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HOME > Res Vestib Sci > Volume 24(1); 2025 > Article
Case Report
Gaze-holding nystagmus in chronic progressive external ophthalmoplegia: a case report
Eugene Jung1orcid, Seo-Young Choi1orcid, Jae Hwan Choi2orcid, Kwang-Dong Choi1orcid
Research in Vestibular Science 2025;24(1):50-53.
DOI: https://doi.org/10.21790/rvs.2025.005
Published online: March 14, 2025

1Department of Neurology and Biomedical Research Institute, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea

2Department of Neurology and Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, Korea

Corresponding author: Kwang-Dong Choi Department of Neurology, Pusan National University Hospital, Pusan National University College of Medicine, 179 Gudeok-ro, Seo-gu, Busan 49241, Korea. E-mail: kdchoi@pusan.ac.kr
• Received: February 12, 2025   • Revised: February 21, 2025   • Accepted: February 26, 2025

© 2025 The Korean Balance Society

This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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  • We report a patient with chronic progressive external ophthalmoplegia (CPEO) who developed bilateral horizontal gaze-holding nystagmus, a previously unreported phenomenon. Video-oculography showed marked slowing of horizontal and vertical saccades, and bilateral horizontal gaze-evoked nystagmus with decreasing-velocity slow-phases waveforms. Horizontal rebound nystagmus was also observed. No abnormalities were identified in the brainstem or cerebellum on brain magnetic resonance imaging. A genetic analysis demonstrated a heterozygous missense mutation c.311A>G (p. D104G, rs28999114) in the SLC25A4 gene. Twitch motoneurons of the global layer receive inputs from premotor areas involved in the generation of eye movement, such as saccadic burst neurons, while non-twitch motoneurons of the orbital layer receive inputs from the medullary structures concerned with gaze-holding. In our patient with CPEO, the presence of omnidirectional ophthalmoplegia and bilateral horizontal gaze-holding nystagmus may indicate the involvement of the global layers of all extraocular muscles, as well as the orbital layers of the horizontal extraocular muscles.
  • Keywords: Nystagmus; Ophthalmoplegia; Cerebellum
Pathologic gaze-evoked nystagmus (GEN) is most often associated with impaired gaze-holding function resulting from lesions in the brainstem and cerebellar networks that control eye position commands (the neural integrator) [1-3]. In such instances, the condition may be designated as gaze-holding nystagmus. In contrast, the term gaze-paretic nystagmus can only be applied in cases of GEN that are associated with paresis of gaze [2]. Gaze-paretic nystagmus has been occasionally observed in patients with lesions in the brainstem or hemispheres, as well as in cases of extraocular muscle weakness, such as in myasthenia gravis.
We report a unique case with chronic progressive external ophthalmoplegia (CPEO) who exhibited bilateral horizontal gaze-holding nystagmus, a previously unreported phenomenon.
We conducted this study in compliance with the principles of the Declaration of Helsinki. Written informed consent for publication of the research details and clinical images was obtained from the patient.
A 50-year-old female presented with chronic diplopia and ptosis for five years. The patient’s aunt had been diagnosed with CPEO due to the presence of chronic ophthalmoplegia with ptosis. However, she denied any history of ophthalmoplegia in other family members. The neurological examination revealed bilateral symmetric ptosis and external ophthalmoplegia, as well as horizontal GEN. Video-oculography showed marked slowing of horizontal and vertical saccades (Fig. 1A, B and Supplementary Video 1). Both horizontal gazes induced horizontal GEN with decreasing-velocity slow-phase waveforms (Fig. 1C and Supplementary Video 1). No evidence of perverted head-shaking nystagmus, positional nystagmus, or vertical GEN was observed. Upon resuming the primary position, horizontal rebound nystagmus was observed (Fig. 1C). The results of the remaining neurological examinations were unremarkable. No abnormalities were identified in the brainstem or cerebellum on brain magnetic resonance imaging. A genetic analysis of the patient and her aunt demonstrated a heterozygous missense mutation c.311A>G (p. D104G, rs28999114) in the SLC25A4 gene. The examination of the patient’s aunt revealed bilateral symmetric ptosis and external ophthalmoplegia devoid of GEN.
The present case demonstrated external ophthalmoplegia and horizontal nystagmus exclusively during bilateral horizontal gazes, a phenomenon that has not been previously documented in CPEO. Although it is challenging to differentiate between gaze-paretic and gaze-holding nystagmus, the nystagmus observed in our patient exhibits traits more akin to gaze-holding nystagmus than gaze-paretic nystagmus. Both the patient and her aunt had omnidirectional ophthalmoplegia. However, the aunt did not present with GEN, whereas the patient exhibited GEN only during bilateral horizontal gazes. The decreasing-velocity slow-phase waveforms of the GEN, and the presence of rebound nystagmus upon resuming the primary position in the patient provide additional evidence in support of the gaze-holding nystagmus [2].
CPEO represents a clinical manifestation of mitochondrial diseases characterized by progressive ptosis and impaired eye movements [4,5]. The high energy demands of extraocular muscles render them particularly susceptible to mitochondrial myopathy. The extraocular muscle is composed of two functionally segregated layers: the outer orbital and inner global layer [6,7] (Fig. 1D). The orbital fibers maintain eye position by opposing the elastic load, while the global fibers facilitate rapid eye movement by overcoming viscoelastic forces. During saccades, both the global and orbital fibers are activated, but the activity of the global fibers subsequently may decline, whereas that of the orbital fibers is sustained. This functional segregation of the layers of extraocular muscles is consistent with their relative anatomical independence, with the global fibers inserting via a tendon in the sclera and the orbital fibers inserting in the pulley system. Twitch motoneurons of the global layer receive inputs from premotor areas involved in the generation of eye movements, such as saccadic burst neurons and the vestibular nuclei (magnocellular part) [8]. In contrast, non-twitch motoneurons of the orbital layer receive inputs predominantly from the pretectal area and medullary structures concerned with gaze-holding [8]. In our patient with CPEO, the presence of omnidirectional ophthalmoplegia and bilateral horizontal GEN may indicate the involvement of the global layers of all extraocular muscles, as well as the orbital layers of the horizontal extraocular muscles. The lesion of the orbital layer may lead to gaze-holding nystagmus, which is analogous to that observed in lesions of the brainstem and cerebellum.
Mitochondrial DNA mutations may also impair energy production in the cerebellum [9], which could potentially lead to GEN in our patient. However, the absence of additional cerebellar signs including limb or truncal ataxia, downbeat nystagmus, perverted head-shaking, and positional nystagmus, and the normal results of neuroimaging do not support the assumption.

Funding/Support

This work was supported by a clinical research grant from Pusan National University Hospital in 2024.

Conflicts of Interest

Jae Hwan Choi is a member of the Editorial Board of Research in Vestibular Science and was not involved in the review process of this article. The authors declare no other conflicts of interest.

Availability of Data and Materials

The datasets are not publicly available but are available from the corresponding author upon reasonable request.

Authors’ Contributions

Conceptualization: Choi SY, Choi KD; Data curation: All authors; Formal analysis, Methodology: Jung E, Choi JH, Choi KD; Funding acquisition: Choi KD; Writing–original draft: Jung E; Writing–review and editing: All authors.

All authors read and approved the final manuscript.

Supplementary materials can be found via https://doi.org/10.21790/rvs.2025.005.

Supplementary Video 1.

The patient shows marked slowing of the horizontal saccades and horizontal gaze-evoked nystagmus.
Fig. 1.
Video-oculography (VOG) shows horizontal saccadic slowing in both directions (A), which is confirmed by plotting the saccadic velocities over the amplitude (main sequence, B). (C) VOG reveals bilateral horizontal gaze-evoked nystagmus with decreasing-velocity slow-phase waveforms. (D) A schematic drawing of two functionally segregated layers of extraocular muscles.
RH, Horizontal recording of the right eye movement; T, target. Upward deflections indicate rightward eye rotations with respect to the patient.
rvs-2025-005f1.jpg
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  • 9. Bargiela D, Shanmugarajah P, Lo C, et al. Mitochondrial pathology in progressive cerebellar ataxia. Cerebellum Ataxias 2015;2:16. ArticlePubMedPMC

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        Gaze-holding nystagmus in chronic progressive external ophthalmoplegia: a case report
        Res Vestib Sci. 2025;24(1):50-53.   Published online March 14, 2025
        DOI: https://doi.org/10.21790/rvs.2025.005
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      Gaze-holding nystagmus in chronic progressive external ophthalmoplegia: a case report
      Image
      Fig. 1. Video-oculography (VOG) shows horizontal saccadic slowing in both directions (A), which is confirmed by plotting the saccadic velocities over the amplitude (main sequence, B). (C) VOG reveals bilateral horizontal gaze-evoked nystagmus with decreasing-velocity slow-phase waveforms. (D) A schematic drawing of two functionally segregated layers of extraocular muscles.RH, Horizontal recording of the right eye movement; T, target. Upward deflections indicate rightward eye rotations with respect to the patient.

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      Gaze-holding nystagmus in chronic progressive external ophthalmoplegia: a case report
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