Preserved Ganglion Cell Analysis in a Case of Longstanding Leber Hereditary Optic Neuropathy: A Sign of Hibernating Neurons?

We describe a middle-aged man with bilateral progressive visual loss over 6 months. Vision was counting fingers in each eye, and both optic discs were slightly elevated on ophthalmoscopy. MRI brain showed bilateral ovoid T2 hyperintensities within the thickened optic chiasm. Mitochondrial genome testing revealed 11,778 mutations at homoplasmy conforming Leber hereditary optic neuropathy (LHON). Despite 6-month history of visual loss, ganglion cell analysis was normal in each eye. We postulate that preservation of ganglion cell layer–inner plexiform layer (GCL–IPL) thickness might represent dormant retinal ganglion cells (RGCs) that adapted a decreased metabolic rate under adverse conditions to avoid apoptosis. A 58-year-old man noticed gradual onset of blurry vision in both eyes. Vision continued to deteriorate over the next 3 months. CT of the head was normal, and MRI of the orbits with contrast was interpreted as normal. Syphilis serology, anti-neuromyelitis optica (NMO), and anti-myelin oligodendrocyte glycoprotein (MOG) protein antibody titers were negative. On neuro-ophthalmic examination 6 months after the onset of symptoms, vision was counting fingers in each eye with no relative afferent pupillary deficit. Ophthalmoscopy demonstrated subtle bilateral optic disc swelling (Fig. 1A). Optic coherence tomography showed mild peripapillary retinal nerve fiber layer thickening in each eye (Fig. 1B). Ganglion cell analysis was unexpectedly normal in each eye (Fig. 1C). Formal visual fields were black in both eyes. On our review, the MRI demonstrated enlargement of the chiasm associated with striking bilateral ovoid T2 hyperintensities without contrast enhancement (Fig. 1D, E). Mitochondrial genome sequencing and anti-NMO and anti-MOG titers testing using live cell-based assay were obtained. Despite a slowly progressive course, presumptive treatment with high-dose oral prednisone with 1250 mg daily for 5 days followed by 60 mg oral taper commenced. Vision did not improve 10 days after the initiation of treatment; thus, plasma exchange commenced. Three weeks later, vision remained unchanged. NMO/MOG antibody titers returned negative. Mitochondrial genome sequencing revealed the presence of 11,778 mutations at homoplasmy, and treatment with idebenone 900 mg daily was advised. Three months later, visual function and GCL–IPL (Fig. 1F) remained unchanged.FIG. 1. A.: Fundoscopy depicting mild bilateral optic disc swelling. B. Optical coherence tomography (OCT) demonstrating bilateral mild retinal nerve fiber layer thickening. C. OCT confirming intact ganglion cell analysis 6 months after symptom onset. D. Coronal MRI brain with T2 sequence showing chiasmal enlargement and symmetric T2 hyperintensities (arrows). E. Corresponding coronal MRI brain with contrast enhanced T1 sequences without obvious enhancement.While simultaneous onset of visual loss in patients with LHON without any obvious precipitating factors for phenotypic conversion has been described,1 the most unusual part of this case was preserved thickness of GCL–IPL despite long-standing presence of visual loss due to severe bilateral optic neuropathy. It is known that GCL–IPL is measurably decreased in patients with LHON not only at the time of presentation but even in presymptomatic fellow eyes and continues to thin until it reaches the floor effect (see Supplemental Digital Content, Table 1, https://links.lww.com/WNO/A847, #1). One retrospective study assessed 14 eyes of 7 LHON patients with 12 of 14 eyes showing thinning of GCL–IPL in the acute phase within 12 weeks (see Supplemental Digital Content, Table 1, https://links.lww.com/WNO/A847, #2). Another study reported on 7 eyes with acute and 54 eyes with chronic LHON (chronicity was defined 6 months after symptoms onset) and demonstrated significant thinning of GCL–IPL in all patients with acute LHON although the exact time from symptoms onset to measurement of GCL–IPL was not reported (see Supplemental Digital Content, Table 1, https://links.lww.com/WNO/A847, #3). When comparing with other optic neuropathies such as nonarteritic anterior ischemic optic neuropathy (NAION), a prospective study consisting of 16 participants showed significant thinning of GCL–IPL within the first 2 weeks from symptoms onset (see Supplemental Digital Content, Table 1, https://links.lww.com/WNO/A847, #4). Similarly, a study comparing hemispheric differences of GCL–IPL thickness in patients with presumed demyelinating optic neuritis and NAION demonstrated that loss of RGCs in both entities was visible as early as 11 days after the onset of symptoms (see Supplemental Digital Content, Table 1, https://links.lww.com/WNO/A847, #5). In addition, a prospective study of 27 patients with demyelinating optic neuritis, GCL–IPL progressively decreased over the course of 3 months, with initial thinning detectable at 1 month (see Supplemental Digital Content, Table 1, https://links.lww.com/WNO/A847, #6). This stresses the fact that RGC loss typically occurs very early in various optic neuropathies which makes this case, where GCL–IPL remained preserved despite long-standing severe visual loss in LHON, especially noteworthy. Supplemental Digital Content (see Table 1, https://links.lww.com/WNO/A847) lists studies that we identified in the literature reporting on the onset of GCL–IPL thinning in various optic neuropathies. About 70% of patients with LHON will demonstrate T2 hyperintensity and tissue enlargement along any part of the anterior visual pathway on MRI. This hyperintense signal is thought to represent gliosis.2 However, in our case, GCL–IPL was normal despite the 6-month history of visual loss. Thus, we hypothesize that T2 hyperintensities within the optic chiasm which was thickened rather than atrophic represented cellular edema due to ATP shortage and subsequent dysfunctional electrolyte membrane transporter, which would also be in keeping with preserved GCL–IPL. We subsequently postulate that under adverse conditions, RGCs in LHON might enter a dormant state with decreased metabolic rate, reflecting a coping strategy against ongoing ATP shortage to avoid apoptosis. This in turn might represent the basis for spontaneous visual recovery in some patients with LHON. The ability to enter a state of hibernation to endure a phase of increased environmental adversity is well known in the mammals. One study conducted on ground squirrels (GS) reported on RGC death in awake and hibernating GS after their optic nerve was surgically crushed.3 Intriguingly, RGC death was reported in 80% of awake GS, whereas none of the hibernating GSs demonstrated RGC death. According to the authors, this extraordinary neuronal survival in hibernating animals was associated with the lack of aggregation and activation of microglia in the retina and attributed to metabolic adaptations in the hibernating GSs. This was thought to alter the local immune response to injury and thus deter neuronal cell death. In summary, the case highlights 2 important facts: it typifies a rare presentation of LHON with slowly progressive simultaneous onset of visual loss and demonstrates that rarely GCL–IPL can remain preserved for several months after phenotypic conversion and onset of visual loss. This could reflect a hibernating state of RGC neurons, which might serve as an explanation for spontaneous visual recovery in LHON. STATEMENT OF AUTHORSHIP Conception and design: A. Handzic, L. Donaldson, E. Margolin; Acquisition of data: A. Handzic, L. Donaldson, E. Margolin; Analysis and interpretation of data: A. Handzic, L. Donaldson, E. Margolin. Drafting the manuscript: A. Handzic, L. Donaldson, E. Margolin; Revising the manuscript for intellectual content: A. Handzic, L. Donaldson, E. Margolin. Final approval of the completed manuscript: A. Handzic, L. Donaldson, E. Margolin.

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