Convergence-Retraction Nystagmus and Ophthalmoplegia as the Presenting Sign of Leigh Syndrome in a Young Boy

A 6-year-old boy complained of droopy eyelids and double vision for 2 months. There was no associated fever and headache nor any history of vision loss, developmental delay, or movement disorder.

Photo and Video Essay Section Editors: Kimberly M. Winges, MD Michael J. Gilhooley, MA, MB, BChir, DPhil Convergence-Retraction Nystagmus and Ophthalmoplegia as the Presenting Sign of Leigh Syndrome in a Young Boy Weimin Chen, MD, Chaoyi Feny, MD, PhD, Shuguang Chu, MD, PhD, Guixian Zhao, MD, PhD, Xinghuai Sun, MD, PhD, Zhenxin Li, MD, PhD, Qian Chen, MD, PhD, Guohong Tian, MD, PhD FIG. 1. A. Fundus photographs showing bilateral optic disc with temporal pallor. B. External photographs of the 9 cardinal gaze positions showing both horizontal and vertical eye movement dysfunction. C. MRI T2-Flair revealing longitudinal dorsal hyperintensity lesions from cerebellar peduncles, pontine, midbrain, up to medial thalamus. D and E. Brain MRI sequence showing the lesions with a reduced signal in T1WI, hyperintensity in T2WI, without enhancement on T1WI after gadolinium; no hemorrhage on SWI, with marginal diffusion restriction on DWI, and the lesions showing a dramatic hyperperfusion on ASL. Department of Neurology (WC), Shanghai Deji Hospital, Shanghai, China; Department of Ophthalmology (CF, XS, QC, GT), Eye and ENT Hospital, Fudan University, Shanghai, China; Department of Radiology (SC), Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China; Department of Neurology (GZ, ZL), Hua Shan Hospital, Shanghai Medical College, Fudan University, Shanghai, China; and NHC Key Laboratory of Myopia (Fudan University) (XS,GT), Key Laboratory of Visual Impairment and Restoration, Shanghai, China. The authors were supported by the grants from major projects of Natural Science Foundation of China (81790641). The authors report no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s Web site (www. jneuro-ophthalmology.com). W. Chen, C. Feng, and S. Chu contributed equally to this work. Address correspondence to Guohong Tian, 83 Fenyang Road, Shanghai 200031, China; E-mail: [e-mail] e58 A 6-year-old boy complained of droopy eyelids and double vision for 2 months. There was no associated fever and headache nor any history of vision loss, developmental delay, or movement disorder. The ptosis improved, but the double vision persisted. Routine brain CT showed no pathological findings. The boy had 2 siblings, none of whom exhibited any similar symptoms. The neuro-ophthalmological examination revealed that the boy was alert and oriented. His best-corrected visual acuity was 20/20 bilaterally. Pupils were round and equal, and both reacted briskly to light. Funduscopic examination showed slight temporal pallor of the bilateral optic disc (Fig. 1A). There was no ptosis, but the horizontal and vertical extraocular motility was dramatically limited (Fig. 1B). A convergence-retraction nystagmus was observed while attempting up-gaze and down-gaze (see video, Supplemental Digital Content, http://links.lww.com/WNO/ A635). Other neurological examinations, including cranial nerves, Chen et al: J Neuro-Ophthalmol 2023; 43: e58-e59 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Photo and Video Essay muscle strength, deep tendon reflexes, and gait and coordination, were normal. The plantar response was bilaterally flexed. Broad autoimmune and infectious serologic workup and COVID19 PCR testing were negative. Blood lactate was normal, and the B1 level was 49.19 nmol/L (normal, 50.00–150.00). Anti-AQP4, antiMOG-GFAP, anti-NMDA, anti-AMPA, and anti-GABAB immunoglobulin G’s were absent. A lumbar puncture revealed normal opening pressure and elevated red blood cell count from a traumatic puncture. Cerebrospinal fluid white blood cell count, protein, and glucose levels were within the normal limits. The lactic acid level was elevated to 2.47 mmol/L (normal: 0.63–2.44). MRI of the brain showed symmetric diffused longitudinal lesions from cerebellar pedunculus, pontine, dorsal midbrain, up to medial thalamus level. These lesions showed decreased signal intensity on T1 imaging (T1WI) and hyperintensity on T2 imaging (T2WI), which the central of the lesions demonstrated a distinct lower/more hyper signal on T1WI/T2WI. After gadolinium injection, there was no obvious enhancement of the lesions and there was no hemorrhage on susceptibility-weighted imaging. The diffusion-weighted imaging (DWI) showed a specific borderline diffusion restriction around the lesions, which with extremely hyper perfusion signals on arterial spin labeling (ASL) perfusion-weighted imaging. The DWI noticeably revealed a marginated diffusion restriction around the lesions, whereas the ASL imaging showed extremely hyper perfusion integral (Figs. 1C, 1D, 1E). The patient was treated with methylprednisolone 120 mg intravenous for 5 days, followed by oral prednisone 20 mg/d and IVIG 0.4 mg/kg/d for 3 days. Meanwhile, intramuscular vitamin B1 was also given. The horizontal eye movement improved slightly after treatment, although a subsequent MRI of the brain showed a stable lesion. The patient’s parents declined brain tissue biopsy, muscle biopsy, or repeated lumbar puncture aiming for CSF cytology for malignant cells. Whole-exome sequencing together with whole mitochondrial genome sequencing were conducted. The results revealed a heterozygous deletion and a hemizygous mutation in NDUFA12 gene indicating for Leigh syndrome. Prednisone was thus tapered off, and coenzyme Q10 together with idebenone and vitamin supplements were given instead. The patient’s eye movements improved, and his diplopia disappeared during the follow-up. Leigh syndrome, also referred to as subacute necrotizing encephalopathy, was first reported by Denis Leigh in 1951, whereas the pathogenic mutations had been implicated 1 decade later (1). Mutation of nuclear gene NDUFA12, leading to complex I deficiency, has been reported to be associated with Leigh syndrome (2). As one of the life-threating, earlyonset hereditary mitochondrial diseases, which are associated with oxidative phosphorylation (OXPHOS) pathway dysfunction, the affected children usually suffer from severe neurological symptoms arising from basal ganglia and brainstem and rapidly decline to functional disability and even death (3). Generally, Leigh syndrome initially presents with abnormal motor functions including developmental delay and regression, hypotonia, ataxia, and dystonia in most patients (4). Abnormal ocular findings were reported for approximately half of all patients, including nystagmus, strabismus, visual impairment, optic atrophy, ptosis, and ophthalmoplegia. Our patient had nystagmus and partial ophthalmoplegia, while other neurological examinations were unremarkable. The potential involveChen et al: J Neuro-Ophthalmol 2023; 43: e58-e59 ment of multiple organ systems and variable course in Leigh syndrome made the diagnosis challenging. The presence of eye findings associated with Leigh syndrome is not unique, but the lack of extraocular manifestations of this condition is very atypical. Convergence-retraction nystagmus is a very specific neuroophthalmic localizing sign for the diagnosis of dorsal midbrain lesions. Furthermore, the preserved pupil light-reflex without light-near dissociation in this patient together with the horizontal gaze palsy indicate the diffuse localization of his symptoms. Apart from the standard MRI scan that usually demonstrates the localization of the lesions, functional sequences such as DWI and ASL are essential for searching the pathologenesis according to different series. The overall hyperperfusion of the lesion on ASL sequence, which could be a very unique feature, distinguished mitochondrial disease from adrenoleukodystrophy or inflammatory etiology. According to a recent investigation of Leigh syndrome, the increased cerebral blood flow detected by the ASL sequence is a hallmark in acute episodes, which coincides with our patient’s MRI results (5). One hint to consider a mitochondrial disorder as a differential diagnosis was the presence of bilateral optic atrophy. Similarly, in the acute stages of Leber hereditary optic neuropathy, the optic nerve head often takes on a hyperemic telangiectatic appearance. The presence of optic atrophy in this case suggests a more chronic involvement of the optic nerves vs. the more acutely symptomatic and appearing brainstem lesions. STATEMENT OF AUTHORSHIP Conception and design: S. Chu, G. Tian. Acquisition of data: W. Chen, G. Zhao, C. Feng, Z. Li, X. Sun, Q. Chen. Analysis and interpretation of data: G. Zhao, C. Feng, Z. Li, X. Sun, S. Chu, G. Tian. Drafting the manuscript: C. Feng, S. Chu, G. Tian. Revising the manuscript for intellectual content: Z. Li, X. Sun, S. Chu, G. Tian. Final approval of the completed manuscript: W. Chen, G. Zhao, C. Feng, Z. Li, X. Sun, Q. Chen, S. Chu, G. Tian. REFERENCES 1. Hammans SR, Sweeney MG, Brockington M, Morgan-Hughes JA, Harding AE. Mitochondrial encephalopathies: molecular genetic diagnosis from blood samples. Lancet. 1991;337:1311–1313. 2. 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