Title: Orthoptic and video-oculographic analyses in oculopharyngeal muscular dystrophy Authors: Dimitri Renard, MD1 Adelaide Ferraro, MD1 Marie-Celine Lorenzini2 Luc Jeanjean, MD2 Marie-Claire Portal1 Elisabeth Llinares1 Pierre Labauge, MD, PhD1 Giovanni Castelnovo, MD1
Acknowledgement: We would like to thank Dr Bertrand Gaymard (AP-HP, Hôpital Pitié-Salpêtrière, Paris, France) for the excellent and critical reading of our paper.
Affiliation: 1) Department of Neurology CHU Nîmes, Hôpital Caremeau Place du Pr Debré 30029 Nîmes Cedex 4 France 2) Department of Ophthalmology CHU Nîmes, Hôpital Caremeau Place du Pr Debré
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24600 This article is protected by copyright. All rights reserved.
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30029 Nîmes Cedex 4 France
Corresponding Author: Dimitri Renard Department of Neurology CHU Nîmes, Hôpital Caremeau Place du Pr Debré 30029 Nîmes Cedex 4 France Phone: (33) 4 66 68 32 61 Fax: (33) 4 66 68 40 16 Email: [email protected]
Type of submission: Main article Letter count title: 79 Word count abstract: 150 Word count text: 2538 Number of references: 17 Number of Tables: 5 Disclosure: Authors do not report any conflict of interest Running title: Oculographic analysis in OPMD
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Title: Orthoptic and video-oculographic analyses in oculopharyngeal muscular dystrophy
Abstract: Introduction: Mild ophthalmoparesis can be seen in oculopharyngeal muscular dystrophy (OPMD). Methods: Orthoptic analysis: assessment of phoria/tropia, eye excursion, saccades, pursuit, stereoacuity, and Hess-Lancaster screen test. Video-oculography: fixation, horizontal and vertical saccades, and pursuit. Results: Orthoptic abnormalities were: tropia (4/6), abnormal eye excursion (4/6, 78% involved lateral or superior rectus muscles), abnormal horizontal or vertical saccades (2/6), abnormal pursuit (0/6), abnormal stereoacuity (2/6), and pathological Hess-Lancaster screen (4/6). Video-oculographic abnormalities were present for: fixation (1/6), saccade latency (1/6), horizontal pursuit (3/6), and vertical pursuit (0/6). For horizontal saccades: mean velocity, peak velocity, and gain were pathological in 5/6, 5/6 (61% of pathological mean and peak velocities involved abducting eye movements), and 3/6, respectively. For vertical saccades: mean velocity, peak velocity, and gain were pathological in 4/6, 4/6 (53% involved upward movements), and 3/6, respectively. Discussion: The data indicate preferential involvement of lateral and (to a lesser degree) superior rectus muscles in OPMD.
Key Words: orthoptic; video-oculography; oculopharyngeal muscular dystrophy; oculomotor; ophthaloparesis
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Introduction: Oculopharyngeal muscular dystrophy (OPMD) is a dominantly inherited myopathy caused by a short GCG-triplet expansion in the PABPN1 gene. It is characterized by onset in late adulthood and progressive ocular (including ptosis, which is generally most prominent, and restricted ocular motility) and bulbar (especially dysphagia) symptoms. Ptosis and diplopia in OPMD are thought to be caused by muscle weakness in the levator palpebrae superioris muscle and asymmetrical oculomotor muscle involvement, respectively. The vast majority of OPMD cases are caused by heterozygote mutations. In contrast to other muscular dystrophies (especially myotonic dystrophy type 1), few data exist on eye movement abnormalities in OPMD.1-8 Ophthalmoparesis has only been described in a few OPMD series and was present in between 42% and 69% of the OPMD patients studied.4,5 One study reported systematic analysis of the oculomotor deficit in OPMD.8 In that study, however, the infrared videooculography device only analyzed horizontal saccades, and no orthoptic analyses were performed. Horizontal saccades were found to be significantly slower in OPMD patients than in healthy controls, whereas latency, amplitude, and gain showed no differences between the 2 groups. Our aim was to study OPMD patients more extensively with the same infrared video-oculography device (i.e. Mobile EyeBrain Tracker, e(ye)BRAIN, Ivry-sur-Seine, France) and with orthoptic analysis.
Methods: Patients: Nine genetically proven OPMD patients followed in our center were invited to undergo videooculography and orthoptic analysis. Seven patients agreed to participate. One patient had a severe cognitive deficit, and video-oculography and orthoptic analysis could not be performed because of poor cooperation. The other 6 patients had normal cognitive function according to
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the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) classification, and minimental status examination was normal. All included patients gave informed consent. Six patients (4 men and 2 women, originating from 5 different families) were included and analyzed. Patient characteristics are shown in Table 1. All were heterozygous for the mutation. At the time of ocular analysis, mean age was 63.5 years, and mean disease duration was 11 years. Orthoptic analysis: Before starting orthoptic analysis, best corrected visual acuity was tested. During orthoptic testing, upper eyelids were fixed with adhesive tape in patients with ptosis. Cover, coveruncover, and alternate eye cover tests were performed, both for distant and near vision, to look for eso/exo/hyper/hypophoria (non-pathological oculomotor disorder) and eso/exo/hyper/hypotropia (pathological oculomotor disorder). Eye excursion was tested in 9 different directions (neutral, upper, lower, left, right, upper-left, upper-right, lower-left, and lower-right positions; tested to 30° in each direction). If eye excursion was incomplete, the paretic muscle was identified. For horizontal saccades, a lateral fixation target at 30° was used. For vertical saccades, a vertical fixation target was used at 20°. Horizontal and vertical pursuit was tested within a 60° and 40° arc at a speed of about 20°/s ° and 10°/s, respectively. For testing stereoacuity, the Worth Lights test was used for distance vision and the TNO test for near vision.9,10 Finally, a Hess-Lancaster screen test was performed.11 Video oculography: Eye movements were recorded using the Mobile Eyebrain Tracker (EBT) head-mounted, a CE-marked (indicating conformity with the essential health and safety requirements set out in European Directives) eye-tracking device. The Mobile EBT® is equipped with a camera that captures the movements of each eye independently. Stimuli were presented on a 22 inch PC screen with a resolution of 1920x1080 pixels and a refresh rate of 60 Hz. Screen luminance
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was 250 cd/m2, and static contrast ratio was 1000/1. The diameter of the target was 0.5°. The distance of the patient’s eye to the monitor was 60 cm (subtending an arc of 40° for horizontal saccades and 26° for vertical saccades, an arc of 39° for horizontal smooth pursuit, and an arc of 20° for vertical smooth pursuit). Upper eye lids were lifted and fixed to perform video-oculography in patients with ptosis. We tested for: fixation, horizontal and vertical reflex saccades, and horizontal and vertical smooth pursuit. For fixation analysis (of particular interest for showing nystagmus and saccadic oscillations/intrusions), a stationary target was fixed in central position for 3s, and for 8s for extreme (right- and left-side and up- and downward) target positions (with recovery of central position between each change for extreme target position). Three main characteristics of visually-guided saccades were analyzed: latency (time between the appearance of a target and saccade initiation), velocity (both mean and peak velocities between the beginning and end of the saccade), and gain (saccade amplitude/target step amplitude). Identification of starting and ending times of all saccadic eye movements was performed automatically using an algorithm based on a velocity threshold (velocity threshold >10°/s). Low saccade gain indicates that the saccade was hypometric, and high saccade gain corresponds to a hypermetric saccade. In each patient, 8 trials for each horizontal and each vertical saccade were performed. Analyses were done for each eye in each horizontal and vertical direction and were compared with age-matched healthy controls (n=15 for age 51-66, n=12 for age >66). Latency, mean velocity, peak velocity, and gain were called abnormal when values differed > 2SD from controls. For horizontal saccades, a lateral fixation target at 20° was used. For vertical saccades, the vertical fixation target was presented at 13°. Before testing the reflex saccade, a central
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fixation target was presented for 2500-3500ms. Then, the fixation disappeared for 200ms (configuring a gap period), and a lateral or vertical fixation target was presented for 1000ms and disappeared again, followed by the presentation of the central fixation target. For smooth pursuit analyses, a slow moving target (following a sinusoidal movement) had to be followed. Horizontal smooth pursuit was studied with a target moving 20°/s towards a lateral angle of 19.5°. For vertical smooth pursuit, the moving target was studied at 8°/s towards a vertical angle of 10.1°. In each patient, 14 sine wave cycles were performed for each horizontal and vertical pursuit. Smooth pursuit was called pathological when a clear degradation of the sinusoidal pattern to a saccadic pattern was observed in ≥1 of the sine wave cycles.
Results: Orthoptic analysis: The best corrected visual acuity measured with the Snellen chart was 1.0 or more in both eyes in all patients. Results of orthoptic analyses are shown in Table 2. Some form of phoria or tropia was present in all patients. Tropia was present in 4 of 6 patients (vertical deviation in patients 3 and 4, horizontal deviation in patient 5, and mixed deviation in patient 1). Testing for eye excursion revealed abnormalities in 4 of 6 patients (2 patients with involvement of 1 oculomotor muscle and 2 patients with involvement of multiple oculomotor muscles). Seven of 9 (78%) pathological oculomotor muscles were superior or lateral rectus muscles. Abnormal saccades (i.e. hypometric saccades with a catch-up saccade) were found in 2 of 6 patients (in 1 patient for horizontal saccades to the left and for downward saccades, and in 1 patient for both up- and downward saccades). Smooth pursuit was normal in all patients. Worth Lights and TNO tests were normal in all patients except for patient 1, who had abnormal TNO testing. The Hess-Lancaster screen test was abnormal in 4 of 6 patients. We
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found a comitant vertical deviation in patient 1 and incomitant vertical deviation in patients 3 and 4. A comitant horizontal deviation was found in patient 5. No pathological abnormalities were found in patients 2 and 6 (simple horizontal deviation due to their phoria).
Video-oculography: Fixation analysis was normal in all patients except patient 2, who showed 19 square-wave jerks during 49 seconds of analysis with an amplitude of 2-3° and intersaccadic intervals of 200-300 ms. Nystagmus was not seen in any patient. Video-oculographic findings for horizontal and vertical saccades and pursuit are shown in Tables 3, 4, and 5. In patient 2, vertical saccades could not be analyzed because of lack of cooperation. Latencies for both horizontal and vertical saccades were normal in all patients (horizontal latency, mean 202 ms, range 143-262 ms; vertical latency, mean 217 ms, range 153-412 ms), except for patient 4, who showed pathological vertical upward latency (412 ms). In the age 50-65 years patients (patients 1, 4, and 6), mean values of mean and peak velocities for horizontal saccades were 184 °/s (normal: mean 295 °/s, SD 49 °/s) and 314 °/s (normal: mean 565 °/s, SD 101 °/s) respectively, and for vertical saccades 172 °/s (normal: mean 245 °/s, SD 47 °/s) and 261 °/s (normal: mean 508 °/s, SD 103 °/s), respectively. In patients >age 65 years (patients 2, 3, and 5), mean and peak velocities for horizontal saccades were 220 °/s (normal: mean 311 °/s, SD 54 °/s) and 409 °/s (normal: mean 588 °/s, SD 89 °/s) respectively, and for vertical saccades were 156 °/s (normal: mean 236 °/s, SD 48 °/s) and 290°/s (normal: mean 485 °/s, SD 93 °/s) respectively. In the patient group as a whole (i.e. independent of age), mean and peak velocities for horizontal saccades for each eye movement were: mean velocity for the left eye to the left, 181 °/s; left eye to the right, 193 °/s; right eye to the left 220 °/s; right eye to the right 242 °/s;
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peak velocity for the left eye to the left 332 °/s; left eye to the right 337 °/s; right eye to the left 411 °/s; right eye to the right 417 °/s. Mean values of mean and peak velocities for vertical saccades for each eye movement were: mean velocity for the left eye downward 144 °/s; left eye upward 141 °/s; right eye downward 178 °/s; right eye upward 200 °/s; peak velocity for the left eye downward 268 °/s; left eye upward 254 °/s; right eye downward 296 °/s; right eye upward 287 °/s. In the age 50-65 year-old patients, mean gain values for horizontal and vertical saccades were 0.90 (normal: mean 0.94 ± SD 0.06) and 0.83 (normal: mean 0.91 ± SD 0.09), respectively. In patients aged >65 years, gain values for horizontal and vertical saccades were 0.82 (normal: mean 0.91 ± SD 0.04) and 0.78 (normal: mean 0.91 ± SD 0.04), respectively. In the patient group as a whole, mean gain values for horizontal saccades for different eye movements were: 0.83 for the left eye to the left, 0.84 for the left eye to the right, 0.89 for the right eye to the left, 0.87 for the right eye to the right. Mean gain values for vertical saccades for different eye movements were: 0.84 for the left eye downward, 0.81 for the left eye upward, 0.82 for the right eye downward, 0.74 for the right eye upward. Thirthy-three percent (4 patients) of all saccades showed pathological gain, all hypometric. For saccade gains, no significant difference was seen between adducting, abducting, upward, or downward saccades. Half of the saccades showing pathological gain were dysconjugate. For horizontal saccades, mean velocity, peak velocity, and gain were pathological in 5, 5, and 2 of 6 patients, respectively. When analyzing the mean values, no difference was seen between abducting and adducting eye movements. When analyzing only the mean and peak velocities of pathological horizontal saccades, however, abnormalities were found in 61% (20of 33 abnormal eye saccades) in abducting eye movements and in 39% of adducting eye movements. Half of these pathological horizontal saccades were dysconjugate.
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For vertical saccades, mean velocity, peak velocity, and gain were pathological in 4, 4, and 3 of 5 patients, respectively. Pathological mean and peak velocities of vertical saccades were found in 53% (16 of 30 abnormal eye saccades) of upward eye movements and in 47% of downward eye movements. As for horizontal saccades, half of the pathological vertical saccades were dysconjugate. Horizontal smooth pursuit was pathological in 3 of 6 patients. Vertical smooth pursuit was normal in all patients.
Discussion: We assessed 6 OPMD patients using orthoptic and video-oculographic analyses. None of the patients had completely normal analyses. The most frequent abnormalities were: tropia, limitation of eye excursion, reduced (mean and peak) velocity of horizontal and vertical saccades, hypometric gain, and pathological horizontal smooth pursuit. In contrast to the findings of Gautier et al, some of our patients also had abnormal latency (n=1 patient) or gain (n=4 patients) of saccades.8 Genetic muscle diseases with frequent oculomotor involvement include myotonic dystrophy (especially type 1), congenital myopathies (e.g. centronuclear myopathy), chronic progressive external ophthalmoplegia (CPEO) and other mitochondrial disorders, and OPMD. In myotonic dystrophy type 1, ptosis is frequent, whereas defects in ocular motility are usually absent or mild. Observed abnormalities of ocular motility include reduced smooth pursuit gain, reduced saccadic peak velocity, increased duration and abnormal skewness of saccades, and elevated error rates in the antisaccades and remember saccade paradigms.1-3 Some of these oculomotor abnormalities are thought to be due to oculomotor muscle dysfunction (weakness and/or myotonia) whereas other abnormalities suggest brain dysfunction.
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In CPEO, severe defects in ocular motility are typically seen, although diplopia is most often absent due to symmetrical involvement. Despite frequent brain abnormalities in mitochondrial diseases, oculomotor abnormalities are thought to be of muscular origin.12 In CPEO, symmetrical muscle volume reduction measured by MRI is seen in the oculomotor muscles with less severe muscle involvement in the lateral rectus muscles than in other extraocular muscles.13,14 In centronuclear myopathy, predominant upgaze limitation (in favor of superior rectus muscle deficit) is sometimes described, although most reports of this and other congenital myopathies report diffuse ocular motor weakness.15 In contrast to myotonic dystrophy and mitochondrial diseases, clinical and radiological abnormalities in favor of central nervous system involvement are typically absent in heterozygous OPMD. However, executive functions have been found to be impaired in some patients.16 In some of the rare homozygous OPMD cases, cognitive decline, recurrent depression, psychotic episodes, and lacunar infarcts, leukoaraiosis, and brain atrophy on imaging have been described.17 Therefore, the possibility of involvement of brain structures controlling eye movements cannot be ruled out in the heterozygous patients we analyzed, especially since brain imaging was not performed systematically. Although our videooculographic data were compared with age-matched controls, and clinical findings suggestive of brain disease were not seen in our patients, one cannot exclude associated brain pathologies (e.g. asymptomatic vascular disease, early-stage degenerative diseases) potentially interfering with orthoptic and video-oculographic analyses. Slow saccades of restricted amplitude (i.e. the most frequent video-oculographic abnormality found in our patients) usually reflect abnormalities in the ocular motor periphery, such as extraocular muscle or ocular motor nerve pareses, probably related to muscle weakness. Although dysconjugate eye movements can be seen in central nervous system involvement
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(e.g. internuclear ophthalmoplegia), dysconjugate eye movements are most often of peripheral origin. Half of the pathological saccadic velocities and gains were dysconjugate in our patients. The most likely cause seems to be muscle weakness in the orbital muscles. The low gain (horizontal) pursuit seen in some of our patients has been described in a multitude of brain pathologies but can also be observed in disorders involving the ocular motor periphery. Our data point to preferential involvement of lateral (and to a lesser degree superior) rectus muscles. This contrasts with CPEO, where the lateral rectus muscles are the least severely involved orbital muscles and with centronuclear myopathy, where there is sometimes preferential involvement of superior rectus muscles. Our study shows the multitude of infraclinical, most often asymmetric, eye movement abnormalities, which probably explains the diplopia in these OPMD patients.
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Table 1: Patient characteristics Patient Age 1 57 2 70 3 68 4 65 5 69 6 52
Gender GCG expansion size Onset M 9 Bulbar M 8 Bulbar M 9 Ptosis W 9 Ptosis W 9 Ptosis M 10 Ptosis
Ptosis (onset) Ptosis surgery Diplopia (onset) Bulbar (onset) No No Yes (56y) Yes (50y) Yes (65y) No No Yes (62y) Yes (56y) Yes (60y) No Yes (63y) Yes (49y) Yes (62y) Yes (65y) No Yes (52y) Yes (62y) Yes (58y) Yes (59y) Yes (47y) Yes (50y) No No
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Table 2: Orthoptic analyses Nr Phoria
Tropia
Eye excursion limit
Saccades Smooth pursuit
1
Esotropia (+7D, left, DV) Hypotropia (5D, right, DV) Esotropia (+18D, left, NV) Hypotropia (6D, right, NV)
No
Normal
Normal
2 Exophoria (-8D, NV)
No
No
Normal
Normal
3 Exophoria (-6D, NV)
Hypotropia (2D, left, NV)
Superior rectus, left Abnormal Normal (hor, to left) (vert, down)
4 Exophoria (-8D, NV)
Hypotropia (5D, left, DV)
Superior rectus, left Lateral rectus, right Medial rectus, right Lateral rectus, left Medial rectus, left
Normal
Normal
5 Exophoria (-8D, NV)
Esotropia (+4D, left, DV)
Superior rectus, left Lateral rectus, right
Normal
Normal
6 Exophoria (-4D, DV) Exophoria (-14D, NV)
No
Lateral rectus, right Abnormal (vert, up & down)
No
Normal
Nr, patient number; D, diopter; DV, distance vision; NV near vision, hor, horizontal; vert, vertical; down, downward; up, upward)
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Table 3: Video-oculographic analyses for horizontal saccades Nr Latency
Mean velocity
Peak velocity
1 2 3 4 5 6
Abnormal (LLE, RRE) Normal Abnormal (LLE, RLE, LRE, RRE) Abnormal (LLE, RLE) Abnormal (LLE, RLE, LRE, RRE) Abnormal (LLE, RLE, LRE, RRE)
Abnormal (LLE, RRE) Normal Normal Abnormal (RLE, RRE) Abnormal (LLE) Abnormal (LLE, RLE, LRE) Abnormal (LLE, RLE) Normal Abnormal (LLE, RLE, LRE, RRE) Abnormal (LLE, RLE) Abnormal (LLE, RLE) Normal
Normal Normal Normal Normal Normal Normal
Gain
Nr, patient number; LLE, leftward saccade of the left eye; RLE, rightward saccade of the left eye; LRE, leftward saccade of the right eye; RRE, rightward saccade of the right eye.
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Table 4: Video-oculographic analyses for vertical saccades Nr Latency
Mean velocity
Peak velocity
Gain
1 2 3 4 5 6
Normal / Abnormal (ULE, DLE) Abnormal (ULE, URE) Abnormal (ULE, URE) Abnormal (DLE, DRE)
Abnormal (ULE, DLE, DRE) / Abnormal (ULE, DLE, DRE) Abnormal (ULE, DLE) Abnormal (ULE, URE) Abnormal (DLE, URE, DRE)
Normal / Abnormal (ULE, URE, DRE) Normal Abnormal (ULE, DLE, URE, DRE) Abnormal (URE)
Normal / Normal Abnormal (ULE) Normal Normal
Nr, patient number; / , lack of patient cooperation; ULE, upward saccade of the left eye; DLE, downward saccade of the left eye; URE, upward saccade of the right eye; DRE, downward saccade of the right eye.
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Table 5: Video-oculographic analyses for horizontal and vertical pursuit Nr
Horizontal pursuit
Vertical pursuit
1 2 3 4 5 6
Saccadic Saccadic Normal Saccadic Normal Normal
Normal / Normal Normal Normal Normal
Nr, patient number; / , lack of patient cooperation.
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Abbreviations: OPMD: oculopharyngeal muscular dystrophy EBT: Mobile Eyebrain Tracker DSM-IV: Diagnostic and Statistical Manual of Mental Disorders CPEO: chronic progressive external ophthalmoplegia
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References: 1. Anastasopoulos D, Kimmig H, Mergner T, Psilas K. Abnormalities of ocular motility in myotonic dystrophy. Brain. 1996;119:1923-32. 2. Versino M, Rossi B, Beltrami G, Sandrini G, Cosi V. Ocular motor myotonic phenomenon in myotonic dystrophy. J Neurol Neurosurg Psychiatry. 2002;72:236-40. 3. Shaunak S, Orrell R, Henderson L, Kennard C. Saccades and smooth pursuit in myotonic dystrophy. J Neurol. 1999;246:600-6. 4. Witting N, Mensah A, Køber L, Bundgaard H, Petri H, Duno M, et al. Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy. Acta Neurol Scand. 2014 Mar 10. [Epub ahead of print] 5. Tondo M, Gámez J, Gutiérrez-Rivas E, Medel-Jiménez R, Martorell L. Genotype and phenotype study of 34 Spanish patients diagnosed with oculopharyngeal muscular dystrophy. J Neurol. 2012;259:1546-52. 6. Hill ME1, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain. 2001;124:522-6. 7. Nadaj-Pakleza A, Richard P, Lusakowska A, Gajewska J, Jamrozik Z, Kostera-Pruszczyk A, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic characteristics of 9 Polish patients. Neurol Neurochir Pol. 2009;43:113-20. 8. Gautier D, Pénisson-Besnier I, Rivaud-Péchoux S, Rabaute C, Milea D. Ocular motor deficits in oculopharyngeal muscular dystrophy. Eur J Neurol. 2012;19:e38. 9. Roper-Hall G. The "worth" of the worth four dot test. Am Orthopt J. 2004;54:112-9. 10. Tomaç S, Altay Y. Near stereoacuity: development in preschool children; normative values and screening for binocular vision abnormalities; a study of 115 children. Binocul Vis Strabismus Q. 2000;15:221-8.
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11. Awadein A. A computerized version of the Lancaster red-green test. J AAPOS. 2013;17:197-202. 12. Ritchie AE, Griffiths PG, Chinnery PF, Davidson AW. Eye movement recordings to investigate a supranuclear component in chronic progressive external ophthalmoplegia: a cross-sectional study. Br J Ophthalmol. 2010;94:1165-8. 13. Carlow TJ, Depper MH, Orrison WW Jr. MR of extraocular muscles in chronic progressive external ophthalmoplegia. AJNR Am J Neuroradiol. 1998;19:95-9. 14. Yu-Wai-Man C, Smith FE, Firbank MJ, Guthrie G, Guthrie S, Gorman GS, et al. Extraocular muscle atrophy and central nervous system involvement in chronic progressive external ophthalmoplegia. PLoS One. 2013;8:e75048 15. Jeannet PY, Bassez G, Eymard B, Laforêt P, Urtizberea JA, Rouche A, et al. Clinical and histologic findings in autosomal centronuclear myopathy. Neurology. 2004;62:1484-90. 16. Dubbioso R1, Moretta P, Manganelli F, Fiorillo C, Iodice R, Trojano L, et al. Executive functions are impaired in heterozygote patients with oculopharyngeal muscular dystrophy. J Neurol. 2012;259:833-7 17. Blumen SC, Bouchard JP, Brais B, Carasso RL, Paleacu D, Drory VE, et al. Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes. Neurology. 2009;73:596-601.
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Acknowledgement: We would like to thank Dr Bertrand Gaymard (AP-HP, Hôpital Pitié-Salpêtrière, Paris, France) for the excellent and critical reading of our paper.
Affiliation: 1) Department of Neurology CHU Nîmes, Hôpital Caremeau Place du Pr Debré 30029 Nîmes Cedex 4 France 2) Department of Ophthalmology CHU Nîmes, Hôpital Caremeau Place du Pr Debré
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24600 This article is protected by copyright. All rights reserved.
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30029 Nîmes Cedex 4 France
Corresponding Author: Dimitri Renard Department of Neurology CHU Nîmes, Hôpital Caremeau Place du Pr Debré 30029 Nîmes Cedex 4 France Phone: (33) 4 66 68 32 61 Fax: (33) 4 66 68 40 16 Email: [email protected]
Type of submission: Main article Letter count title: 79 Word count abstract: 150 Word count text: 2538 Number of references: 17 Number of Tables: 5 Disclosure: Authors do not report any conflict of interest Running title: Oculographic analysis in OPMD
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Title: Orthoptic and video-oculographic analyses in oculopharyngeal muscular dystrophy
Abstract: Introduction: Mild ophthalmoparesis can be seen in oculopharyngeal muscular dystrophy (OPMD). Methods: Orthoptic analysis: assessment of phoria/tropia, eye excursion, saccades, pursuit, stereoacuity, and Hess-Lancaster screen test. Video-oculography: fixation, horizontal and vertical saccades, and pursuit. Results: Orthoptic abnormalities were: tropia (4/6), abnormal eye excursion (4/6, 78% involved lateral or superior rectus muscles), abnormal horizontal or vertical saccades (2/6), abnormal pursuit (0/6), abnormal stereoacuity (2/6), and pathological Hess-Lancaster screen (4/6). Video-oculographic abnormalities were present for: fixation (1/6), saccade latency (1/6), horizontal pursuit (3/6), and vertical pursuit (0/6). For horizontal saccades: mean velocity, peak velocity, and gain were pathological in 5/6, 5/6 (61% of pathological mean and peak velocities involved abducting eye movements), and 3/6, respectively. For vertical saccades: mean velocity, peak velocity, and gain were pathological in 4/6, 4/6 (53% involved upward movements), and 3/6, respectively. Discussion: The data indicate preferential involvement of lateral and (to a lesser degree) superior rectus muscles in OPMD.
Key Words: orthoptic; video-oculography; oculopharyngeal muscular dystrophy; oculomotor; ophthaloparesis
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Introduction: Oculopharyngeal muscular dystrophy (OPMD) is a dominantly inherited myopathy caused by a short GCG-triplet expansion in the PABPN1 gene. It is characterized by onset in late adulthood and progressive ocular (including ptosis, which is generally most prominent, and restricted ocular motility) and bulbar (especially dysphagia) symptoms. Ptosis and diplopia in OPMD are thought to be caused by muscle weakness in the levator palpebrae superioris muscle and asymmetrical oculomotor muscle involvement, respectively. The vast majority of OPMD cases are caused by heterozygote mutations. In contrast to other muscular dystrophies (especially myotonic dystrophy type 1), few data exist on eye movement abnormalities in OPMD.1-8 Ophthalmoparesis has only been described in a few OPMD series and was present in between 42% and 69% of the OPMD patients studied.4,5 One study reported systematic analysis of the oculomotor deficit in OPMD.8 In that study, however, the infrared videooculography device only analyzed horizontal saccades, and no orthoptic analyses were performed. Horizontal saccades were found to be significantly slower in OPMD patients than in healthy controls, whereas latency, amplitude, and gain showed no differences between the 2 groups. Our aim was to study OPMD patients more extensively with the same infrared video-oculography device (i.e. Mobile EyeBrain Tracker, e(ye)BRAIN, Ivry-sur-Seine, France) and with orthoptic analysis.
Methods: Patients: Nine genetically proven OPMD patients followed in our center were invited to undergo videooculography and orthoptic analysis. Seven patients agreed to participate. One patient had a severe cognitive deficit, and video-oculography and orthoptic analysis could not be performed because of poor cooperation. The other 6 patients had normal cognitive function according to
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the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) classification, and minimental status examination was normal. All included patients gave informed consent. Six patients (4 men and 2 women, originating from 5 different families) were included and analyzed. Patient characteristics are shown in Table 1. All were heterozygous for the mutation. At the time of ocular analysis, mean age was 63.5 years, and mean disease duration was 11 years. Orthoptic analysis: Before starting orthoptic analysis, best corrected visual acuity was tested. During orthoptic testing, upper eyelids were fixed with adhesive tape in patients with ptosis. Cover, coveruncover, and alternate eye cover tests were performed, both for distant and near vision, to look for eso/exo/hyper/hypophoria (non-pathological oculomotor disorder) and eso/exo/hyper/hypotropia (pathological oculomotor disorder). Eye excursion was tested in 9 different directions (neutral, upper, lower, left, right, upper-left, upper-right, lower-left, and lower-right positions; tested to 30° in each direction). If eye excursion was incomplete, the paretic muscle was identified. For horizontal saccades, a lateral fixation target at 30° was used. For vertical saccades, a vertical fixation target was used at 20°. Horizontal and vertical pursuit was tested within a 60° and 40° arc at a speed of about 20°/s ° and 10°/s, respectively. For testing stereoacuity, the Worth Lights test was used for distance vision and the TNO test for near vision.9,10 Finally, a Hess-Lancaster screen test was performed.11 Video oculography: Eye movements were recorded using the Mobile Eyebrain Tracker (EBT) head-mounted, a CE-marked (indicating conformity with the essential health and safety requirements set out in European Directives) eye-tracking device. The Mobile EBT® is equipped with a camera that captures the movements of each eye independently. Stimuli were presented on a 22 inch PC screen with a resolution of 1920x1080 pixels and a refresh rate of 60 Hz. Screen luminance
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was 250 cd/m2, and static contrast ratio was 1000/1. The diameter of the target was 0.5°. The distance of the patient’s eye to the monitor was 60 cm (subtending an arc of 40° for horizontal saccades and 26° for vertical saccades, an arc of 39° for horizontal smooth pursuit, and an arc of 20° for vertical smooth pursuit). Upper eye lids were lifted and fixed to perform video-oculography in patients with ptosis. We tested for: fixation, horizontal and vertical reflex saccades, and horizontal and vertical smooth pursuit. For fixation analysis (of particular interest for showing nystagmus and saccadic oscillations/intrusions), a stationary target was fixed in central position for 3s, and for 8s for extreme (right- and left-side and up- and downward) target positions (with recovery of central position between each change for extreme target position). Three main characteristics of visually-guided saccades were analyzed: latency (time between the appearance of a target and saccade initiation), velocity (both mean and peak velocities between the beginning and end of the saccade), and gain (saccade amplitude/target step amplitude). Identification of starting and ending times of all saccadic eye movements was performed automatically using an algorithm based on a velocity threshold (velocity threshold >10°/s). Low saccade gain indicates that the saccade was hypometric, and high saccade gain corresponds to a hypermetric saccade. In each patient, 8 trials for each horizontal and each vertical saccade were performed. Analyses were done for each eye in each horizontal and vertical direction and were compared with age-matched healthy controls (n=15 for age 51-66, n=12 for age >66). Latency, mean velocity, peak velocity, and gain were called abnormal when values differed > 2SD from controls. For horizontal saccades, a lateral fixation target at 20° was used. For vertical saccades, the vertical fixation target was presented at 13°. Before testing the reflex saccade, a central
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fixation target was presented for 2500-3500ms. Then, the fixation disappeared for 200ms (configuring a gap period), and a lateral or vertical fixation target was presented for 1000ms and disappeared again, followed by the presentation of the central fixation target. For smooth pursuit analyses, a slow moving target (following a sinusoidal movement) had to be followed. Horizontal smooth pursuit was studied with a target moving 20°/s towards a lateral angle of 19.5°. For vertical smooth pursuit, the moving target was studied at 8°/s towards a vertical angle of 10.1°. In each patient, 14 sine wave cycles were performed for each horizontal and vertical pursuit. Smooth pursuit was called pathological when a clear degradation of the sinusoidal pattern to a saccadic pattern was observed in ≥1 of the sine wave cycles.
Results: Orthoptic analysis: The best corrected visual acuity measured with the Snellen chart was 1.0 or more in both eyes in all patients. Results of orthoptic analyses are shown in Table 2. Some form of phoria or tropia was present in all patients. Tropia was present in 4 of 6 patients (vertical deviation in patients 3 and 4, horizontal deviation in patient 5, and mixed deviation in patient 1). Testing for eye excursion revealed abnormalities in 4 of 6 patients (2 patients with involvement of 1 oculomotor muscle and 2 patients with involvement of multiple oculomotor muscles). Seven of 9 (78%) pathological oculomotor muscles were superior or lateral rectus muscles. Abnormal saccades (i.e. hypometric saccades with a catch-up saccade) were found in 2 of 6 patients (in 1 patient for horizontal saccades to the left and for downward saccades, and in 1 patient for both up- and downward saccades). Smooth pursuit was normal in all patients. Worth Lights and TNO tests were normal in all patients except for patient 1, who had abnormal TNO testing. The Hess-Lancaster screen test was abnormal in 4 of 6 patients. We
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found a comitant vertical deviation in patient 1 and incomitant vertical deviation in patients 3 and 4. A comitant horizontal deviation was found in patient 5. No pathological abnormalities were found in patients 2 and 6 (simple horizontal deviation due to their phoria).
Video-oculography: Fixation analysis was normal in all patients except patient 2, who showed 19 square-wave jerks during 49 seconds of analysis with an amplitude of 2-3° and intersaccadic intervals of 200-300 ms. Nystagmus was not seen in any patient. Video-oculographic findings for horizontal and vertical saccades and pursuit are shown in Tables 3, 4, and 5. In patient 2, vertical saccades could not be analyzed because of lack of cooperation. Latencies for both horizontal and vertical saccades were normal in all patients (horizontal latency, mean 202 ms, range 143-262 ms; vertical latency, mean 217 ms, range 153-412 ms), except for patient 4, who showed pathological vertical upward latency (412 ms). In the age 50-65 years patients (patients 1, 4, and 6), mean values of mean and peak velocities for horizontal saccades were 184 °/s (normal: mean 295 °/s, SD 49 °/s) and 314 °/s (normal: mean 565 °/s, SD 101 °/s) respectively, and for vertical saccades 172 °/s (normal: mean 245 °/s, SD 47 °/s) and 261 °/s (normal: mean 508 °/s, SD 103 °/s), respectively. In patients >age 65 years (patients 2, 3, and 5), mean and peak velocities for horizontal saccades were 220 °/s (normal: mean 311 °/s, SD 54 °/s) and 409 °/s (normal: mean 588 °/s, SD 89 °/s) respectively, and for vertical saccades were 156 °/s (normal: mean 236 °/s, SD 48 °/s) and 290°/s (normal: mean 485 °/s, SD 93 °/s) respectively. In the patient group as a whole (i.e. independent of age), mean and peak velocities for horizontal saccades for each eye movement were: mean velocity for the left eye to the left, 181 °/s; left eye to the right, 193 °/s; right eye to the left 220 °/s; right eye to the right 242 °/s;
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peak velocity for the left eye to the left 332 °/s; left eye to the right 337 °/s; right eye to the left 411 °/s; right eye to the right 417 °/s. Mean values of mean and peak velocities for vertical saccades for each eye movement were: mean velocity for the left eye downward 144 °/s; left eye upward 141 °/s; right eye downward 178 °/s; right eye upward 200 °/s; peak velocity for the left eye downward 268 °/s; left eye upward 254 °/s; right eye downward 296 °/s; right eye upward 287 °/s. In the age 50-65 year-old patients, mean gain values for horizontal and vertical saccades were 0.90 (normal: mean 0.94 ± SD 0.06) and 0.83 (normal: mean 0.91 ± SD 0.09), respectively. In patients aged >65 years, gain values for horizontal and vertical saccades were 0.82 (normal: mean 0.91 ± SD 0.04) and 0.78 (normal: mean 0.91 ± SD 0.04), respectively. In the patient group as a whole, mean gain values for horizontal saccades for different eye movements were: 0.83 for the left eye to the left, 0.84 for the left eye to the right, 0.89 for the right eye to the left, 0.87 for the right eye to the right. Mean gain values for vertical saccades for different eye movements were: 0.84 for the left eye downward, 0.81 for the left eye upward, 0.82 for the right eye downward, 0.74 for the right eye upward. Thirthy-three percent (4 patients) of all saccades showed pathological gain, all hypometric. For saccade gains, no significant difference was seen between adducting, abducting, upward, or downward saccades. Half of the saccades showing pathological gain were dysconjugate. For horizontal saccades, mean velocity, peak velocity, and gain were pathological in 5, 5, and 2 of 6 patients, respectively. When analyzing the mean values, no difference was seen between abducting and adducting eye movements. When analyzing only the mean and peak velocities of pathological horizontal saccades, however, abnormalities were found in 61% (20of 33 abnormal eye saccades) in abducting eye movements and in 39% of adducting eye movements. Half of these pathological horizontal saccades were dysconjugate.
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For vertical saccades, mean velocity, peak velocity, and gain were pathological in 4, 4, and 3 of 5 patients, respectively. Pathological mean and peak velocities of vertical saccades were found in 53% (16 of 30 abnormal eye saccades) of upward eye movements and in 47% of downward eye movements. As for horizontal saccades, half of the pathological vertical saccades were dysconjugate. Horizontal smooth pursuit was pathological in 3 of 6 patients. Vertical smooth pursuit was normal in all patients.
Discussion: We assessed 6 OPMD patients using orthoptic and video-oculographic analyses. None of the patients had completely normal analyses. The most frequent abnormalities were: tropia, limitation of eye excursion, reduced (mean and peak) velocity of horizontal and vertical saccades, hypometric gain, and pathological horizontal smooth pursuit. In contrast to the findings of Gautier et al, some of our patients also had abnormal latency (n=1 patient) or gain (n=4 patients) of saccades.8 Genetic muscle diseases with frequent oculomotor involvement include myotonic dystrophy (especially type 1), congenital myopathies (e.g. centronuclear myopathy), chronic progressive external ophthalmoplegia (CPEO) and other mitochondrial disorders, and OPMD. In myotonic dystrophy type 1, ptosis is frequent, whereas defects in ocular motility are usually absent or mild. Observed abnormalities of ocular motility include reduced smooth pursuit gain, reduced saccadic peak velocity, increased duration and abnormal skewness of saccades, and elevated error rates in the antisaccades and remember saccade paradigms.1-3 Some of these oculomotor abnormalities are thought to be due to oculomotor muscle dysfunction (weakness and/or myotonia) whereas other abnormalities suggest brain dysfunction.
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In CPEO, severe defects in ocular motility are typically seen, although diplopia is most often absent due to symmetrical involvement. Despite frequent brain abnormalities in mitochondrial diseases, oculomotor abnormalities are thought to be of muscular origin.12 In CPEO, symmetrical muscle volume reduction measured by MRI is seen in the oculomotor muscles with less severe muscle involvement in the lateral rectus muscles than in other extraocular muscles.13,14 In centronuclear myopathy, predominant upgaze limitation (in favor of superior rectus muscle deficit) is sometimes described, although most reports of this and other congenital myopathies report diffuse ocular motor weakness.15 In contrast to myotonic dystrophy and mitochondrial diseases, clinical and radiological abnormalities in favor of central nervous system involvement are typically absent in heterozygous OPMD. However, executive functions have been found to be impaired in some patients.16 In some of the rare homozygous OPMD cases, cognitive decline, recurrent depression, psychotic episodes, and lacunar infarcts, leukoaraiosis, and brain atrophy on imaging have been described.17 Therefore, the possibility of involvement of brain structures controlling eye movements cannot be ruled out in the heterozygous patients we analyzed, especially since brain imaging was not performed systematically. Although our videooculographic data were compared with age-matched controls, and clinical findings suggestive of brain disease were not seen in our patients, one cannot exclude associated brain pathologies (e.g. asymptomatic vascular disease, early-stage degenerative diseases) potentially interfering with orthoptic and video-oculographic analyses. Slow saccades of restricted amplitude (i.e. the most frequent video-oculographic abnormality found in our patients) usually reflect abnormalities in the ocular motor periphery, such as extraocular muscle or ocular motor nerve pareses, probably related to muscle weakness. Although dysconjugate eye movements can be seen in central nervous system involvement
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(e.g. internuclear ophthalmoplegia), dysconjugate eye movements are most often of peripheral origin. Half of the pathological saccadic velocities and gains were dysconjugate in our patients. The most likely cause seems to be muscle weakness in the orbital muscles. The low gain (horizontal) pursuit seen in some of our patients has been described in a multitude of brain pathologies but can also be observed in disorders involving the ocular motor periphery. Our data point to preferential involvement of lateral (and to a lesser degree superior) rectus muscles. This contrasts with CPEO, where the lateral rectus muscles are the least severely involved orbital muscles and with centronuclear myopathy, where there is sometimes preferential involvement of superior rectus muscles. Our study shows the multitude of infraclinical, most often asymmetric, eye movement abnormalities, which probably explains the diplopia in these OPMD patients.
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Table 1: Patient characteristics Patient Age 1 57 2 70 3 68 4 65 5 69 6 52
Gender GCG expansion size Onset M 9 Bulbar M 8 Bulbar M 9 Ptosis W 9 Ptosis W 9 Ptosis M 10 Ptosis
Ptosis (onset) Ptosis surgery Diplopia (onset) Bulbar (onset) No No Yes (56y) Yes (50y) Yes (65y) No No Yes (62y) Yes (56y) Yes (60y) No Yes (63y) Yes (49y) Yes (62y) Yes (65y) No Yes (52y) Yes (62y) Yes (58y) Yes (59y) Yes (47y) Yes (50y) No No
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Table 2: Orthoptic analyses Nr Phoria
Tropia
Eye excursion limit
Saccades Smooth pursuit
1
Esotropia (+7D, left, DV) Hypotropia (5D, right, DV) Esotropia (+18D, left, NV) Hypotropia (6D, right, NV)
No
Normal
Normal
2 Exophoria (-8D, NV)
No
No
Normal
Normal
3 Exophoria (-6D, NV)
Hypotropia (2D, left, NV)
Superior rectus, left Abnormal Normal (hor, to left) (vert, down)
4 Exophoria (-8D, NV)
Hypotropia (5D, left, DV)
Superior rectus, left Lateral rectus, right Medial rectus, right Lateral rectus, left Medial rectus, left
Normal
Normal
5 Exophoria (-8D, NV)
Esotropia (+4D, left, DV)
Superior rectus, left Lateral rectus, right
Normal
Normal
6 Exophoria (-4D, DV) Exophoria (-14D, NV)
No
Lateral rectus, right Abnormal (vert, up & down)
No
Normal
Nr, patient number; D, diopter; DV, distance vision; NV near vision, hor, horizontal; vert, vertical; down, downward; up, upward)
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Table 3: Video-oculographic analyses for horizontal saccades Nr Latency
Mean velocity
Peak velocity
1 2 3 4 5 6
Abnormal (LLE, RRE) Normal Abnormal (LLE, RLE, LRE, RRE) Abnormal (LLE, RLE) Abnormal (LLE, RLE, LRE, RRE) Abnormal (LLE, RLE, LRE, RRE)
Abnormal (LLE, RRE) Normal Normal Abnormal (RLE, RRE) Abnormal (LLE) Abnormal (LLE, RLE, LRE) Abnormal (LLE, RLE) Normal Abnormal (LLE, RLE, LRE, RRE) Abnormal (LLE, RLE) Abnormal (LLE, RLE) Normal
Normal Normal Normal Normal Normal Normal
Gain
Nr, patient number; LLE, leftward saccade of the left eye; RLE, rightward saccade of the left eye; LRE, leftward saccade of the right eye; RRE, rightward saccade of the right eye.
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Table 4: Video-oculographic analyses for vertical saccades Nr Latency
Mean velocity
Peak velocity
Gain
1 2 3 4 5 6
Normal / Abnormal (ULE, DLE) Abnormal (ULE, URE) Abnormal (ULE, URE) Abnormal (DLE, DRE)
Abnormal (ULE, DLE, DRE) / Abnormal (ULE, DLE, DRE) Abnormal (ULE, DLE) Abnormal (ULE, URE) Abnormal (DLE, URE, DRE)
Normal / Abnormal (ULE, URE, DRE) Normal Abnormal (ULE, DLE, URE, DRE) Abnormal (URE)
Normal / Normal Abnormal (ULE) Normal Normal
Nr, patient number; / , lack of patient cooperation; ULE, upward saccade of the left eye; DLE, downward saccade of the left eye; URE, upward saccade of the right eye; DRE, downward saccade of the right eye.
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Table 5: Video-oculographic analyses for horizontal and vertical pursuit Nr
Horizontal pursuit
Vertical pursuit
1 2 3 4 5 6
Saccadic Saccadic Normal Saccadic Normal Normal
Normal / Normal Normal Normal Normal
Nr, patient number; / , lack of patient cooperation.
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Abbreviations: OPMD: oculopharyngeal muscular dystrophy EBT: Mobile Eyebrain Tracker DSM-IV: Diagnostic and Statistical Manual of Mental Disorders CPEO: chronic progressive external ophthalmoplegia
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References: 1. Anastasopoulos D, Kimmig H, Mergner T, Psilas K. Abnormalities of ocular motility in myotonic dystrophy. Brain. 1996;119:1923-32. 2. Versino M, Rossi B, Beltrami G, Sandrini G, Cosi V. Ocular motor myotonic phenomenon in myotonic dystrophy. J Neurol Neurosurg Psychiatry. 2002;72:236-40. 3. Shaunak S, Orrell R, Henderson L, Kennard C. Saccades and smooth pursuit in myotonic dystrophy. J Neurol. 1999;246:600-6. 4. Witting N, Mensah A, Køber L, Bundgaard H, Petri H, Duno M, et al. Ocular, bulbar, limb, and cardiopulmonary involvement in oculopharyngeal muscular dystrophy. Acta Neurol Scand. 2014 Mar 10. [Epub ahead of print] 5. Tondo M, Gámez J, Gutiérrez-Rivas E, Medel-Jiménez R, Martorell L. Genotype and phenotype study of 34 Spanish patients diagnosed with oculopharyngeal muscular dystrophy. J Neurol. 2012;259:1546-52. 6. Hill ME1, Creed GA, McMullan TF, Tyers AG, Hilton-Jones D, Robinson DO, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain. 2001;124:522-6. 7. Nadaj-Pakleza A, Richard P, Lusakowska A, Gajewska J, Jamrozik Z, Kostera-Pruszczyk A, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic characteristics of 9 Polish patients. Neurol Neurochir Pol. 2009;43:113-20. 8. Gautier D, Pénisson-Besnier I, Rivaud-Péchoux S, Rabaute C, Milea D. Ocular motor deficits in oculopharyngeal muscular dystrophy. Eur J Neurol. 2012;19:e38. 9. Roper-Hall G. The "worth" of the worth four dot test. Am Orthopt J. 2004;54:112-9. 10. Tomaç S, Altay Y. Near stereoacuity: development in preschool children; normative values and screening for binocular vision abnormalities; a study of 115 children. Binocul Vis Strabismus Q. 2000;15:221-8.
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11. Awadein A. A computerized version of the Lancaster red-green test. J AAPOS. 2013;17:197-202. 12. Ritchie AE, Griffiths PG, Chinnery PF, Davidson AW. Eye movement recordings to investigate a supranuclear component in chronic progressive external ophthalmoplegia: a cross-sectional study. Br J Ophthalmol. 2010;94:1165-8. 13. Carlow TJ, Depper MH, Orrison WW Jr. MR of extraocular muscles in chronic progressive external ophthalmoplegia. AJNR Am J Neuroradiol. 1998;19:95-9. 14. Yu-Wai-Man C, Smith FE, Firbank MJ, Guthrie G, Guthrie S, Gorman GS, et al. Extraocular muscle atrophy and central nervous system involvement in chronic progressive external ophthalmoplegia. PLoS One. 2013;8:e75048 15. Jeannet PY, Bassez G, Eymard B, Laforêt P, Urtizberea JA, Rouche A, et al. Clinical and histologic findings in autosomal centronuclear myopathy. Neurology. 2004;62:1484-90. 16. Dubbioso R1, Moretta P, Manganelli F, Fiorillo C, Iodice R, Trojano L, et al. Executive functions are impaired in heterozygote patients with oculopharyngeal muscular dystrophy. J Neurol. 2012;259:833-7 17. Blumen SC, Bouchard JP, Brais B, Carasso RL, Paleacu D, Drory VE, et al. Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes. Neurology. 2009;73:596-601.
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