5. Zak TA. Infantile convergence- evoked nystagmus. Ann Ophthalmol 1983; 15: 368- 9. 6. Averbuch- Heller L, Zivotofsky AZ, Remler BF, Das VE, Dell'Osso LF, Leigh RJ. Convergent- divergent pendular nystagmus. Neurology 1995; 45: 509- 15. 7. 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