A Tale of Progressive Painless Vision Loss in a 64-Year-Old Man Due to Leber Hereditary Optic Neuropathy

A 64-year-old man presented with painless sequential bilateral vision loss, consistent with optic neuropathy, over the span of months. The significant decline in his visual function was out of proportion to the appearance of the optic nerves (which were not pale) or changes in his retinal nerve fiber layer thickness on optical coherence tomography. Neuroimaging revealed only mild T2 signal abnormality and faint enhancement in the left optic nerve. Extensive workup for potential infectious, metabolic, inflammatory, and ischemic etiologies was unremarkable. Empiric treatment with intravenous steroids did not slow or ameliorate the vision loss. Ultimately, genetic analysis revealed a missense m.11778G>A mutation in mitochondrial MT-ND4 gene, consistent with Leber hereditary optic neuropathy. Initiation of multivitamin supplements and idebenone unfortunately did not result in recovery of vision.

Clinical-Pathological Case Study Section Editors: Daniel R. Gold, DO Marc Levin, MD, PhD A Tale of Progressive Painless Vision Loss in a 64-YearOld Man Due to Leber Hereditary Optic Neuropathy Moe H. Aung, MD, PhD, Nicholas J. Volpe, MD, Daniel J. Choi, MD, Joel M. Stein, MD, PhD, Amy Goldstein, MD, Grant T. Liu, MD Abstract: A 64-year-old man presented with painless sequential bilateral vision loss, consistent with optic neuropathy, over the span of months. The significant decline in his visual function was out of proportion to the appearance of the optic nerves (which were not pale) or changes in his retinal nerve fiber layer thickness on optical coherence tomography. Neuroimaging revealed only mild T2 signal abnormality and faint enhancement in the left optic nerve. Extensive workup for potential infectious, metabolic, inflammatory, and ischemic etiologies was unremarkable. Empiric treatment with intravenous steroids did not slow or ameliorate the vision loss. Ultimately, genetic analysis revealed a missense m.11778G.A mutation in mitochondrial MT-ND4 gene, consistent with Leber hereditary optic neuropathy. Initiation of multivitamin supplements and idebenone unfortunately did not result in recovery of vision. Journal of Neuro-Ophthalmology 2022;42:390–395 doi: 10.1097/WNO.0000000000001651 © 2022 by North American Neuro-Ophthalmology Society Case Report Drs. Aung, Volpe, Choi, and Liu: A 64-year-old man with a history of Crohn disease, hyperlipidemia, and obstructive sleep apnea first Departments of Neurology (MHA, GTL), Ophthalmology (DJC, GTL), and Radiology (JMS), The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania; Divisions of Human Genetics and Metabolism (AG) and Ophthalmology (GTL), The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Ophthalmology (MHA), Dell Medical School, The University of Texas at Austin, Austin, Texas; Department of Ophthalmology (NJV), Feinberg School of Medicine, Northwestern University, Chicago, Illinois. The authors report no conflicts of interest. Address correspondence to Moe H. Aung, MD, PhD, Department of Ophthalmology, Dell Medical School, The University of Texas at Austin, 1601 Trinity Street, Bldg. B, Stop Z1200 Austin, TX 78712; E-mail: [e-mail] 390 presented to his local ophthalmologist with painless decreased left eye vision in the absence of antecedent illness or trauma. Examination then revealed counting fingers vision in the left eye with an associated relative afferent pupillary defect (RAPD). Fundus examination reportedly showed a small flame-shaped hemorrhage along the inferior border of the optic disc but no signs of disc edema. Ensuing workup for retinal pathologies and giant cell arteritis, including fluorescein angiogram and laboratory work with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), was unremarkable. He denied any other neurologic symptoms. The patient did not recall any family history of early-onset vision loss. Two weeks after symptom onset, our initial examination was notable for 20/60 acuity in the left eye along with reduced color vision and a left RAPD. Afferent visual function of his right eye was within normal limits. Automated visual field testing revealed a superior field defect with cecocentral involvement in the left eye (Fig. 1). He had normal-appearing optic nerves bilaterally on fundus examination and normal retinal nerve fiber layer thickness (RNFL) on optical coherence tomography (OCT) in both eyes (Fig. 2). However, additional OCT analysis did reveal mild asymmetry of the ganglion cell layer (GCL) volumes in the maculae, with left inner retina being slightly thinner than the right one (Fig. 3). As his findings were consistent with left optic neuropathy, he underwent an MRI of the brain and orbits. Dr. Stein: MRI of the orbits obtained 20 days after symptom onset revealed increased T2 signal in the left aspect of the optic chiasm extending to the orbital segment of the left optic nerve, as well as probable faint enhancement, consistent with a suspected retrobulbar optic neuropathy (Fig. 4). The optic nerve did not appear swollen or atrophic at the time of imaging. The differential diagnosis included optic neuritis Aung et al: J Neuro-Ophthalmol 2022; 42: 390-395 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 1. Automated visual field 30-2 testing results over time. On his initial visual field testing (A), there were superior visual field deficits (worse temporally than nasally) with a cecocentral deficit in the left eye (MD = 29.72 at 10day time point). On subsequent studies (at 12-week time point [B] and at 16-week time point [C]), the visual fields of his left eye progressively became severely depressed (MD = 226.49 at 12-week time point and MD = 226.31 at 16week time point). Similarly, the visual field defect of his right eye progressed: gradual enlargement of the superior visual field loss with development of a cecocentral scotoma (MD = 22.14 at 10-day time point, MD = 24.49 at 12-week time point, and MD = 28.57 at 16-week time point). (due to multiple sclerosis, neuromyelitis optica, or other inflammatory or infectious entities), ischemic optic neuropathy, and toxic–metabolic neuropathy. The retrobulbar optic nerve enhancement argued against noninflammatory or noninfectious etiologies. Drs. Aung, Volpe, Choi, and Liu: Given the signal abnormalities noted in the left optic nerve, serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) were evaluated, but these returned negative. Repeat assessment of serum inflammatory markers (platelet count, ESR, and CRP) was also normal. As his left eye vision had improved from reportedly counting fingers vision, he opted for monitoring. Unfortunately, approximately 2 months later, Aung et al: J Neuro-Ophthalmol 2022; 42: 390-395 he returned with worsening left eye symptoms. A repeat MRI showed similar findings of T2 hyperintensity and faint enhancement of the left optic nerve. Over the next several weeks, he experienced gradual worsening of his left eye visual acuity as well as involvement of his right eye vision. His repeat examination then revealed 20/25 acuity in the right eye and 20/250 acuity in the left eye. There was also mildly decreased color vision in the right eye, in addition to profound dyschromatopsia in the left eye. A left RAPD remained. There was now left more than right temporal disc pallor, without elevation, hemorrhages, or telangiectasias (Fig. 5). The level of vision loss was felt out of proportion to the degree of optic disc pallor. Subsequent serial automated visual field testing revealed severe depression in the left eye with development of a cecocentral scotoma in the right eye (Fig. 1). Repeat OCT again showed full global RNFL thickness bilaterally, although there was mild interval thinning of the left papillomacular nerve bundle (Fig. 2). Analysis of his macular GCL volumes was more revealing, demonstrating a significant GCL volume reduction in the left eye (Fig. 3). With vision loss now involving both eyes, the patient was admitted for expedited workup for atypical etiologies for optic neuropathy. Infectious etiologies (e.g., Lyme disease and syphilis), metabolic derangements (e.g., vitamin deficiency), and rheumatologic laboratory panels were explored but were all unremarkable. Repeat testing for MOG and AQP4 autoantibodies remained negative. CSF analysis was pursued and revealed normal chemistries and cellular constituents. Cytological analysis of the CSF sample did not uncover atypical or malignant cells. Analysis for oligoclonal band in CSF was also negative with normal CSF IgG index. Computerized tomography of his chest did not show concerning structural lesions, such as hilar adenopathy or mass. At this point, given the progressive nature of his vision loss along with faint enhancement of left optic nerve (otherwise negative workup thus far), he was treated with empiric high-dose intravenous methylprednisolone treatment for 3 days. Unfortunately, the pulse corticosteroid treatment did not improve his vision. In summary, this 64-year-old man presented with a progressive painless sequential bilateral optic neuropathy. Workup for compressive, infectious, demyelinating, inflammatory, and metabolic etiologies was unremarkable. Although he has some vascular risk factors, our suspicion for ischemic optic neuropathy was low as he did not have a disc at risk (cup-to-disc ratio of 0.45) or acute disc swelling on presentation, and he had normal inflammatory markers. Given the incongruence of his relatively benign-appearing fundus examination with his severe afferent visual deficits and progressive GCL loss preceding RNFL thinning, genetic analysis for mitochondrial DNA sequencing was sent, and this identified a pathogenic variant: a missense m.11778G.A mutation in mitochondrial MT-ND4 gene. 391 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 2. Progression of OCT RNFL thickness over time. His baseline global OCT RNFL thickness (A) was normal bilaterally at baseline (around 10 days after symptom onset). On subsequent follow-up scans (at 10-week time point [B] and at 12-week time point [C]), his global RNFL thickness remained normal in both eyes, despite significant vision loss (left eye worse than right eye). We did observe a gradual decline in the thickness of his PMB of the left eye starting at 10-week time point. FINAL DIAGNOSIS Bilateral painless vision loss in the setting of Leber hereditary optic neuropathy (LHON) due to a mitochondrial DNA m.11778G.A mutation. DISCUSSION LHON is a maternally inherited disorder caused by mutations in mitochondrial DNA (mtDNA) affecting the complex I subunit of the mitochondrial respiratory chain (1,2). The majority of patients with LHON (90%–95%) harbor 1 of the 3 common mtDNA point mutations, namely m.3460G.A (in MT-ND1 gene), m.14484T.C (in MT-ND6 gene), and m.11778G.A (in MT-ND4 gene) (1,2). The mutations impair ATP synthesis and increase production of reactive oxygen species, leading to lipid peroxidation and neuronal cell death. Owing to their high metabolic demands, complex dendritic arbors, and long axons, it is not surprising that retinal ganglion cells (whose axonal fibers form the optic nerves) are particularly susceptible to the increased oxidative stress and perturbed mito392 chondrial functions associated with LHON (3). However, the mtDNA mutation is necessary but not sufficient to cause optic nerve dysfunction in LHON, with penetrance being on average about 50% for males and 10% for females (4,5). For instance, in a previous population-based epidemiological study in England, researchers found w1 in 8,500 carried a primary LHON mutation but only w1 in 30,000 developed vision loss (6). There is increasing evidence in the literature implicating environmental factors as potential disease triggers, such as cigarette smoking and heavy alcohol use, especially for those with late disease onset (1,4,5,7,8). When we reviewed any relevant social history with our patient, he did endorse smoking when he was younger but had quit for at least 20+ years before the onset of his vision loss. We advised him to refrain from smoking and drinking alcohol. He denied any medical therapies (namely antimicrobials such as ethambutol and tetracyclines) that might potentially damage mitochondrial function and trigger LHON (9). Phenotypically, LHON affects males predominantly at an age of onset around 15–35 years. However, there are Aung et al: J Neuro-Ophthalmol 2022; 42: 390-395 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study microangiopathy, and optic nerve hyperemia with obscuration of the disc margin (12). Absence of leakage from the papillary region on fluorescein angiography and mild thickening of the inferotemporal RNFL may also be found (12,13). Interestingly, it is also noted that about 20% of LHON cases can present with normal-appearing optic discs despite evidence of significant afferent visual dysfunction (1,2,11). Such discrepancy can often lead to these patients with LHON being diagnosed with functional visual loss. Therefore, it is important to keep LHON as part of one’s differential diagnosis when faced with visual deficits out of proportion to the fundus appearance. Advances in ophthalmic imaging, especially OCT, have revolutionized how one diagnoses and monitors neuroophthalmic disease. Consistent with previous case reports, we observed reductions in the macular GCL volume and thickness of papillomacular bundle (PMB) in our patient as the earliest biomarkers of his disease progression (Figs. 2, 3) (14–17). In a previous longitudinal analysis that examined the potential relationship between different structural changes on OCT and worsening of visual acuities in LHON patients, thinning of macular GCL and PMB seemed to best correlate with vision loss in patients with LHON (15). In terms of neuro-imaging, though the presence of enhancement in the anterior visual pathways on MRI would typically align more with inflammatory or infectious etiologies that result from disruption of the blood–brain barrier, there have been rare case reports of patients affected by LHON exhibiting contrast enhancement within weeks of vision loss, as seen here (18,19). More FIG. 3. Progression of OCT macular GCL volumes over time. At his initial visit (A), there was mild asymmetry in his GCL volume in the macula between the 2 eyes, with left eye (0.91 mm3) thinner than the right eye (1.04 mm3). On subsequent follow-up macular GCL analyses (at 10-week time point [B] and at 12-week time point [C]), we observed a significant drop in the macular GCL volume of the left eye, from initial 0.91 to 0.79 mm3 (later to 0.76 mm3 at 12week time point). There was also a gradual decline in the GCL volume of the right eye as well, from 1.04 to below 1 mm3 at his follow-up visits. previous studies reporting many individuals with LHON outside of this age range, occurring as young as 2 years to as old as 80 years (1,2,10). Vision loss from LHON is typically characterized by acute painless loss of central acuity and color vision, most often unilateral at onset (2,11). If initial symptoms are unilateral, the fellow eye is usually affected weeks to months later, as with the clinical course for our patient. Classic ophthalmoscopic abnormalities during the acute phase of vision loss include vascular tortuosity of the central retinal vessels, circumpapillary telangiectatic Aung et al: J Neuro-Ophthalmol 2022; 42: 390-395 FIG. 4. Initial MRI. T2 fat-saturated coronal (A) and axial (B) images show increased signal in the left optic nerve (arrows). Postcontrast axial (C) and coronal (D) images reveal faint enhancement of the intraorbital segment of the left optic nerve (arrows). 393 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical-Pathological Case Study FIG. 5. Fundus images of the patient at his 3.5-month follow-up visit, which was approximately 4 months after the onset of his progressive painless vision loss. Despite his visual acuities now at 20/200 in the right eye and counting fingers in the left eye, there was only mild or moderate temporal disc pallor in both eyes, left eye worse than the right eye. common MRI findings present in patients with LHON when imaged within a year from symptom onset include T2 hyperintensity in retrobulbar optic nerve and enlargement of optic chiasm (20). After reaching the diagnosis of LHON, we referred our patient to a mitochondrial specialist for more extensive counseling. He was advised to be mindful of risk factors that might increase metabolic demand (such as fever, illness, or anesthesia) and worsen his disease. Full mitogenome analysis did not reveal additional pathologic mutations but confirmed his heteroplasmy (mutation load) of 100% in a saliva sample and documented his mitochondrial DNA haplogroup of H7f (some of the LHON mutations cluster on haplogroup J) (21). Although vision loss is the cardinal feature of LHON, cardiac conduction abnormalities and neurologic deficits have been reported with LHON carriers. There was no extraocular involvement identified in our patient. Current therapies for LHON remain limited. Combinations of nutritional supplements, such as vitamins (B1, B2, B3, B12, C, E), folic acid, carnitine, and L-arginine, have been used as means to improve mitochondrial biogenesis and reduce oxidative stress, although with limited or variable success (22,23). Only one medication, idebenone (a synthetic analog for coenzyme Q10), is approved in Europe (but not in the United States) to limit or partially reverse vision loss (24–27). Fortunately, multiple clinical trials have demonstrated gene therapy as a potential avenue to promote visual recovery in patients with LHON (23,25,28–31). In recent clinical trials, patients with visual loss due to m.11778G.A mutation were treated with unilateral intravitreal injection of recombinant replication-deficiency adeno-associated virus vector–containing human wild-type MT-ND4 DNA (28,30). Interestingly, these studies demonstrated encouraging data of improvement of visual function in not only the treated eyes but also in control fellow eyes, suggesting the possibility of viral vector DNA transfer from the injected eye to the contralateral noninjected eye. 394 Despite the initiation of multivitamin supplementation and idebenone, our patient’s vision continued to decline to a nadir of counting fingers vision bilaterally (approximately 10 months after symptom onset). Although the patient did not qualify for any current ongoing gene therapy trials regarding LHON, he was still able to receive an intravitreal injection of GenSight gene therapy (GS010) into the right eye via compassionate use. We were unable to obtain follow-up examination as he had since relocated to a different city. As described in a meta-analysis by Newman et al (11) on the natural history and visual outcomes for LHON with m.11778G.A mutation, the visual prognosis for patients harboring this mutation is typically poor, especially for patients with age of onset after 15 years. However, the advent of gene therapy offers some hope for partial visual recovery for these patients. In conclusion, hereditary optic neuropathy should be considered on the differential diagnosis in patients with bilateral optic neuropathies, especially in male patients (of any age) and when there is a decrease in macular OCT GCL thickness but with relatively preserved RNFL measures at onset. ACKNOWLEDGMENTS The authors would like to thank James Wilson for preparing the OCT figures. REFERENCES 1. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies. 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