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Show Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Clinical Correlation Between Vertical Gaze Palsy and Midbrain Volume in Progressive Supranuclear Palsy Karen A. Buch, MD, Marc A. Bouffard, MD, Randy H. Kardon, MD, PhD, Anne-Marie A. Wills, MD, MPH, Claudio M. Privitera, PhD, Mansi Sharma, BS, Shirley H. Wray, MD, PhD Background: Supranuclear vertical gaze palsies and slowed vertical saccades are characteristic clinic features of progressive supranuclear palsy (PSP). The “hummingbird sign,” reflective of midbrain atrophy, is a classic radiographic sign of PSP. Correlation between eye movement abnormalities and radiographic findings in PSP has been reported previously. However, due to the use of clinical criteria not commonly employed in neuroophthalmic practice and neuroimaging techniques that are not widely available, it remains unclear whether correlation between midbrain structure and characteristic ocular-motor disturbances can be helpful to neuroophthalmologists seeking to adjudicate difficult or unusual diagnostic cases. Methods: Patients with a diagnosis of probable PSP according to Movement Disorders Society criteria were studied retrospectively. A neuroradiologist calculated brainstem volumes in enrolled participants and normal controls. Spearman correlations were used to correlate the extent of eye movement limitation as assessed by 2 neuroophthalmologists with brainstem volumes. Results: Fourteen participants with PSP and 15 healthy controls with similar age and gender distribution were enrolled and evaluated retrospectively. All 14 participants with PSP had undergone MRIs. Midbrain atrophy significantly correlated with the PSP rating scale (P , 0.001). PSP patients had significantly reduced volumes in the midbrain (P 20.0026), tegmentum (0.0001), tectum (0.0001), and medulla (P = 0.0024) compared with normal controls. Notes documenting quantified ocular motor function were availDepartment of Radiology (KB), Massachusetts General Hospital, Boston, Massachusetts; Department of Neuro-Ophthalmology (MB), Beth Israel Deaconess Medical Center, Boston, Massachusetts; Department of Ophthalmology and Visual Sciences (RHK), University of Iowa Hospital and Clinics, Iowa City, Iowa; Iowa City VA Center for the Prevention and Treatment of Visual Loss (RHK), Iowa City VA Health Care System, Iowa City, Iowa; Department of Neurology (A-MW, MS, SHW), Massachusetts General Hospital, Boston, Massachusetts; and School of Optometry (CP), University of California, Berkeley, California. Funding was provided for this project by CureAD. The authors report no conflicts of interest. Address correspondence to Karen A. Buch, MD, Department of Radiology, Massachusetts General Hospital, Boston, MA02114; E-mail: kbuch@partners.org 246 able in 7 of 14 participants with PSP. Midbrain atrophy significantly correlated with in the extent of upward gaze limitation (P = 0.03). Conclusions: The severity of upward gaze limitation correlates with the severity of midbrain atrophy in patients with PSP. Recognition of this correlation may help to adjudicate diagnostic dilemmas and guide further evaluation. Journal of Neuro-Ophthalmology 2022;42:246–250 doi: 10.1097/WNO.0000000000001393 © 2021 by North American Neuro-Ophthalmology Society S upranuclear vertical gaze palsies and slowed vertical saccades are characteristic features of progressive supranuclear palsy (PSP) in its classically described form, now referred to as Richardson syndrome (1,2). Clinical evaluation of patients with suspected PSP often includes inspection for classic radiographic signs of PSP, including the “hummingbird sign” or an increased pons–midbrain ratio, resulting from midbrain atrophy (3). However, the extent to which the severity of clinically appreciable ocular motor abnormalities correlates with the severity of easily appreciated midbrain atrophy is unclear. Potential diagnostic pitfalls for the neuro-ophthalmologist evaluating patients with vertical gaze impairment include strategically located MRI-negative stroke, Parkinson disease, atypical parkinsonism, additional neurodegenerative processes, paraneoplastic syndromes (including anti-Ma, anti-IgLONS), or low-grade glioma affecting the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF) or misattribution of limited upgaze to a central process rather than degenerative orbital changes in cases wherein it is not entirely clear whether vertical gaze limitation is supranuclear. Establishing the relationship between the severity of limited vertical eye movements and the severity of midbrain atrophy in PSP offers clinical utility to neuro-ophthalmologists. The association between pertinent focal brainstem atrophy and typical ocular motility disturbances in PSP Buch et al: J Neuro-Ophthalmol 2022; 42: 246-250 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution has been suggested using both eye tracking and neuroimaging techniques not readily available to the clinician. Prior investigations are lacking for quantifying the association between vertical saccades abnormalities and riMLF atrophy, to which dysfunctional vertical saccades are typically ascribed (4). Gorges et al (5) delineated a linear relationship between vertical and horizontal saccadic velocities and fractional anisometropic changes in the pons, medial lemniscus, and superior cerebellar peduncles, hypothesizing that the disruption of more diffuse saccadic circuitry accounted for the association between saccadic abnormalities and nonmidbrain structures. Choi et al (6) reported a correlation between superior cerebellar peduncle atrophy and vertical saccadic velocity and accuracy as assessed by video-oculography. Amtage et al (7) described an association between downgaze palsy and reduced glucose metabolism using fluorodeoxyglucose-positron emission tomography in the bilateral anterior cingulate gyri and right lingual gyrus. Peak velocity of the optokinetic reflex correlated with regional metabolism in the oculomotor vermis. Paviour et al (8) reported an association between a gaze palsy score including gross quantification of saccadic speed (employing a scale of “normal, mild, moderate, or severely hypometric” saccades rather than conventional ophthalmic scoring) and midbrain volume. Quattrone et al (9) reported an association between binary assessment of vertical supranuclear gaze palsy and slowness of vertical saccades and midbrain fractional anisotropic values. Pathological confirmation of these observations is limited, although Horn et al (10) described 8 patients with PSP in whom histochemical examination confirmed abnormal tau accumulation in neurons and glia of the riMLF, paramedian pontine reticular formation, and olivary pretectal nucleus (and motor nuclei in advanced cases). We sought to clarify whether these insights translate clinically by correlating the severity of ocular motor limitation, expressed in conventional ophthalmic terminology, with the severity of midbrain atrophy, which is simple to estimate and measure using MRI. although we did not record blink rate.The extent of eye movement limitation was denoted as follows: 1. 2. 3. 4. 25% decrease in excursion 50% decrease in excursion 75% decrease in excursion Complete lack of movement in the intended direction. All participants with probable PSP underwent a brain MRI with acquisition of an isotropic T1-weighted sequence. Additionally, 15 age-matched normal controls were identified from a normative neuroradiology database and were included in this study. These control patients all underwent brain MRI with acquisition of the same isotropic T1-weighted sequence. Brainstem substructure volumes were manually contoured by a single radiologist using Visage 7 (Visage Imaging, Berlin, GE) for all PSP and normal control subjects. Brainstem substructures contoured include the midbrain, tegmentum, tectum, pons, and medulla. Because the performance of a 3-dimensional volumetric contour is not always feasible in routine clinical practice, we also sought to correlate a linear anterior-toposterior measurement made off of the midsagittal plane (Fig. 1) of the midbrain with midbrain volume calculations. METHODS Patients with a diagnosis of probable PSP according to movement disorders society criteria were studied retrospectively. Six of the subjects had a prospective evaluation of ocular motility. The remaining subjects in this cohort had ocular motility data derived from a retrospective chart review of neuro-ophthamology notes and/or notes from a movement disorders neurologist employing movement disorder society (MDS) criteria for quantifying eye movement limitation. Gaze limitation was confirmed to be supranuclear in nature in all participants with Bell reflex and/or optokinetic nystagmus (OKN) testing. Decreased blink rate was a universal observation in this cohort, Buch et al: J Neuro-Ophthalmol 2022; 42: 246-250 FIG. 1. Midsagittal image through the brainstem in a 71year-old health control subject. The dotted white line represents the short axis anterior-to-posterior measurement of the midbrain. This measurement is made on the midsagittal plane perpendicular to the long axis of the cerebral aqueduct. 247 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Analysis of variance (Graphpad Prism 8) was used to evaluate atrophy in brainstem substructures between PSP and normal control subjects. Spearman correlations were performed to assess the correlation in extent of ocular motor limitation with the extent of midbrain atrophy. The extent of limited upward gaze correlated with the midbrain atrophy (P = 0.03). Correlation between downward gaze limitation and midbrain atrophy trended toward but did not reach statistical significance (P = 0.08). CONCLUSIONS RESULTS PSP participants had a mean age of 72.1 years (range, 59– 83 years) and were composed of 6 women and 8 men. Controls had a mean age of 73.1 years (range, 60–84 years) with 7 women and 8 men. No significant difference in age was noted between these groups (P = 0.98). Volumetric measurements of the midbrain in patients with PSP ranged from 2.9 to 6.5 mm compared with 5.3–7.2 mm in control subjects. Significant differences were noted in brainstem substructure volumes in PSP compared with control subjects including the midbrain (P = 0.0026), tegmentum (P = 0.0001), tectum (P = 0.0001), and the medulla (P = 0.0024). No significant difference was noted in pontine volume between PSP and control subjects (P = 0.18). Midbrain atrophy significantly correlated with the PSP severity score (P , 0.0001). Midline T1-weighted sagittal and axial images through the brainstem sorted by midbrain volume, which is also numerically displayed for PSP (Fig. 2) and control subjects (Fig. 3). A range of midbrain atrophy is present in patients with PSP (Fig. 2). The previously described medullary atrophy is also evident on visual inspection. In Figure 3, the normal range of midbrain and medullary volumes is displayed, depicting normal age-related variations in these structures. The anterior-to-posterior linear measurement of the midbrain performed on a midsagittal plane was found to have a strong correlation (r = 0.71) with 3-dimensional midbrain volumetric calculations. A detailed ophthalmic examination was available in 7 of the 14 participants with PSP. The severity of gaze palsy in participants is depicted in Table 1. We report a robust correlation between the severity of midbrain atrophy and severity of upward gaze limitation in PSP patients. Despite the presumed nonlinear relationship between ocular motility deficit and brainstem volume, we did find a significant correlation. The cohort of PSP patients in this cohort spanned a range of severity and are likely representative of what might come to medical attention in a typical clinical setting in which these patients are evaluated. Midbrain volume may be easily approximated as a “gestalt” on sagittal MRI sequences (Figs. 1–3) or measured with basic neuroradiographic techniques. The range of MRI brainstem morphology observed in PSP and control subjects and sorted by midbrain volume depicted in this report also provides a useful guide for interpreting neuroimaging studies of patients suspected of having PSP. The correlation of vertical supranuclear gaze abnormality with an easily quantifiable MRI measurement of midbrain atrophy provides a meaningful complement to the existing literature describing structure–function association in ocular motor function in PSP. The majority of the literature on this topic generally does not employ practical appraisals of eye movement and uses advanced neuroimaging not readily available to the neuro-ophthalmologist (5–11). The linear anterior-to-posterior measurements performed in the midsagittal plane of the brainstem used in this study was applied to a standard T1 sagittal image of the brain. This sagittal T1 sequence is widely considered a standard MRI brain sequence, which is performed on both noncontrast and contrastenhanced MRI examinations irrespective of clinical indication. Therefore, the methodology for reproducing this linear FIG. 2. T1-weighted midsagittal and axial images of patients diagnosed with progressive supranuclear palsy ranked from smallest midbrain volume to largest midbrain volume. Volume measurements are measured as cubic millimeter. The subject number is displayed along the bottom row of images (beginning with a denotation “S”). PSP, progressive supranuclear palsy. 248 Buch et al: J Neuro-Ophthalmol 2022; 42: 246-250 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 3. T1-weighted midsagittal and axial MRI images of the brainstem in normal subjects. The range of midbrain volumes in normal subjects is shown ranked by smallest midbrain volume to largest midbrain volume. The normal control subject number is displayed along the bottom row of images (beginning with a denotation “N”). anterior-to-posterior measurement can readily be performed on a brain MRI without having to request a specific sequence. Despite the significant correlations between midbrain atrophy and limitations in upward gaze noted in this study, there were few patients in this study who had a significant upward gaze palsy but did not have severe midbrain atrophy. This highlights that this tool measuring midbrain atrophy on MRI is not accurate in all cases. In cases where there is significant upward gaze palsy, and the midbrain is not significantly atrophied on MRI, additional clinical tools may be needed to help confirm the suspected diagnosis. While there may be such cases, we feel that the use of measuring midbrain atrophy as described in this study, which can be easily performed on any acquired brain MRI examinations, is still of significant clinical utility for the evaluation of patients with suspected PSP. A major limitation of this study was the small sample size with a limited number of patients with a clinical diagnosis of PSP undergoing brain MRI evaluation and neuroophthalmologic testing. Additionally, the patients included TABLE 1. Depiction of the extent of gaze limitation in participants with progressive supranuclear palsy Subject ID S3 S8 S12 S13 S14 S20 S26 Upgaze Downgaze 24 23 24 21 22 24 22 24 22 24 0 23 24 0 Note that 24 is denotes no movement in the intended direction of gaze, 23 denotes 25% movement, 22 denotes 50% movement, and 21 signifies 75% movement in the intended direction of gaze. PSP, progressive supranuclear palsy. Buch et al: J Neuro-Ophthalmol 2022; 42: 246-250 in this study had a clinical diagnosis of PSP by MDS criteria; however, there was no histopathologic proof of PSP. Because the majority of patients included in this study are not deceased, correlation with histopathology is not possible. Furthermore, the lack of tissue for a pathologic diagnosis is a common limitation of PSP research, which we acknowledge. Within these confines, we have attempted to maintain as high a standard of specificity as possible using MDS diagnostic criteria and working in collaborating with the participants’ treating physicians, who are movement disorders–trained neurologists at our institution. There was some heterogeneity in ocular motility data collection in this study with 6 of the subjects having a prospective evaluation of ocular motility. The remaining subjects in this cohort had ocular motility data derived from a retrospective chart review of neuro-ophthamology notes and/or notes from a movement disorders neurologist employing MDS criteria for quantifying eye movement limitation. While it would be ideal for a uniform methodology to have been applied to all subjects in this study, we feel that the ocular motility results reported for the subjects is highly accurate. With regards to the neuroophthalmologic examination, while decreased blink rate was a universal observation in this cohort, we did not record blink rate and we did not prospectively record saccadic velocity. In the absence of an eye tracker, we felt this to be too subjective to be employed in a statistical correlation, particularly if reduced to a binary “slow” or “normal” assignment. An additional limitation is that the control subjects included in this study did not undergo formal ophthalmologic testing. Based on a review of the medical records, these control subjects did not have any neurologic or neuro-ophthalmologic abnormalities, and thus, we presumed that these patients had normal eye movements. This retrospective correlation of vertical eye movement abnormalities and midbrain atrophy suggests that the presence of a robust midbrain volume in patients with a supranuclear vertical gaze palsy should prompt neuroophthalmologists to consider diagnoses other than PSP, 249 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution such as MRI-negative stroke, Parkinson disease, atypical parkinsonism, paraneoplastic syndromes, or low-grade glioma. We hope that establishing a correlation between easily observed eye movement limitation and focal brainstem atrophy aids examiners in raising or lowering clinical suspicion for a PSP mimic. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: K. A. Buch, S. H. Wray, R. H. Kardon, M. A. Bouffard, A.-M. A. Wills, C. M. Privitera, and M. Sharma; b. Acquisition of data: K. A. Buch, S. H. Wray, M. A. Bouffard, A.-M. A. Wills, and M. Sharma; c. Analysis and interpretation of data: K. Buch, S. H. Wray, R. H. Kardon, M. A. Bouffard, A.-M. A. Wills, C. M. Privitera, and M. Sharma. Category 2: a. Drafting the manuscript: K. Buch, S. H. Wray, R. H. Kardon, M. A. Bouffard, A.-M. A. Wills, C. M. Privitera, and M. Sharma; b. Revising it for intellectual content: K. Buch, S. H. Wray, R. H. Kardon, M. A. Bouffard, A.-M. A. Wills, C. M. Privitera, and M. Sharma. Category 3: a. Final approval of the completed manuscript: K. Buch, S. H. Wray, R. H. Kardon, M. A. Bouffard, A.-M. A. Wills, C. M. Privitera, M. Sharma. ACKNOWLEDGMENTS The authors thank CureAD for funding this project. They also tank Dr. Rudolph Tanzi for assistance with this project. REFERENCES 1. Steele JC, Richardson JC, Olszewski J. Progressive supranuclear palsy. 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