Central Nervous System Demyelination in Leber Hereditary Optic Neuropathy

Patrick Yu-Wai-Man, PhD, FRCPath, FRCOphth,1,2,3,4,5

  1. NIHR Biomedical Research Centre at Moorfields Eye Hospital and UCL Institute of Ophthalmology, London, UK.
  2. Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
  3. Newcastle Eye Centre, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
  4. Cambridge Eye Unit, Addenbrooke’s Hospital, Cambridge University Hospitals, Cambridge, UK.
  5. Cambridge Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.

Case Report

A 22-year-old woman presented in July 2015 with a one-week history of rapidly worsening vision in her right eye, which was associated with some mild ocular discomfort. Her best-corrected visual acuity (BCVA) was 3/60 in her right eye and counting fingers (CF) in her left eye. Back in 2013, she had experienced sudden, painless loss of vision in her left eye with no subsequent visual recovery. She was systemically well and there had not been any recent foreign travel. The patient was a non-smoker and a social drinker, and she denied any drug abuse. There was no relevant family history. On examination, there was a left relative afferent pupillary defect. Goldmann visual fields showed bilateral dense central scotomas. Anterior segment examination was normal and there was no evidence of intraocular inflammation. The right optic disc was hyperaemic with telangiectactic vessels and mild swelling of the peripapillary retinal nerve fibre layer (RNFL). There was total pallor of the left optic disc (Figure 1). Fluorescein angiography did not show any optic disc leakage or choroidal ischaemia, but there were areas of segmental vasculitis (Figure 2). A comprehensive blood panel was negative including for aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) antibodies. A brain MRI scan revealed white matter signal abnormalities consistent with demyelination (Figure 3). There were no lesions in the spinal cord. On lumbar puncture, the opening cerebrospinal fluid (CSF) pressure was not elevated, but the protein level was slightly raised and oligoclonal bands that were not matched in serum were detected.

The patient received a 3-day course of intravenous methylprednisolone at a daily dose of 1 gram. There was no significant visual improvement and a decision was made to proceed with plasma exchange at a monthly interval. At the end of the third cycle in October 2015, the patient’s vision in her right eye improved to 6/24 whereas the vision in her left eye remained unchanged at CF. Shortly afterwards, the results of genetic testing for Leber hereditary optic neuropathy (LHON) became available and the patient was found to harbour the m.11778G>A mitochondrial DNA (mtDNA) mutation at homoplasmic level. At the one-year follow-up visit, there had not been any further visual improvement (Figure 1).

LHON and Demyelination

The majority of patients with LHON will only develop a bilateral optic neuropathy and the reasons that underlie this preferential vulnerability of retinal ganglion cells have not yet been fully clarified (Yu-Wai-Man P et al, 2016). However, some LHON carriers can manifest additional neurological features and the strongest causal association is with central nervous system (CNS) demyelination. In a seminal paper published in Brain in 1992, Anita Harding and colleagues described eight female LHON carriers harbouring the m.11778A>G mutation who developed a neurological syndrome that was indistinguishable from multiple sclerosis (MS) with unmatched CSF oligoclonal bands and typical neuroradiological features of demyelination (Harding AE et al, 1992). Harding’s disease, as it is now frequently referred to, was subsequently reported in the context of the two other common mtDNA mutations that cause LHON, namely m.3460A>G and m.14484T>C. There is no convincing evidence to suggest an increased risk of MS among LHON carriers. The mtDNA LHON mutations are known to exert an inhibitory effect on mitochondrial complex I activity and oxidative phosphorylation. Rather than being the primary driving factor, they could instead potentiate axonal loss and neurological disability among those individuals who already have a pre-existing predisposition to developing MS.

Natural History and Prognosis

In a systematic review of 56 patients with LHON-MS, 45 patients (80.4%) carried the m.11778A>G mutation, 6 patients (10.7%) carried the m.3460G>A mutation and 5 patients (8.9%) carried the m.14484T>C mutation (Pfeffer G et al, 2013). LHON-MS was found to have a distinct clinical phenotype compared with classical LHON and demyelinating optic neuritis (Table 1). As in the case report provided, the majority of patients experienced two or more discrete episodes of visual loss and recurrences were invariably accompanied by cumulative optic nerve damage. Although the visual prognosis is relatively better compared with classical LHON, about half of all patients with LHON-MS in this retrospective case series were registered legally blind (Pfeffer G et al, 2013). This group of patients should therefore be warned about the high likelihood of permanent visual impairment and the possibility of further acute episodes.

Patient Management

Given the rarity of LHON-MS, there is a limited evidence base to guide management. Idebenone has been found to be partially effective in a subgroup of patients treated in the acute phase of the disease (Carelli V et al, 2017). The possibility of a beneficial effect in the context of LHON-MS is unproven, but given the well-established safety profile of idebenone, a trial period of treatment could be justified depending on access and the patient’s preference. As the presence of a pathogenic mtDNA mutation is a poor visual prognostic factor in a patient with disseminated CNS demyelination, the early initiation of disease-modifying treatment could be considered on a case-by-case basis. Such a course of action will require the involvement of an experienced MS specialist to facilitate a detailed discussion with the patient about the available options and the perceived risk-benefit ratio.

Table 1. Clinical characteristics of patients with LHON-MS.

This summary table is based on the key references provided (Yu-Wai-Man P et al,2016; Harding AE et al, 1992; Pfeffer G et al, 2013).

Figure 1:
Optic disc appearance. (A) July 2015: the right optic disc is hyperaemic with telangiectactic vessels and mild swelling of the peripapillary RNFL. The left optic disc is globally pale. BCVA was 3/60 in the right eye and CF in the left eye.
(B) October 2015: the vascular changes and RFNL swelling around the right optic disc have resolved. BCVA was 6/24 in the right eye and CF in the left eye. (C) August 2016: bilateral optic disc pallor. BCVA remained unchanged at 6/24 in the right eye and CF in the left eye. 

Figure 2:
Fluorescein angiogram of the left eye: there are areas of segmental retinal vasculitis with late leakage along the superior and inferior temporal arcades, extending into the mid-periphery.


Figure 3:
Brain MRI scan: the axial FLAIR images show multiple foci of white matter signal changes in the periventricular and pericallosal areas consistent with demyelinatio.

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