OCULAR LATERAL DEVIATION WITH BRIEF REMOVAL OF VISUAL FIXATION DIFFERENTIATES CENTRAL FROM PERIPHERAL VESTIBULAR SYNDROME

Abstract

Objective:

Ocular lateral deviation (OLD) is a conjugate, ipsilesional, horizontal ocular deviation associated with brief (3–5 sec) closing of the eyes, commonly linked to the lateral medullary syndrome (LMS). There is limited information regarding OLD in patients with the acute vestibular syndrome (AVS). In one case series 40 years ago OLD was suggested to be a central sign. Recently, horizontal ocular deviation on imaging (RadOLD) was frequently associated with anterior circulation stroke and horizontal gaze palsy. Similarly, RadOLD has been associated with posterior circulation stroke, e.g., LMS and cerebellar stroke, but without clinical correlation with OLD.

Methods:

This is a prospective, cross-sectional diagnostic study of 151 acute AVS patients. Patients had spontaneous nystagmus. Horizontal gaze deviation was an exclusion criterion. We noted the effect of brief 3–5 sec eyelid closure on eye position, and then used the HINTS algorithm (the head impulse test, nystagmus characteristics and skew deviation) and RadOLD, to establish a correlation between clinical and radiologic findings

Results:

Of the 151 AVS patients, 100 had a central lesion and 51 a peripheral lesion; 29 of the central lesions were LMS, and 11 had OLD. Additionally, one lateral pontine syndrome had OLD. On opening the eyes 11 patients with OLD and LMS made multiple, hypometric corrective saccades to bring gaze back to straight ahead, n=10/11 patients with LMS showed RadOLD.

Conclusions:

OLD with multiple hypometric corrective saccades on opening the eyes was infrequent but highly localizing and lateralizing. We emphasize how simple it is to test for OLD, with the caveat that to be specific, it must be present after just brief (3–5 sec) eyelid closure.

Introduction:

The acute vestibular syndrome (AVS) is the sudden onset of dizziness accompanied by nausea or vomiting, unsteady gait, sustained nystagmus and intolerance to head motion, that persists for a day or more.¹ A small though important subset of AVS patients have a high risk for stroke, particularly in the brainstem and cerebellum. The lateral medullary syndrome (LMS) is one central cause of the AVS. Patients with LMS commonly have ocular lateral deviation (OLD).^{1, 2} OLD was first described by Moberg and colleagues in one patient with LMS in 1962³ and characterized further by Hagström and colleagues in 1969 in three patients with LMS as “a conjugate deviation of the eyes as soon as fixation ceased ”.⁴ In 1974, Hörnsten described the clinical characteristics of OLD in a larger group of patients, including 14 with LMS and 15 with vestibular neuritis.⁵ He described OLD as “moderate to very marked, and almost maximal horizontal ocular deviation due to elimination of visual fixation.” OLD was never associated with a horizontal gaze palsy. Moreover, return to center eye position was always possible with fixation. They noted only minimal (3 degree) OLD in vestibular neuritis.⁵

Similar findings were reported in another group of LMS patients.⁶ While OLD has been occasionally described in other conditions, such as rostral medial medullary infarction⁷ and lateral pontine stroke,^{8, 9} the incidence of OLD and its clinical characteristics in larger cohorts of patients are unknown. Here, we sought the incidence of OLD in patients with AVS to aid localization and diagnosis. We hypothesized that when OLD is maximal, with a complete horizontal conjugate deviation of the eyes, a central cause of AVS is most likely.

Radiographic horizontal gaze deviation (RadOLD) has also been described in patients with stroke.^{10, 11} In a recent, large cohort of patients with anterior circulation stroke, 65.2 % of the patients with RadOLD had complete or partial horizontal gaze palsy that contributed one or two points to the NIH stroke scale. But the remaining 34.6 % patients did not have horizontal gaze abnormalities.¹⁰ In posterior circulation stroke, cerebellar stroke was associated with RadOL in a small series, but without clinical correlation,¹² In a recent larger series, patients with pure LMS, with LMS and ipsilateral cerebellar stroke, and with presumed brainstem transient ischemic attacks, had RadOL.¹³ Previously, we prospectively studied clinical and RadOL in a small group of AVS patients; the direction of the RadOLD correlated with the presence and direction of the slow phase of the nystagmus or OLD.¹⁴ Finally, in a recent report, RadOLD was contralesional to the side of medial posterior inferior cerebellar (m-PICA) strokes.¹⁵ Here we attempt to clarify the contribution of radiological and bedside signs of OLD as diagnostic markers in patients with AVS.

Methods:

We prospectively assessed for OLD and RadOLD in consecutive patients with AVS seen at the Illinois Neurologic Institute, Saint Francis Medical Center in Peoria, Illinois beginning in 2010. We have previously reported some of these patients and their RadOLD, but clinical OLD was not analyzed.^{14, 16} All patients with vestibular neuritis had continuous vertigo and nystagmus, and were admitted for 48 hours of observation. We summarize the protocol in the study diagram in Supplementary Figure 1. JCK examined all the patients including their eye movements as part of a complete neurological examination. The patients with vestibular neuritis were examined within 12 to 24 hours after they arrived at the hospital. The time to examination for all patients ranged from 1.5 hours to 96 hours (average 14 hours), Two of 29 patients with LMS who were transferred from another facility were evaluated 72 and 96 hours after their symptoms began; the remaining were examined within 48 hours after their symptoms began (Table 1, and Supplementary Table 1). Paralysis of horizontal gaze was an exclusion criterion. The patients sat at the edge of the stretcher or hospital bed; we helped them sit up if needed.

Table 1.

Ocular laterodeviation (OLD) and radiographic h-CGD

Patient number	Age and gender	RadOLD in degrees, and	Direction of conjugate lateral gaze deviation (LGD) with brief eyelid closure or fixation block	Nystagmusb	Initial examination after symptom onseta	Skew	Timing and duration of OLDc	Neurologic findings second in-patient examination
1 R OLD	52, M	RE: 32; LE: 32.2	Ipsilesional R lateral medulla, R cerebellar tonsil, uvula and nodulus stroke	h-LBN with -torsional component, top pole beating to left ear in straight-ahead gaze noted 24 h after onset of symptoms	Had 3 TIA’s. No OLD, at 6 h exam	No	OLD at 18-h exam, present 6 weeks later, resolved between 6 weeks and 5 months	Nystagmus subsided. Ipsilesional truncal ataxia grade 3
2 R OLD	75, F	RE: 21.9; LE 22.4	Ipsilesional R lateral medulla and lateral cerebellum	h-LBN with torsional component, top pole beating to left ear in straight-ahead gaze noted 24 h after onset of symptoms	No OLD at 3 h exam	Left OTR	OLD at 30-h exam, and during 3-day hospital stay	Nystagmus diminished. Ipsilesional truncal ataxia type 3. Crossed sensory loss
3 L OLD	88, F	RE: 22.4; LE 26.6	Ipsilesional L lateral pons, L flocculus, L MCP, L SCP mid basilar stenosis	Spontaneous straight ahead and gaze evoked h-RBN	L OLD at 24-h first exam	No	OLD at 24-h exam and during 5-day in ICU until cardiac arrest	Ipsilesional truncal ataxia type 2. Acute left hearing loss
4 L OLD	61, F	RE: 25.9; LE:30.3	Ipsilesional L lateral medulla	Spontaneous straight ahead and gaze evoked h-RBN	Woke up with symptoms. No OLD at 48 h exam	Yes	OLD at 72-h exam, lost to follow-up	Ipsilesional truncal ataxia type 3. Crossed sensory loss
5 R OLD	41, F	RE: 34.9; LE 25	Ipsilesional R lateral medulla	Spontaneous straight-ahead h-LBN	No OLD at 6-h exam	Yes	OLD at 12 h resolved by 48 h	Ipsilesional ataxia type 3. Crossed sensory loss. Neck pain
6 L OLD	49, F	RE: 21.4; LE: 36.2	Ipsilesional L lateral medulla	h-gaze evoked RBN	No OLD at 12 h exam	Yes	Present at 36-h exam; lost to f/u	Ipsilesional grade 2 ataxia
7 R OLD	62, F	RE: 18.9; L:5.3	Frist MRI: normal second MRI (48 h later): ipsilesional R lateral medulla	Spontaneous straight ahead and gaze evoked h-LBN	No OLD at 12 h exam	Yes	OLD at 24-h exam, resolved in 12-h	Ipsilesional grade 3 ataxia. Crossed sensory loss
8 R OLD	63, M	RE: 29.3; LE: 27.35	Ipsilesional R lateral medulla	Spontaneous h-LBN with a torsional component, top pole beating to left ear in straight-ahead gaze/h-RBN in right gaze	No OLD at 12 h exam	Right OTR	OLD at 32-h exam and present for 72 h Lost to f/u	Ipsilesional grade 3 ataxia. Dysarthria
9 R OLD	51, M	RE: 35.6; LE 26.6	Ipsilesional R lateral medulla	Spontaneous straight-ahead UBN	No OLD.at 24 h exam	Yes	Noted at 48-h exam resolved in 4 days	Ipsilesional grade 3 ataxia, right limb ataxia crossed sensory loss
10 R OLD	59	RE: 45.3; LE: 42.3	Ipsilesional R dorsolateral medulla	Bilateral h-gaze evoked nystagmus	Woke up with symptoms. OLD at 6 h exam, contralateral pain sensation loss, hiccups	Yes	OLD present during 8-day hospital stay OLD not present at the 1-month exam	Bilateral upper and lower limb dysmetria, ataxia grade 2. Bilateral gaze evoked nystagmus
11 R OLD	28, M	RE 35.6; LE: 20.9	Ipsilesional R lateral medulla and cerebellum	Spontaneous h-LBN with a torsional component, top pole beating to left ear in straight-ahead gaze	No OLD at 6 h exam	No	OLD 24 h after symptom onset decreased 1 week after initial exam	At 24 h ipsilesional grade 3 ataxia. Crossed sensory loss. Horner’s syndrome
12 L OLD	39,M	RE:22.4; LE18.1	Ipsilesional L lateral medulla and cerebellum	Spontaneous h-RBN, bilateral h-gaze evoked nystagmus, hypometric saccades	No OLD at 6 h exam	Left OTR	OLD at 24 h exam present 3 months later	At 24 h crossed sensory loss. Transient dysphagia

h-CGD horizontal conjugate gaze deviation, h-HIT horizontal head-impulse test, L left, LBN left-beating nystagmus, MCP middle cerebellar peduncle, OLD ocular lateropulsion, OTR ocular tilt reaction, PML progressive multifocal leukoencephalopathy, R right, RBN right-beating nystagmus, SCP superior cerebellar peduncle, UBN upbeat-nystagmus

^aAll patients had on initial exam severe truncal ataxia and needed assistance to sit up on the side of the bed

^b11 patients had a normal horizontal HIT, except for patient 3 with an abnormal left h-HIT

^cAll patients with OLD had centripetal corrective saccades when they opened their eyes, except for patient 3 who had a single corrective saccade

The patients underwent a HINTS examination (nystagmus direction, tests for skew deviation and head impulse test), then the effect on horizontal ocular position of ~3–5 seconds of eye closure was recorded. The instructions to the patient were 1. Without moving your head, fix on a center fixation point (which was located ~ 4 feet in front of the patient). 2. Close your eyes gently for 35 seconds. 3. Open your eyes and look at the center fixation point. Each patient performed this maneuver three times and was tested twice daily in the first 48–72 hours when possible, then daily before discharge, and subsequently in follow-up visits. After testing for OLD, the standard neurologic examination, and tests of posture and gait followed. We defined OLD as a complete ocular lateral deviation, seen immediately upon opening of the eyes. (i.e., the far lateral aspect of the corneal limbus was “buried” and no sclera was visible between the limbus and lateral canthus) (See Video 1 for an example of OLD). We defined minimal OLD, as a small amplitude deviation of less than 5 degrees. The examiner knew how unstable the patient was while sitting or standing, and knew the results of the HINTS examination, but did not know previous neurologic or imaging findings.

We correlated these findings with the results of the head impulse test (HIT), the characteristics of nystagmus, the presence of a skew deviation and bedside hearing tests, using the HINTS algorithm, with hearing loss added (HINTS-plus).^{16, 17} We tested horizontal and vertical saccades and pursuit at the bedside, and quantified truncal ataxia using the recently described scale in AVS.¹⁸ We localized a lesion as central if there was a positive HINTS-plus, additional neurologic abnormalities, or characteristic abnormalities on magnetic resonance imaging (MRI) including diffusion-weighted imaging (DWI). We diagnosed vestibular neuritis if there was a unidirectional contralesional horizontal nystagmus, a unilateral abnormal HIT, no skew deviation, normal MR imaging, and characteristic clinical course. Testing for OLD on follow up examinations provided information on the time course of OLD. We also quantified the degree of RadOLD, using the method described by Lesley and colleagues¹⁹, measuring the angle between a line bisecting the lens (zonular or “long axis” of the lens) in each eye and a line perpendicular to the head axis (nasal septal or naso-occipital axis).We calculated ocular torsion by measuring the tilt angle between the macula and optic nerve on digital fundus photographs.

We used descriptive statistics with 95% confidence intervals (CI) calculated using Stata v.14.2 (College Station, TX).²⁰ This project is part of an on-going prospective study of acute stroke in AVS patients approved by the University of Illinois, Peoria IRB-1. We followed the tenets of the Helsinki Declaration. This report is prepared following STROBE guidelines.²⁰

Data Availability Statement:

We will share by request non-published anonymized study data with any qualified investigator per request.

Results:

We evaluated 151 patients with AVS, 100 (66%) of whom had central lesions (including 84 strokes) and 51 of whom had vestibular neuritis (34 %) (Supplementary Figure 1). Of the patients with strokes, 29 had LMS. All patients with LMS initially presented with isolated AVS (i.e., they had no non-vestibular eye signs nor general neurologic signs other than imbalance). For some, however, other eye signs or neurologic findings developed later. By the time, we identified OLD, nystagmus had often decreased, and nausea and vomiting had subsided, but new neurologic findings had developed (Table 1). All patients with vestibular neuritis had continuous vertigo and were admitted for observation for 48 hours.

OLD was ultimately found in 12% (n=12/100) of central patients with AVS, but in none of 51 patients with vestibular neuritis (Supplementary Figure 1). Thus, the sensitivity of OLD for a central lesion was 12% (95% CI 5.7–19.0%) and the specificity for a central lesion was 100%. OLD in patients with AVS from a central cause was noted in 39.9% (n=11/29) of patients with LMS and in 11.1% (n=1/9) of patients with the lateral pontine syndrome. Except for one patient with OLD, on the first examination (patient 3, Table 1), nine patients did not have the initial maximal lateral gaze deviation. Two had robust grade 3 horizontal nystagmus so that OLD could not be confidently determined (cases 1 and 2, Table 1). The average time for the first examination after onset of symptoms was 14.7 hours (range 3–48 hours). However, we found maximal OLD on the second examination (average time from onset of symptoms 27.6 +/− 17.5 hours, range 18–48 hours). The time to initial examination in two patients with LMS but without OLD was longer than 48 hours. (Supplementary Table 1). Once present, we elicited OLD from a minimum of 48 hours to greater than six months. In five patients OLD was present for a period ranging from 12 to 96 hours (Table 1). In two patients OLD persisted for some time after the LMS stroke, being present at the six-week examination. It had resolved by a follow-up visit five months later in patient 1 (Table 1, Figure 1). Patient 12, Table 1, had OLD at his three-month follow-up examination (Video 1), which persisted at his most recent six-month examination. The overall prevalence of OLD in our patients with AVS was 8%.

Figure 1.

GRAPHIC RECORDINGS OF OCULAR LATERODEVIATION (OLD) IN A PATIENT WITH RIGHT DORSOLATERAL MEDULLARY SYNDROME (A). Patient 1 (see table 1), AND A PATIENT WITH RIGHT VESTIBULAR NEURITIS (B). Recording of eye movements with video-oculography was performed with the Otometrics ICS device

Patients were first asked to look at a center fixation target. Then they were asked to gently close their eyes (E), and finally, to open their eyes and look at the target again (vertical arrow E1). In A when the patient opened his eyes they were maximally deviated to the right. Small left, hypometric saccades (black arrow) brought the eyes back to the fixation target. In B, when the patient opened his eyes, there was a small amplitude drift to the right, corrected by a single leftward saccade.

In 18 patients with LMS and in all 51 patients with vestibular neuritis we found a partial ipsilesional ocular deviation, measuring about 3 deg by video-oculography (Figure 1), and estimated by clinical observation to be less than 5 deg. We did not see ocular lateral deviation in the remaining 72 patients with central causes (56 with strokes). All gaze deviations after lid closure by patients with vestibular neuritis were in the direction of the slow phase of nystagmus.

OLD was never the only ocular motor abnormality on examination. Eleven patients with OLD and LMS stroke made a series of hypometric, corrective saccades from the deviated side back to straight ahead when they opened their eyes. The patient with the lateral pontine syndrome with OLD (Table 1, Case 3; Supplementary Figure 2) had a single, normal-velocity, accurate, corrective saccade back to straight ahead when opening the eyes. All patients with OLD had horizontal and vertical ipsilesional saccade lateropulsion (saccades overshot to the side of the OLD) and vertical saccades had an oblique bias toward the side of the OLD (Video 1, Figure 2). Horizontal pursuit was qualitatively impaired in both directions, and slow vertical pursuit was repeatedly interrupted by an ipsilesional OLD.

Figure 2.

REFIXATIONS BETWEEN TWO STATIONARY VERTICAL TARGETS LOCATED +/− 20 degrees ABOVE AND BELOW CENTER FIXATION

Video-Oculography Recording of patient 12 (see Table 1), with a left dorsolateral medulla/cerebellar stroke. When the patient looks up, he makes oblique saccades (saccade lateropulsion) with hypometric upward and leftward components. He then corrects the horizontal deviation with small hypometric saccades to the right. The first arrow marks when he finally reaches the target. When the patient looks down the patient makes several oblique saccade (saccade lateropulsion) with downward and leftward components. He then corrects the horizontal deviation with small hypometric saccades to the right. The second arrow marks when he finally reaches the target. Horizontal traces are in black, vertical traces in gray.

Only one of the 100 patients with a central AVS had a peripheral HINTS pattern. The horizontal HIT was abnormal in the one patient with OLD and the lateral pontine syndrome (Case 3) and normal in the other 11 patients with both AVS and OLD due to a central cause. Nine patients with OLD had a skew deviation and three of them had a complete ocular tilt reaction (OTR) (Table 1). The one patient with a lateral pontine syndrome due to an anterior inferior cerebellar artery stroke reported new hearing loss on the affected side.

All 12 patients with OLD had ipsilesional truncal lateropulsion; nine could not sit without support, implying a grade 3 truncal ataxia and three could stand but only with a wide base, implying a grade 2 truncal ataxia.¹⁸ All patients with OLD also showed lateropulsion with horizontal and vertical saccades. The clinical characteristics of patients with LMS but without OLD are in Supplementary Table 1; their degree of truncal lateropulsion was similar to that of patients with OLD.

Four of twelve patients with OLD and a stroke initially had a negative MRI-DWI (three previously reported cases¹⁷ [Table 1, cases 4, 5, 7, and one new case (Case 9)]. Seven patients with OLD had isolated medullary strokes, four had cerebellar-medullary strokes and one had a lateral pontine stroke (Figure 3, Supplementary Figure 2). The direction of RadOLD matched the direction of OLD in 10/12 patients (MRI in 10 and CT in two). Using the Lesley method to measure RadOLD,²¹ the mean values for the OLD cohort were: RE: 25.8 deg ± 5.3, and LE: 25.4 deg ± 8.8, with the average for both eyes: 25.6 deg ± 6). A group of normal subjects had an average eye position that measured RE: 9.2 deg ± and LE 3.6 ± 7.0 deg, average 6.4 ± 3.6 deg. Patients with vestibular neuritis have RadOLD in the same direction as the slow phase of the nystagmus RE: 20.7 ± 10.6 deg and LE: 21.2 ± 11.0 deg with the average eye position being 21.0 deg ± 10.3 deg (Unpublished data)). The LMS patients had the greatest degree of RadOLD.

Figure 3.

Axial diffusion-weighted (DWI) MRI images in 11 patients with OL and a stroke. Four patients have lateral medullary and ipsilateral cerebellar strokes (patients 1, 2, 4, 12). The DWI restriction signal in the cerebellum in these patients, is more pronounced than the DWI signal in the lateral medulla. Seven patients have isolated lateral medullary strokes (patients 3, 5–11)

Discussion:

Our study shows that, although infrequent (8.4%) in patients with the AVS, the finding of OLD is highly specific for a central disturbance and usually reflects LMS, particularly when associated with hypometric corrective saccades on opening the eyes.

Clinical Insights

The symptoms and signs in patients with an AVS associated with a stroke commonly evolve over hours and often require frequent monitoring. OLD is easily tested at the bedside and can be a quick confirmatory sign when patients have a HINTS pattern of eye movements suggesting a central cause, particularly, when initial imaging is negative. Our findings suggest that, to maintain specificity, a complete horizontal deviation must be present after a brief period (i.e., no more than ~3–5 seconds) of simply closing the eyes. We did not use forced eye closure against resistance (see below regarding the differential diagnosis of gaze deviation on eye closure in hemispheric strokes). Our study focused on the diagnostic role of OLD during an evolving stroke, and we found OLD and horizontal and vertical saccade lateropulsion, in an average of 27.5 +/− 17.5 hours after symptoms began in all our 12 patients. Finally, we found that OLD was correlated with RadOLD as previously reported.¹³

As the intensity of the nystagmus in straight-ahead gaze lessened over a few hours, OLD became easier to see in most patients. This suggests that re-examining patients during the early period of symptoms is important to detect OLD. The timing and duration of OLD in our patients ranged from few hours to persisting for at least six weeks. Although the precise duration is unknown, the longest persistence of OLD in stroke in our series is six months (patient 12, Table 1). Video 1 was obtained at his three- month follow-up visit. In a second patient, OLD lasted at least greater than six weeks (patient 1 Table 1) but had resolved on the follow-up visit five months later. In the remaining 10 patients with OLD we noted gradual improvement of the horizontal deviation, and corrective saccades decreased in number and increased in size. However, OL has been reported to persist for years.⁴

Ischemic lesions in the dorsolateral medulla often cause vestibular signs followed by other neurologic findings that evolve over hours after symptoms begin.^22–24 Isolated vestibular symptoms are frequent in LMS, probably second to sensory findings,²² and may represent a greater vulnerability of vestibular neurons to ischemia.²⁵ As in previous reports, however, persistent isolated vertigo is exceptional in LMS.^{23, 26} Eliciting OLD in our patients with LMS, who initially had primarily vestibular findings, helped to correctly localize the lesion to the lateral medulla. However, because our study focused on AVS patients, we did not include LMS without an AVS, and therefore do not know the broad potential diagnostic value of OL in all LMS patients.

We reviewed the literature related to OLD; Supplementary Table 2 is a summary of some of the key results. Analyses of our 12 patients with OLD and those from the literature suggest that lesions in different locations can lead to OLD and possibly by different mechanisms. Most of the patients with OLD had lesions in the lateral medulla.³ However, lesions in the pons can also cause OLD, as shown by one of our patients.⁹ The horizontal bias producing OLD when fixation is removed can be strong and literally noted in a “blink of an eye.”²⁷ Extending the time that the eyes are closed or other methods to remove fixation helps to determine the characteristics of the centripetal saccades, which usually are a series of hypometric saccades back to straight-ahead when the eyes open.

Possible Mechanism of OL in our Patients

In the case of lateropulsion of saccades, previous experimental and clinical studies support the importance of the interruption of projections from the inferior olive to lobules 5–7 of the cerebellar vermis (called the oculomotor vermis or OMV). The OMV, in turn, projects to the posterior portion of the fastigial nucleus called the fastigial oculomotor region (FOR).^27–30 When the activity of climbing fibers from the inferior olive is interrupted, usually because of a lesion in the inferior cerebellar peduncle, Purkinje cells in the OMV increase their discharge and in turn inhibit neurons within the FOR. However, the Purkinje cells of the OMV and neurons in the FOR also influence horizontal gaze position during fixation and may contribute to the OLD seen with acute lesions in the lateral medulla. In our stroke patients with OLD, seven had isolated brainstem lesions and four had lesions in both the medulla and the cerebellum but sparing the OMV and FOR (cases 1, 2, 4 and 12). An acute loss of input from the inferior olive to the OMV is a plausible explanation for their OLD.^27–31

Physiologically, the interruption of the climbing fibers from the inferior olive as they traverse the inferior cerebellar peduncle leads to enhanced GABAergic activity of Purkinje cells that inhibits the underlying FOR. The inhibition of the FOR can cause the ipsilateral gaze bias and saccade hypermetria.³¹ In support of this hypothesis, the findings in LMS are mimicked by the results of experimental injections of muscimol (GABA agonist) into the FOR of monkeys,³² and the opposite results after injections of bicuculline (GABA antagonist).³³ These studies provide a neurophysiologic basis for a transient deficiency of GABAergic activity in the FOR as a cause for OLD. Since a structural lesion in one FOR must always interrupt the projection from the contralateral FOR, which immediately crosses and course through its fellow FOR, there are no reports of structural lesions limited to one FOR in humans. Hence, OLD is usually associated with lesions in the brainstem or the cerebellar peduncles as shown in this study. Hypothetically, a selective unilateral lesion of the cerebellar vermis could produce OLD, though this must be rare. Studies of patients with saccade lateropulsion further support a role for the cerebellum in the execution of saccades^34–36

To recapitulate, maintaining a normal straight-ahead horizontal eye position requires a symmetric balance of activity between brainstem pre-oculomotor circuits including the vestibular and gaze-holding networks, and the OMV and FOR of the cerebellum.^{27 29, 32, 33, 37} The function of neurons in the FOR are affected indirectly by brainstem lesions by virtue of interruption of inputs to the OMV, which in turn affects the function of the FOR. We also note that experimental lesions affecting one side of the OMV more than the other, produce a contralateral position bias.^{38, 39} In addition, experimental, transient unilateral inactivation of the FOR causes an ipsilateral position bias, as was found in our patients with OLD (Video 1, table 1, case 12).

The mechanism of OLD in lateral pontine syndrome is more complicated because the structures affected could include 1) vestibular afferents (root, fascicle) as they course to their target nuclei, 2) descending inputs to the gaze-holding networks in the vestibular nuclei, and to the inferior olive in the medulla, 3) projections to and from the cerebellum via the cerebellar peduncles, and 4) the cerebellar flocculus itself. A point perhaps to help with localization was that our patient with OLD and the lateral pontine syndrome had a single, large corrective saccade back to straight ahead when opening the eyes, and not the series of hypometric saccades back to straight as occurs in patients with the LMS and OLD. Finally, in our patients with OLD except the patient with the lateral pontine syndrome, both horizontal and vertical saccades showed ipsipulsion, as previously reported.^{6, 8, 28, 40, 41}

Minimal lateral gaze deviation in vestibular neuritis

The lateral eye deviation in our patients with vestibular neuritis was mild (less than 5 degrees) if the period of eye closure was relatively brief (3–5 sec). Longer periods of eyelid closure can increase the lateral gaze deviation in patients with vestibular neuritis,¹⁴ and it is a common radiographic finding, usually noted best in T2-weighted axial MRI scans.¹⁴ Patients with presumed LMS may show OLD even when the MRI does not show lesions in the medulla, or even when there have been transient ischemic attacks without other deficits¹³. We did not have a subgroup of patients with TIA in this series, because continuous vertigo was an inclusion criterion.¹³

In general, removing fixation by any means, including eye closure as used in this study, beyond a few seconds may lead to greater ocular deviation in the direction of the slow phase when there is nystagmus. Especially, in patients with vestibular neuritis prolonged removal of fixation suppresses the quick phases of nystagmus and the eyes may deviate further in the direction of the slow phase of nystagmus.¹⁴ Based on semi–quantitative measures of horizontal eye deviation, an average of 3 degrees of lateral deviation in patients with vestibular neuritis was noted in a previous study.⁵

Clinical-imaging correlation in LMS lesions with OL

We noted OLD in our patients with LMS who presented with an isolated AVS; but we did not include patients with LMS without vestibular symptoms or signs.²² In addition, with exception of two patients without OLD due to small lacunar strokes in the lateral medulla, we did not find differences in the MRI between patients with and without OLD and LMS. We speculate that those patients with LMS without OLD had sparing of fibers in the inferior cerebellar peduncle that came from the inferior olive. Of note, 5/18 patients with lacunar medullary strokes (cases 1–4, 14, supplementary Table 2) did not have OLD. In our cohort, RadOLD was greater than 20 degrees and ipsilesional to the LMS, in agreement with previous reports.¹³

Differentiating OL from Other Causes of Horizontal Gaze Deviation without Gaze Palsy

In the differential diagnosis of ocular deviation related to eye closure one must consider Cogan’s “spasticity of conjugate gaze,” that usually occurs with acute lesions in the cerebral hemispheres, commonly in the parietal lobe. With forced eyelid closure, the eyes deviate under the closed lids away from the side of the lesion, toward the paralyzed limb. As a key distinction from OLD in our patients, this deviation requires forced eye closure, not just simple removal of fixation.^42–44

Limitations

Two thirds of our patients with AVS had a stroke or other central lesions due to the referral patterns at our institution, which exceeds the known ~ 25±15 % of patients with AVS with a central vestibular syndrome.¹ It was not possible to implement a blind analysis of video recordings of every patient. Notwithstanding these limitations, maximal OLD is unambiguous and easy to identify clinically. Moreover, the magnitude of OLD was large and obvious, minimizing a potential “central diagnosis bias” from the examiner (JCK), who was aware of the results of the HINTS algorithm and the truncal ataxia, both present in LMS patients without OLD. Importantly, a precise threshold for OLD is not possible without a quantitative analysis of the degree of OLD. In addition, the potential of false positive cases related to “brief versus longer periods of eyelid closure” is unknown. Therefore, to maintain specificity, we recommend keeping the criterion of a full ocular deviation, as used in this study. Quantification of the characteristics of the dysmetria underlying the lateropulsion of saccades for comparison with OLD might help to better localize ODL. Likewise, quantitative studies of the duration and the degree of OLD might improve the specificity of localization.

In addition, this study did not include patients LMS without vestibular symptoms or findings; therefore, the true incidence of OLD in patients with LMS is unknown. Likewise, OLD was not looked for in patients with peripheral vestibulopathies other than vestibular neuritis. Finally, we recruited patients at a single site; thus, our findings must be confirmed. Even so, pursuing OLD testing in AVS is important because it is highly localizing when present and so easy to perform\.

Conclusions

In summary, OLD is a specific (100%), easy to elicit sign for a central localization and lateralization in AVS. The one patient with OLD with a “peripheral” HINTS had acute ipsilesional hearing loss (and thus a positive HINTS plus pattern) and gait imbalance, due to an anterior inferior cerebellar artery infarct involving the pons. Clinicians should look for OLD with brief, gentle eyelid closure and also for a series of hypometric corrective saccades back to straight ahead on opening the eyes. Both findings point to a central lesion that usually is in the lateral medulla on the same side as the OLD.

Supplementary Material

Supplementary file 1: Video 1

Video 1 (Case 12, Table 1). Video obtained from a patient with a left dorsolateral medullary-cerebellar stroke. The first section obtained during the acute stroke phase shows a left OLD with brief eyelid closure and corrective right hypometric saccades. The second section, obtained three months later show oblique saccades, as the patient refixate between vertical targets. The trajectory of this vertical saccades is modified by ipsilesional, horizontal lateropulsion. Horizontal saccades (not shown) were hypermetric to the left and hypometric to the right. The patient also a left head tilt.

Supplementary file 2

Supplementary Figure 1 OL Study Diagram: The Diagram provides a graphic comparison between HINTS/HINTS plus (associated with hearing loss) and OL in AVS patients.

Supplementary Figure 2 Axial DWI MRI in the patient with left-sided pontine stroke (Patient 3, see also Table 1). The left panel illustrates the rostral extent of the infarction, partially affecting the left superior cerebellar peduncle (SCP), and the right panel shows the caudal extent of the infarction including partial DWI signal in the flocculus. The middle panels show restricted signal in the left pons.

Supplementary Table 1. Clinical findings in lateral medullary syndrome without OLD.

Supplementary Table 2. Previous literature describing location of lesions with OLD, cause, fixation block technique and clinical course.

Glossary of Abbreviations

AVS

acute vestibular syndrome

OLD

ocular lateral deviation

LMS

lateral medullary syndrome

RadOLD

radiographic ocular lateral deviation

HIT

head impulse test

HINTS

Head Impulse, Nystagmus and Tests of Skew

OTR

ocular tilt reaction

OMV

oculomotor vermis

FOR

fastigial oculomotor region