Advertisement

Late-onset Leber hereditary optic neuropathy presenting after intraocular surgery

Published:October 25, 2017DOI:https://doi.org/10.1016/j.jcjo.2017.08.016
      Leber hereditary optic neuropathy (LHON) is a retinal ganglion cell degeneration characterized by bilateral, typically sequential, acute/subacute central visual loss. This maternally inherited condition arises from point mitochondrial DNA (mtDNA) mutations, and more than 90% of affected individuals harbour 1 of 3 primary mtDNA variants, m.11778G>A, m.14484T>C, or m.3460G>A.
      • Yu-Wai-Man P.
      • Griffiths P.G.
      • Chinnery P.F.
      Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies.
      Intriguingly, (i) the majority of subjects harbouring mtDNA mutations do not develop visual symptoms, (ii) a striking number of LHON patients have no family history, and (iii) there is significant male predominance (male:female, ~3:1).
      • Yu-Wai-Man P.
      • Griffiths P.G.
      • Chinnery P.F.
      Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies.
      • Fraser J.A.
      • Biousse V.
      • Newman N.J.
      The neuro-ophthalmology of mitochondrial disease.
      • Kirkman M.A.
      • Yu-Wai-Man P.
      • Korsten A.
      • et al.
      Gene-environment interactions in Leber hereditary optic neuropathy.
      These observations suggest significant variability in disease penetrance and point to a complex disease model with interacting environmental and genetic factors.
      Environmental factors increasing penetrance in mutation carriers include smoking and heavy alcohol consumption.
      • Kirkman M.A.
      • Yu-Wai-Man P.
      • Korsten A.
      • et al.
      Gene-environment interactions in Leber hereditary optic neuropathy.
      Other possible environmental triggers described in case reports include head trauma, raised intraocular pressure (IOP), industrial toxins, and drugs with mitochondrial toxicity.
      • Kirkman M.A.
      • Yu-Wai-Man P.
      • Korsten A.
      • et al.
      Gene-environment interactions in Leber hereditary optic neuropathy.
      • Thouin A.
      • Griffiths P.G.
      • Hudson G.
      • Chinnery P.F.
      • Yu-Wai-Man P.
      Raised intraocular pressure as a potential risk factor for visual loss in Leber hereditary optic neuropathy.
      We report 2 individuals in the seventh decade of life who presented with visual loss within days after penetrating ocular surgery.
      The first study subject is a 69-year-old female diagnosed with ocular hypertension at age 55 years. She subsequently developed narrow angles treated with bilateral iridotomies and cataract surgery. At age 68 years, she underwent a left trabeculectomy procedure; this failed to control the IOP and left glaucoma drainage implant surgery was undertaken 1 year later. There were no visual complaints in the first postoperative week, but soon after, she reported blurring in her left temporal subfield; at 1 month postoperatively, left IOP was 43 mm Hg and left visual acuity (VA) was 0.4 logMAR. Subsequently, the IOP reduced, but vision continued to deteriorate (Fig. 1). A left relative afferent pupillary defect was noted 3 months after the procedure. Five months postoperatively, deterioration of the right eye vision was reported, with the right VA dropping to 0.3 logMAR. Extensive investigations for optic neuropathy (including head magnetic resonance imaging before and after involvement of the right eye, lumbar puncture, temporal artery biopsy, and autoimmune/paraneoplastic antibody screen) were unremarkable. MtDNA analysis revealed a homoplasmic m.11778G>A mutation; this change is the most common LHON-associated mtDNA defect,
      • Yu-Wai-Man P.
      • Griffiths P.G.
      • Chinnery P.F.
      Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies.
      and a diagnosis of LHON was made. At 6 months postoperatively, VA was counting fingers OD and hand movements OS. Optic disc appearance over time is shown in Figure 2, and visual field tests before and after visual deterioration can be found in Supplementary Data (available online).
      Fig. 1
      Fig. 1Fluctuation in visual acuity and intraocular pressure in a 69-year-old m.11778G>A mutation carrier (female; subject 1). On day 0, the patient had glaucoma drainage implant surgery (Baerveldt BG 101–350; Abbott Medical Optics, Abbott Park, Ill.). The flow of aqueous humor was restricted by placing an absorbable suture around the external aspect of the tube. Treatment included oral/topical/intravenous antiglaucoma medications, topical/intravenous steroids, and plasma exchange. RVA and LVA correspond to right and left visual acuity. R IOP and L IOP correspond to right and left intraocular pressure.
      Fig. 2
      Fig. 2Optic disc imaging in a 69-year-old m.11778G>A mutation carrier before and after developing Leber hereditary optic neuropathy symptoms (female; subject 1). Disc appearance and pattern of retinal nerve fibre layer (RNFL) thinning 13 months before (A; acuity 0.0 logMAR OU), 4 months after (B; acuity 0.0 logMAR OD, counting fingers OS), and 6 months after (C; acuity counting fingers OD, hand movements OS) glaucoma drainage implant surgery are presented. Telangiectatic vessels are noted at the right optic disc a few weeks before right visual loss (B).
      The second study subject is a male who underwent uneventful right cataract surgery at age 68 years. Preoperatively, the VA was 0.2 logMAR OD and 0.0 logMAR OS; IOPs were within normal limits, and fundoscopy was unremarkable. The main preoperative symptom that indicated cataract surgery was glare. Right eye vision was reported reduced from day 1 after the procedure, and at 1 month postoperatively, VA was 0.8 logMAR OD. There was mild right optic nerve head swelling with segmental hyperfluorescence on angiography. The patient was managed as having nonarteritic ischaemic optic neuropathy, but 3 months later, further right visual deterioration and a new-onset reduction in the left eye vision were reported; VA was counting fingers OD and 0.5 logMAR OS. Static perimetry results from that visit are shown in Supplementary Data (available online). Further visual field testing using Goldmann kinetic perimetry 5 months after the surgery revealed symmetric, dense, steep-sided central scotomata. Optic neuropathy work-up revealed a homoplasmic m.11778G>A mutation and normal neuroimaging. At 6 months postoperatively, VA was counting fingers OD and 1.0 logMAR OS.
      Mitochondrial dysfunction is increasingly implicated in common ophthalmic disorders of aging, including age-related macular degeneration and glaucoma.
      • Schrier S.A.
      • Falk M.J.
      Mitochondrial disorders and the eye.
      Retinal ganglion cells, the cells primarily affected in in LHON, are particularly susceptible to mitochondrial dysfunction.
      • Yu-Wai-Man P.
      • Griffiths P.G.
      • Chinnery P.F.
      Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies.
      • Fraser J.A.
      • Biousse V.
      • Newman N.J.
      The neuro-ophthalmology of mitochondrial disease.
      It can be speculated that ganglion cells harbouring mtDNA defects may maintain their normal function but are more susceptible to secondary insults that they would normally have tolerated.
      • Osborne N.N.
      Mitochondria: their role in ganglion cell death and survival in primary open angle glaucoma.
      Although LHON is perceived as a disorder of young adults, 8% of cases become symptomatic after the age of 50 years.
      • Dimitriadis K.
      • Leonhardt M.
      • Yu-Wai-Man P.
      • et al.
      Leber’s hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients.
      Here, we report 2 m.11778G>A mutation carriers who developed symptoms in their late 60s. As disease conversion was temporally related to intraocular surgery, a procedure-associated trigger is likely. Importantly, both study subjects were nonsmokers and reported no binge-drinking episodes or exposure to other known mitochondrial stressors.
      Raised IOP has been previously suggested as a potential risk factor for visual loss in 3 individuals with late-onset LHON.
      • Yu-Wai-Man P.
      • Griffiths P.G.
      • Chinnery P.F.
      Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies.
      Notably, the IOP of the first study subject significantly fluctuated before disease manifestation (Fig. 1). In the second study subject, IOP measurements in the immediate postoperative period were not available, but it is known that IOP spikes can occur in association with cataract surgery.
      • Kreutzer T.C.
      • Al Saeidi R.
      • Kampik A.
      • Grueterich M.
      Real-time intraocular pressure measurement in standard and microcoaxial phacoemulsification.
      We speculate that such fluctuations may have played a role in precipitating disease conversion. Therefore, until further evidence becomes available, optimizing IOP control and taking measures to avoid wide IOP fluctuations is advisable in LHON carriers.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.This work was supported in part by grants from the National Institute for Health Research (NIHR) Greater Manchester: Clinical Research Network, UK.

      Acknowledgement

      This work was supported in part by grants from the National Institute for Health Research (NIHR) Greater Manchester: Clinical Research Network, UK.

      References

        • Yu-Wai-Man P.
        • Griffiths P.G.
        • Chinnery P.F.
        Mitochondrial optic neuropathies—disease mechanisms and therapeutic strategies.
        Prog Retin Eye Res. 2011; 30: 81-114
        • Fraser J.A.
        • Biousse V.
        • Newman N.J.
        The neuro-ophthalmology of mitochondrial disease.
        Surv Ophthalmol. 2010; 55: 299-334
        • Kirkman M.A.
        • Yu-Wai-Man P.
        • Korsten A.
        • et al.
        Gene-environment interactions in Leber hereditary optic neuropathy.
        Brain. 2009; 132: 2317-2326
        • Thouin A.
        • Griffiths P.G.
        • Hudson G.
        • Chinnery P.F.
        • Yu-Wai-Man P.
        Raised intraocular pressure as a potential risk factor for visual loss in Leber hereditary optic neuropathy.
        PLoS One. 2013; 8: e63446
        • Schrier S.A.
        • Falk M.J.
        Mitochondrial disorders and the eye.
        Curr Opin Ophthalmol. 2011; 22: 325-331
        • Osborne N.N.
        Mitochondria: their role in ganglion cell death and survival in primary open angle glaucoma.
        Exp Eye Res. 2010; 90: 750-757
        • Dimitriadis K.
        • Leonhardt M.
        • Yu-Wai-Man P.
        • et al.
        Leber’s hereditary optic neuropathy with late disease onset: clinical and molecular characteristics of 20 patients.
        Orphanet J Rare Dis. 2014; 9: 158
        • Kreutzer T.C.
        • Al Saeidi R.
        • Kampik A.
        • Grueterich M.
        Real-time intraocular pressure measurement in standard and microcoaxial phacoemulsification.
        J Cataract Refract Surg. 2010; 36: 53-57