Bedside Assessment of Vergence in Stroke Patients

Given the widely distributed network of midbrain, pontine, cerebellar, and cortical areas involved in the neural control of vergence, one might expect various vergence deficits in stroke patients. In this article, we investigated the localizing value of bedside vergence testing with respect to different supratentorial and infratentorial infarction locations

Clinical Research: Epidemiology Meets Neuro-Ophthalmology Section Editors: Heather E. Moss, MD, PhD Stacy L. Pineles, MD Bedside Assessment of Vergence in Stroke Patients Evangelos Anagnostou, MD, PhD, Penelopi Koutsoudaki, MD, Argyro Tountopoulou, MD, PhD, Konstantinos Spengos, MD, PhD, Sophia Vassilopoulou, MD, PhD Background: Given the widely distributed network of midbrain, pontine, cerebellar, and cortical areas involved in the neural control of vergence, one might expect various vergence deficits in stroke patients. In this article, we investigated the localizing value of bedside vergence testing with respect to different supratentorial and infratentorial infarction locations. Methods: Three hundred five stroke patients and 50 agematched controls were examined prospectively by means of bedside tests to assess slow and fast binocular (i.e., symmetrical) as well as slow and fast monocular (i.e., asymmetrical) convergence. Infarction locations, as identified on MRI, were correlated with vergence performance using multinomial logistic regression. Results: Vergence deteriorated with age in both stroke patients and healthy controls. Most infarction locations did not show significant associations with vergence parameters, apart from cases with parietal lobe lesions, which exhibited insufficient asymmetrical, slow and fast vergence for both the left and the right eye. Finally, patients with severe ischemic small vessel disease showed a slight but significant decrease in their fast binocular vergence performance. Conclusions: There is only a limited localizing value of vergence deficits in stroke. Parietal lobe infarctions are more frequently associated with insufficient binocular and monocular vergence. Midbrain strokes were too few to draw final conclusions. However the most robust factor to emerge from our data is age. Older subjects show poor slow binocular as well as slow and fast monocular vergence. Extended white matter lesions are also correlated with deficient vergence ability suggesting a role for subcortical wide range connections in maintaining an intact vergence circuitry. Journal of Neuro-Ophthalmology 2021;41:424–430 doi: 10.1097/WNO.0000000000001035 © 2020 by North American Neuro-Ophthalmology Society Department of Neurology, University of Athens, Eginition Hospital, Athens, Greece. The authors report no conflicts of interest. Address correspondence to Evangelos Anagnostou, MD, PhD, Department of Neurology, Eginition Hospital, University of Athens, Vas. Sophias Avenue 74, 11528 Athens, Greece; E-mail: [e-mail] 424 V ergence eye movements are disjunctive movements that rotate the eyes in opposite directions. In the laboratory, it is possible to separate the following 2 major vergence components: the disparity (or fusional) vergence and the accommodative (or blur driven) vergence. Disparity vergence is induced whenever there is a difference between the locations of the image of a visual object on each retina, whereas blur driven vergence is accompanied by lens accommodation (1). Bedside testing of convergence is usually performed by simply asking the patient to follow the examiners finger as it is smoothly brought toward her nose, thereby inducing a mixed disparity and accommodative stimulus. Neurologists traditionally assess convergence when they suspect a midbrain lesion or in cases of internuclear ophthalmoplegia, in an attempt to demonstrate intact medial rectus function. This approach stems from the well-established anatomical location of neurons responsive to vergence angle in the mesencephalic reticular formation, dorsal and dorsolateral to the third nerve nucleus (2). This classic view of clinical utility of convergence testing by neurologists, however, neglects a large body of evidence that favors a widely distributed vergence-related network that comprises midbrain, pontine, cerebellar, and cortical areas (3). The fact that vergence is an ocular response to visual stimuli, such as retinal disparity, blur, proximity of targets, and changes in size of an image, makes the involvement of neural connections between the occipital lobe, the parietal lobe, and the frontal eye fields necessary. Neurons responsive to visual depth, located anteriorly to the smooth pursuit and saccade areas in the frontal eye fields, are linked with the initiation of vergence (4,5). Parietal lobe neurons fire with changes in fixation distance and are also modulated by different degrees of retinal blur (6,7). In the occipital lobe, vergence-responsive cells are hosted in the primary (V1) and the secondary (V2) visual cortex. The former respond preferentially to retinal blur and retinal disparity (participating this way also in stereoscopic depth perception), while the latter are implicated in the initiation of vergence eye movements (1,8). Cortical vergence signals are subsequently Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology relayed directly or through the thalamus and the basal ganglia to the midbrain vergence neurons. In this article, we prospectively assessed 305 stroke patients with focal ischemic or hemorrhagic lesions located in various supratentorial and infratentorial areas by using bedside convergence testing in different variations (binocular vergence, monocular vergence, slow vergence, and fast vergence). We aimed to determine the following: (i) the clinical usefulness of bedside vergence assessment in cerebrovascular patients, and (ii) the localizing value of vergence impairments with respect to different stroke locations. The present approach, albeit weak in terms of accurate quantification of vergence performance, may be closer to the real clinical setting because it uses the most widely used method of bedside vergence examination in neurology and ophthalmology clinics. METHODS Study Population A prospective study was undertaken in consecutive stroke patients who were referred to our clinic for cerebrovascular workup and management within 3 days after symptom onset. Exclusion criteria were transitory ischemic attack, absence of an incident-related lesion in brain MRI, and clinical symptoms that may complicate patients’ cooperation (severe aphasia, stupor, or coma). Patients with incident-related or pre-existing ocular motor nerve palsies and patients with neuromuscular diseases (such as myasthenia gravis) that may affect extraocular muscle function were also excluded. Of 471 patients screened, 305 met the above criteria (mean age: 61.4 years ± 13.8). Fifty age-matched individuals served as controls (mean age 68.1 years, ± 11.1) (Table 1). All subjects gave written informed consent for participation in the study that was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Department of Neurology of the University of Athens. Step 1: Slow binocular (symmetrical) vergence. The patient is asked to follow a visual target (red cap of a pen) that is, moved slowly by the examiner from a distant (about 100 cm) to a closer (about 10 to 5 cm) point along the midsagittal line. Step 2: Fast binocular (symmetrical) vergence. The patient fixates steadily a distant target until a close target appears suddenly and the patient is required to fixate the target as quickly as possible. Both the initial and the new target are aligned with the midsagittal line. Step 3: Slow monocular (asymmetrical) vergence of the right eye. Same procedure as in Step 1, only this time the target moves along the axis of vision of the left eye. Step 4: Fast monocular (asymmetrical) vergence of the right eye. Same procedure as in Step 2, only this time the targets are aligned with the axis of vision of the left eye. Step 5: Slow monocular (asymmetrical) vergence of the left eye. Same procedure as in Step 1, only this time the target moves along the axis of vision of the right eye. Step 6: Fast monocular (asymmetrical) vergence of the left eye. Same procedure as in Step 2, only this time the targets are aligned with the axis of vision of the right eye. In each step, the vergence movement of the right and the left eye was evaluated separately. We used a three-point grading scale of 0–2 to assess the integrity of eye movement: “Grade 0” corresponded to “no movement at all” (complete convergence palsy), “Grade 1” corresponded to a partial convergence insufficiency characterized by any degree of hypometric inward eye movement, and “Grade 2” indicated a virtually perfect convergence. Hence, for Step 1, this method yields 9 possible outcomes, that is, Outcome Outcome Outcome Outcome Outcome Outcome Outcome Outcome Outcome 1: 2: 3: 4: 5: 6: 7: 8: 9: both both both right right right right right right eyes Grade 2 eyes Grade 1 eyes Grade 0 eye Grade 2, left eye Grade 2, left eye Grade 1, left eye Grade 1, left eye Grade 0, left eye Grade 0, left eye eye eye eye eye eye Grade Grade Grade Grade Grade Grade 1 0 2 0 2 1 Vergence Assessment The same holds for Step 2. On the other side, Steps 3 to 6 resulted in only the following 3 possible outcomes each because here only one eye was allowed to move: Bedside convergence evaluation consisted of the following steps: Outcome 1: Right (or Left) eye Grade 2 Outcome 2: Right (or Left) eye Grade 1 TABLE 1. Clinical and demographic characteristics Patients Controls Total # of Cases Gender (Female/Male) Age (yrs ± SD) 305 50 102/203 19/31 61.4 ± 13.8 68.1 ± 11.1 Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 Ischemic/ Hemorrhagic Stroke Ischemic Leukoencephalopathy (Fazekas 0 or 1/Fazekas 2 or 3) 283/22 241/64 425 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology Outcome 3: Right (or Left) eye Grade 0 Lesion Location Pilot assessments in 15 healthy elderly individuals using a finer (5-point) grading scale revealed ambiguous results with substantial interexaminer disagreement, in particular with regard to the intermediate convergence insufficiency grades. For that reason we decided to use the three-point grading scale described above. Each step was tested at least 2 times. Patients who were inattentive or showed insufficient cooperation were tested many times under verbal encouragement to maximize effort. Only the best response was taken into account. Absolute numbers of subjects with impaired vergence are presented in Table 3 separately for each stroke location. It became obvious from the data that increasing age is related to vergence dysfunction. Therefore, age was entered as a covariate in the analysis of the effect of lesion location on vergence ability (Table 4). The influence of both supratentorial and infratentorial infarction locations showed, in most cases, no significant effects with regard to vergence parameters. Only infarctions located in the parietal lobe were associated with insufficient or absent asymmetrical, slow and fast vergence for both the left and the right eye (P , 0.01 for all 4 outcomes). In the control group, we found significantly more subjects with unimpaired slow binocular vergence (P , 0.01) and fast monocular vergence of the right eye (P , 0.05). In both patients and controls, age was independently associated with abnormalities of slow binocular vergence (P , 0.001), slow (P , 0.001) and fast (P , 0.01) monocular vergence of the right eye, as well as slow and fast monocular vergence of the left eye (P , 0.01). Lesion side (i.e., location of the infarct on the right or left side of the hemisphere, the brainstem, or the cerebellum) did not show differences in vergence parameters in the pooled multinomial model for all lesion locations, with one exception: a significant difference was observed in Step 4 (fast monocular vergence of the right eye), where right-sided lesions were associated with worse vergence performance (x2 = 9.6, P , 0.01). However, testing the influence of lesion side for each infarct location separately, revealed a significant effect for patients with occipital infarcts and hemianopia (Table 5). Patients with right occipital lesions and left homonymous hemianopia exhibited a deficient fast vergence ability of their ipsilesional (right) eye (x2 = 13.4, P , 0.01). Analogously, patients with left occipital lesions and right homonymous hemianopia exhibited a deficient fast vergence ability of their ipsilesional (left) eye (x2 = 10.6, P , 0.01). Imaging All patients received a brain MRI on a 1.5 or 3.0 T scanner within 5 days of symptom onset. Hence, vergence assessment in some of the patients took place before the MRI. In these cases, stroke diagnosis relied solely on clinical symptoms and/or initial computed tomography . Accordingly, cases lacking new ischemic or hemorrhagic lesions in the MRI were excluded retrospectively from the study. Ischemic infarction locations were identified on fluidattenuated inversion recovery (FLAIR) images, whereas hemorrhagic infarctions were localized on both FLAIR and gradient echo images. 1 = frontal, 2 = temporal, 3 =parietal, 4 = occipital, 5 = insula, 6 = basal ganglia, 7 = thalamus, 8 = internal capsule, 9 = frontoparietal, 10 = frontotemporal, 11 = occipitotemporal, 12 = temporoparietal, 13 = midbrain, 14 = pons, 15 = medulla oblongata, and 16 = cerebellum. Statistics Multinomial logistic regression was applied to each assessment step separately, with the possible outcomes (9 for Steps 1 and 2 and 3 for Steps 3 to 6) serving as dependent and the different anatomical infarction locations as independent variables. Subject age was entered as a covariate in all models to adjust for possible confounding effects on the outcome. RESULTS Stroke Patients vs Controls Seven percent of the patients had a hemorrhagic stroke (Table 1). Most of them had subtotal hemispheric infarctions in the territory of the middle cerebral artery (Table 2). As a group, patients exhibited deficits in slow (x2 = 65.8, P , 0.001) and fast (x2 = 34.3, P , 0.001) binocular vergence compared with controls. The same was true for monocular slow (x2 = 14.1, P , 0.01) and fast (x2 = 30.8, P , 0.001) vergence of the right eye as well as slow (x2 = 13.4, P , 0.01) and fast (x2 = 16.4, P , 0.001) vergence of the left eye. 426 White Matter Lesions Finally, patients with significant ischemic leukoencephalopathy evident in MRI scans (Fazekas 2 or 3) showed a slight but significant decrease in their fast binocular vergence performance (x2 = 15.4, P , 0.05) as well as in the slow (x2 = 6.6, P , 0.05) and fast vergence ability of the left eye (x2 = 7.0, P , 0.05). Slow binocular vergence and slow and fast monocular vergence of the right eye were not affected (Table 6). DISCUSSION A large body of neurophysiological evidence stemming mainly from animal experiments suggests a widely distributed network of cortical and subcortical structures as the neuronal substrate of vergence (1,9,10). It seems that overlapping but nonidentical circuitries support slow and fast Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 2. Infarction location of the 305 stroke patients Total # of Cases # Cases With Right-Sided Lesions # Cases with Left-Sided Lesions 48 10 53 23 3 29 14 30 28 2 6 5 4 24 12 14 16 4 30 5 3 16 9 15 17 1 3 2 2 10 3 9 32 6 23 18 0 13 5 15 11 1 3 3 2 14 9 5 Frontal Temporal Parietal Occipital Insula Basal ganglia Thalamus Internal capsule Frontoparietal Frontotemporal Occipitotemporal Temporoparietal Midbrain Pons Medulla oblongata Cerebellum vergence (11–13) and presumably also binocular vs asymmetrical (monocular) convergence because the latter distinction imposes different neural demands on both Hering’s and Listing’s law (14–23). By contrast, clinical data relating circumscribed lesions with vergence function are scarce and stem mainly from single case descriptions (3,24). In this study, we aimed to determine in a real clinical setting whether bedside vergence testing may be regarded as a useful examination in stroke patients and, more specifically, whether the experimentally established vergence pathways can be reflected in clinicoradiological correlations. Our results showed that age was the factor that most robustly affects vergence performance. Slow binocular and slow and fast monocular vergence deteriorated with age in both stroke patients and healthy controls. This could be an indication that bedside vergence testing is of a limited topodiagnostic value in older individuals. Previous studies on large samples revealed marked effects of age on vergence parameters in nonclinical populations, as tested with different bedside methods and different study designs (25–29). Laboratory investigations using eye movement recordings, on the other hand, yielded contradictory results. A state-of-the art study using magnetic search coil measurements found that fast binocular vergence deteriorated with age (30). Other laboratory findings reported no effects of age on vergence (31), whereas other investigators found age effects only on specific TABLE 3. Vergence performance outcome in patients and controls Number Of Cases With Impaired (Grade 0 or Grade 1) Vergence/Number of Cases With Intact (Grade 2) Vergence Controls (no lesion) Frontal Temporal Parietal Occipital Insula Basal ganglia Thalamus Internal capsule Frontoparietal Frontotemporal Occipitotemporal Temporoparietal Midbrain Pons Medulla oblongata Cerebellum Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 22/28 33/15 7/3 53/0 16/7 1/2 19/10 9/5 22/8 19/9 1/1 5/1 4/1 3/1 16/8 9/3 13/1 31/19 30/18 6/4 52/1 14/9 2/1 8/21 7/7 16/14 19/9 1/1 5/1 3/2 3/1 13/11 6/6 8/6 23/27 23/25 5/5 52/1 8/15 0/3 11/18 3/11 10/20 14/14 1/1 3/3 3/2 1/3 8/16 7/5 7/7 33/17 16/32 3/7 52/1 10/13 0/3 4/25 3/11 6/24 12/16 1/1 1/5 3/2 1/3 3/21 3/9 6/8 19/31 22/26 3/7 52/1 8/15 0/3 10/19 3/11 9/21 14/14 1/1 3/3 2/3 3/1 7/17 5/7 7/7 21/29 17/31 3/7 51/2 11/12 0/3 6/23 3/11 7/23 13/15 1/1 2/4 2/3 2/2 3/21 2/10 5/9 Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 427 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 4. Results of multinomial logistic regression with lesion location on MRI as an independent and vergence dysfunction as a dependent variable Slow Binocular Vergence (Step 1) Age P , 0.001* No lesion P , 0.01* (controls) Frontal — Temporal — Parietal — Occipital — Insula — Basal ganglia — Thalamus — Internal capsule — Frontoparietal — Frontotemporal — Occipitotemporal — Temporoparietal — Midbrain — Pons — Medulla — oblongata Cerebellum — Fast Binocular Vergence (Step 2) Slow Monocular Fast Monocular Slow Monocular Fast Monocular Vergence of the Vergence of the Vergence of the Left Vergence of the Right Eye (Step 3) Right Eye (Step 4) Eye (Step 5) Left Eye (Step 6) — — P , 0.001* — P , 0.01* P , 0.05* P , 0.01* — P , 0.01* — — — — — — — — — — — — — — — — — — P , 0.01† — — — — — — — — — — — — — — P , 0.01† — — — — — — — — — — — — — — P , 0.01† — — — — — — — — — — — — — — P , 0.01† — — — — — — — — — — — — — — — — — The influence of age, entered as a covariate in the regression model, is also presented. Nonsignificant results are denoted with “—” in the corresponding cell. *Significant results: denotes that most subjects showed good vergence performance. † Significant results: denotes that most subjects showed poor vergence performance. vergence adaptation parameters (32). The fact that laboratory studies, in contrast to clinical bedside studies, rely on small subject numbers with relatively younger ages might be one reason for these discrepancies. Another important factor is that laboratory studies focus on kinematic parameters, such as peak velocity and acceleration of the converging eye, which cannot readily be translated into the clinical setting. Still, after controlling for age in our multinomial logistic regression model, there were no consistent clinicoradiological associations for most stroke locations, although our stroke population as a whole showed worse vergence performance than the control group. Notably, midbrain strokes were too few (n = 13) to draw final conclusions. Only parietal lobe lesions correlated significantly with insufficient or absent vergence function. Previous animal and human physiological studies have implicated the parietal lobe in fusional and disparity-driven vergence. Neurons tuned to vergence have been observed in the lateral bank of the simian intraparietal sulcus and in the medial posterior parietal cortex (33,34). A positron emission tomography activation study in healthy adults performing a disparity-driven vergence task, revealed increased regional cerebral blood flow in the inferior parietal lobule (35). A nearby cortical area, the dorsal parieto-occipital sulcus, exhibited significant correlation of the blood-oxygenlevel-dependent signal to vergence in a more recent functional 428 MRI study (36). In a subsequent brain connectivity study, the posterior parietal cortex of binocularly normal subjects showed strong coactivation with the frontal eye field and the cerebellar vermis during a vergence task (37). These data, together with our findings in cerebrovascular patients, highlight a role of parietal areas in human vergence function. Another interesting observation was that patients with extended small vessel disease and subcortical white matter lesions (Fazekas 2 or 3) showed a slight but significant decrease in their fast binocular vergence performance. This finding is in line with the view of the vergence system as a widely distributed network involving cortical and subcortical brain regions, which is presumably perturbed by disruption of long and short range connections that run through the white matter. Slow binocular vergence, however, was not affected in these patients, a finding that is difficult to interpret. One could hypothesize that the known anatomical segregation of slow and fast vergence in the brainstem, implying that slow vergence is mediated by caudal pontine and fast vergence by midbrain and rostral pontine nuclei (11,12) might also hold for the supranuclear (corticopontine and corticomesencephalic) descending tracts. Nonetheless, the anticipated differential role of slow vs fast and symmetrical vs asymmetrical vergence assessment, that was based on the known vergence networks stemming Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology TABLE 5. Patients with occipital infarctions and contralateral homonymous hemianopia (n = 17) Slow Binocular Vergence (Step 1) Right vs left occipital lesion difference Outcome Fast Monocular Vergence of the Left Eye (Step 6) Fast Fast Monocular Slow Monocular Binocular Slow Monocular Vergence of the Vergence of the Vergence Vergence of the (Step 2) Right Eye (Step 3) Right Eye (Step 4) Left Eye (Step 5) — — — P , 0.01 — P , 0.01 8 of 10 left occipital cases had absent and 2 had insufficient vergence All (n = 7) right occipital cases had absent vergence The x2 test with lesion side as an independent and vergence dysfunction as a dependent variable. Nonsignificant results are denoted with “—” in the corresponding cell. recording would quantify vergence function in detail, which is of course feasible in single cases. Therefore, we preferred to keep a coarse vergence grading in our cohort, consisting only of 3 major outcome categories, as described in the Methods section. Another limitation of our study is the overrepresentation of hemispheric vs subcortical infarctions in our sample. Thus, strategic infarctions, for example, in the vicinity of the midbrain aqueduct may have been missed. Overall, we had too few medullar, pontine, and midbrain infarctions in our cohort to draw safe conclusions on the role of these structures in stroke-related vergence abnormalities. Finally, the fact that attention is a crucial factor that affects vergence performance and is the reason why subjects with a visual neglect or impaired level of consciousness were not included; we cannot fully exclude the possibility that milder, clinically covert, attentional deficits in some stroke patients might have biased our data. Taken together, although stroke patients as a group exhibit in general more vergence abnormalities than healthy controls, there is only a limited localizing value of this deficit. Parietal lobe infarctions are more frequently associated with insufficient binocular and monocular vergence. from animal experiments, was generally not reflected in our data. The same was true with regard to presumably lateralized vergence functions. In general, no differences were found between left and right hemispheric lesions or between monocular convergence of the left vs right eye. It is noteworthy, however, that the subgroup analysis of subjects with homonymous hemianopia due to occipital infarctions revealed a robust finding as follows: Asymmetrical (i.e., monocular) fast vergence to stepped stimuli was virtually always associated with insufficient or absent convergence of the ipsilesional eye, presumably due to the fact that the visual stimulus inevitably fell into the blind hemifield, thus being unable to trigger, disparity-driven, vergence movements. The aim of this study, that is, to study a large cohort with a simple bedside method, was at the cost of the accuracy of vergence assessment. The used technique (i.e., moving a finger or a pen along the axis of sight) is certainly the most commonly used bedside vergence assessment method among clinical neurologists but might not be as accurate as the “near point of convergence” or the prism assessment of fusional amplitudes (38). Ideally, a binocular video-oculographic TABLE 6. Results of multinomial logistic regression with presence of significant ischemic leukoencephalopathy on MRI (Fazekas 2 or 3) as an independent and vergence dysfunction as a dependent variable Slow Binocular Vergence (Step 1) Absence vs presence of leukoencephalopathy Outcome — Fast Binocular Vergence (Step 2) P , 0.05 Slow Monocular Vergence of the Right Eye (Step 3) Fast Monocular Vergence of the Right Eye (Step 4) — — Vergence worse in leukoencephalopathy Slow Monocular Vergence of the Left Eye (Step 5) P , 0.05 Fast Monocular Vergence of the Left Eye (Step 6) P , 0.05 Vergence worse in Vergence worse in leukoencephalopathy leukoencephalopathy Nonsignificant results are denoted with “—” in the corresponding cell. Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 429 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Research: Epidemiology Meets Neuro-Ophthalmology However, the most robust factor to emerge from our data is age. Older subjects show poor slow binocular and slow and fast monocular vergence. This is true for both stroke patients and binocularly normal controls. Extended white matter lesions are also correlated with deficient vergence ability. It should be emphasized, however, that midbrain infarctions were likely too few to draw final conclusions. Finally, fast asymmetric vergence with the visual target moving within the blind hemifield of hemianopic patients is virtually always linked to an absent or insufficient convergence of the ipsilesional eye. 16. 17. 18. 19. 20. 21. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: E. Anagnostou; b. Acquisition of data: E. Anagnostou and P. Koutsoudaki; c. Analysis and interpretation of data: E. Anagnostou, A. Tountopoulou, K. Spengos, and S. Vassilopoulou. Category 2: a. Drafting the manuscript: E. Anagnostou; b. Revising it for intellectual content: E. Anagnostou, P. Koutsoudaki, A. Tountopoulou, K. Spengos, and S. Vassilopoulou. Category 3: a. Final approval of the completed manuscript: E. Anagnostou, P. Koutsoudaki, A. Tountopoulou, K. Spengos, and S. Vassilopoulou. 22. 23. 24. 25. 26. 27. REFERENCES 1. Leigh RJ, Zee DS. The neurology of eye movements. In: Book/CDrom. 4th edition. New York, NY: Oxford University Press, 2006. 2. Mays LE, Porter JD, Gamlin PD, Tello CA. Neural control of vergence eye movements: neurons encoding vergence velocity. J Neurophysiol. 1986;56:1007–1021. 3. Serra A, Chen AL, Leigh RJ. Disorders of vergence eye movements. Curr Opin Neurol. 2011;24:32–37. 4. Gamlin PD, Yoon K. An area for vergence eye movement in primate frontal cortex. Nature. 2000;407:1003–1007. 5. Akao T, Kurkin SA, Fukushima J, Fukushima K. Visual and vergence eye movement-related responses of pursuit neurons in the caudal frontal eye fields to motion in-depth stimuli. Exp Brain Res. 2005;164:92–108. 6. Alkan Y, Biswal BB, Taylor PA, Alvarez TL. Segregation of frontoparietal and cerebellar components within saccade and vergence networks using hierarchical independent component analysis of fMRI. Vis Neurosci. 2011;28:247–261. 7. Alkan Y, Biswal BB, Alvarez TL. Differentiation between vergence and saccadic functional activity within the human frontal eye fields and midbrain revealed through fMRI. PLoS One. 2011;6:e25866. 8. Richter HO, Costello P, Sponheim SR, Lee JT, Pardo JV. Functional neuroanatomy of the human near/far response to blur cues: eye-lens accommodative/vergence to point targets varying in depth. Eur J Neurosci. 2004;20:2722–2732. 9. Gamlin P. Neural mechanisms for the control of vergence eye movements. Ann N Y Acad Sci. 2002;956:264–272. 10. Suzuki Y. The near response: the contributions of Kenji Ohtsuka, MD. J Neuroophthalmol. 2007;27:138–142. 11. Rambold H, Neumann G, Helmchen C. Vergence deficits in pontine lesions. Neurology. 2004;62:1850–1853. 12. Rambold H, Sander T, Neumann G, Helmchen C. Palsy of “fast” and “slow” vergence by pontine lesions. Neurology. 2005;64:338–340. 13. Cullen KE, Van Horn MR. The neural control of fast vs. slow vergence eye movements. Eur J Neurosci. 2011;33:2147–2154. 14. Dell’Osso LF. Evidence suggesting individual ocular motor control of each eye (muscle). J Vestib Res. 1994;4:335–345. 15. King WM, Zhou W, Tomlinson RD, McConville KM, Page WK, Paige GD, Maxwell JS. Eye position signals in the abducens 430 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. and oculomotor nuclei of monkeys during ocular convergence. J Vestib Res. 1994;4:401–408. King WM, Zhou W. Initiation of disjunctive smooth pursuit in monkeys: evidence that Hering’s law of equal innervation is not obeyed by the smooth pursuit system. Vis Res. 1995;35:3389–3400. Moschovakis AK. Are laws that govern behavior embedded in the structure of the CNS? The case of Hering’s law. Vis Res. 1995;35:3207–3216. Enright JT. Slow-velocity asymmetrical convergence: a decisive failure of “Hering’s law.” Vis Res. 1996;36:3667–3684. Mays L. Has Hering been hooked? Nat Med. 1998;4:889– 890. Zhou W, King WM. Premotor commands encode monocular eye movements. Nature. 1998;393:692–695. Ramat S, Das VE, Somers JT, Leigh RJ. Tests of two hypotheses to account for different-sized saccades during disjunctive gaze shifts. Exp Brain Res. 1999;129:500–510. King WM, Zhou W. Neural basis of disjunctive eye movements. Ann N Y Acad Sci. 2002;956:273–283. Maxwell JS, Schor CM. Symmetrical horizontal vergence contributes to the asymmetrical pursuit of targets in depth. Vis Res. 2004;44:3015–3024. Brune AJ, Eggenberger ER. Disorders of vergence eye movements. Curr Treat Options Neurol. 2018;20:42. Pickwell LD, Hampshire R. Convergence insufficiency in patients taking medicines. Opthalmic Physiol Opt. 1984;4:151–154. Winn B, Gilmartin B, Sculfor DL, Bamford JC. Vergence adaptation and senescence. Optom Vis Sci. 1994;71:797–800. Palomo Alvarez C, Puell MC, Sánchez-Ramos C, Villena C. Normal values of distance heterophoria and fusional vergence ranges and effects of age. Graefes Arch Clin Exp Ophthalmol. 2006;244:821–824. Leat SJ, Chan LL, Maharaj PD, Hrynchak PK, Mittelstaedt A, Machan CM, Irving EL. Binocular vision and eye movement disorders in older adults. Invest Ophthalmol Vis Sci. 2013;54:3798–3805. Ghadban R, Martinez JM, Diehl NN, Mohney BG. The incidence and clinical characteristics of adult-onset convergence insufficiency. Ophthalmology. 2015;122:1056–1059. Rambold H, Neumann G, Sander T, Helmchen C. Age-related changes of mergence under natural viewing conditions. Neurobiol Aging. 2006;27:163–172. Yang Q, Le TT, Kapoula Z. Aging effects on the visually driven part of vergence movements. Invest Ophthalmol Vis Sci. 2009;50:1145–1151. Alvarez TL, Kim EH, Yaramothu C, Granger-Donetti B. The influence of age on adaptation of disparity vergence and phoria. Vis Res. 2017;133:1–11. Gnadt JW, Mays LE. Neurons in monkey parietal area LIP are tuned for eye-movement parameters in three-dimensional space. J Neurophysiol. 1995;73:280–297. Hadjidimitrakis K, Bertozzi F, Breveglieri R, Bosco A, Galletti C, Fattori P. Common neural substrate for processing depth and direction signals for reaching in the monkey medial posterior parietal cortex. Cereb Cortex. 2014;24:1645–1657. Hasebe H, Oyamada H, Kinomura S, Kawashima R, Ouchi Y, Nobezawa S, Tsukada H, Yoshikawa E, Ukai K, Takada R, Takagi M, Abe H, Fukuda H, Bando T. Human cortical areas activated in relation to vergence eye movements-a PET study. Neuroimage. 1999;10:200–208. Quinlan DJ, Culham JC. fMRI reveals a preference for near viewing in the parieto-occipital cortex. Neuroimage. 2007;36:167–187. Jaswal R, Gohel S, Biswal BB, Alvarez TL. Task-modulated coactivation of vergence neural substrates. Brain Connect. 2014;4:595–607. Lavrich JB, Warner NJK, Hauschild AJ, Thau A, Wasserman BN, DeBenedictis C, Schnall B, Manley D, Gunton KB, Padidam S, Landy JE. Inconsistent diagnostic criteria for convergence insufficiency. J AAPOS. 2019;23:32.e1–32.e4. Anagnostou et al: J Neuro-Ophthalmol 2021; 41: 424-430 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.