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Structural and functional degeneration of retinal nerves in sibling carriers of a Leber’s hereditary optic neuropathy mutation

Published:August 04, 2017DOI:https://doi.org/10.1016/j.jcjo.2017.05.010
      Leber’s hereditary optic neuropathy (LHON)
      • Carelli V.
      • La Morgia C.
      • Valentino M.L.
      • et al.
      Idebenone treatment in Leber’s hereditary optic neuropathy.
      presents with painless bilateral or sequential vision loss caused by degeneration of the papillomacular retinal nerve fibre bundle.
      • Man P.Y.W.
      • Turnbull D.M.
      • Chinnery P.F.
      Leber hereditary optic neuropathy.
      Optical coherence tomography (OCT) has demonstrated thickening of the retinal nerve fibre layer (RNFL) before and during visual decline, followed by long-term axonal degeneration.
      • Barboni P.
      • Savini G.
      • Valentino M.L.
      • et al.
      Retinal nerve fiber layer evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy.
      • Savini G.
      • Barboni P.
      • Valentino M.L.
      • et al.
      Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations.
      • Zhang Y.
      • Huang H.
      • Wei S.
      • et al.
      Characterization of retinal nerve fiber layer thickness changes associated with Leber’s hereditary optic neuropathy by optical coherence tomography.
      Unaffected male carriers of LHON mutations may experience mild temporal RNFL swelling.
      • Savini G.
      • Barboni P.
      • Valentino M.L.
      • et al.
      Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations.
      OCT can further detect ganglion cell complex (GCC) degeneration during disease and preceding symptom onset.
      • Akiyama H.
      • Kashima T.
      • Li D.
      • Shimoda Y.
      • Mukai R.
      • Kishi S.
      Retinal ganglion cell analysis in leber’s hereditary optic neuropathy.
      • Mizoguchi A.
      • Hashimoto Y.
      • Shinmei Y.
      • et al.
      Macular thickness changes in a patient with Leber’s hereditary optic neuropathy.
      We previously defined 3 OCT-detectable phases of nerve fibre change in LHON, each lasting about 12 weeks:
      • 1.
        A presymptomatic phase with RNFL thickening,
      • 2.
        An acute phase with GCC thinning and RNFL normalization, and
      • 3.
        A chronic phase in which both layers degenerate linearly with time.
        • Hedges T.R.
        • Gobuty M.
        • Manfready R.A.
        • et al.
        The optical coherence tomographic profile of leber hereditary optic neuropathy.
      Electrophysiology studies have documented changes in visual evoked potential (VEP), multifocal electroretinography (mfERG), and pattern electroretinography (pERG) in symptomatic patients. In acute LHON, decreased amplitude and increased latency in the VEP P100 wave have been documented.
      • Jarc-Vidmar M.
      • Tajnik M.
      • Brecelj J.
      • et al.
      Clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy.
      Retinal nerve cell damage has been detected by a missing component in the first-order kernel of mfERG. The N95 component of pERG, which reflects activity of retinal ganglion cells,
      • Kurtenbach A.
      • Leo-Kottler B.
      • Zrenner E.
      Inner retinal contributions to the multifocal electroretinogram: patients with Leber hereditary optic neuropathy (LHON).
      but not the P50 component, has been shown to be reduced.
      • Jarc-Vidmar M.
      • Tajnik M.
      • Brecelj J.
      • et al.
      Clinical and electrophysiology findings in Slovene patients with Leber hereditary optic neuropathy.
      There has been one report of dropped pERG amplitudes among asymptomatic carriers of the 11779 LHON mutation.
      • Guy J.
      • Feuer W.J.
      • Porciatti V.
      • et al.
      Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy.

      Methods

      We observed a 19-year-old male with the 3460 mutation who developed sequential vision loss in both eyes. We also evaluated his brother, a carrier of the same mutation who had not developed vision loss. We documented the simultaneous progression of structural (RNFL, GCC, and funduscopic examination) and functional (VEP, pERG, and mfERG) disease manifestations in the symptomatic brother both before and after symptom onset and compared these findings with those of the asymptomatic carrier brother. All patients herein have provided written consent in accordance with the guidelines of Tufts Medical Center.

      Results

      A 19-year-old male student-athlete with a history of migraine presented to the neuro-ophthalmology clinic with 5 weeks of worsening central vision OD (20/200). Vision was limited to counting fingers with a central scotoma detected on automated visual fields (30-2 strategy, Humphrey Field Analyzer, Carl Zeiss Meditec, Dublin, Calif.). The patient noted photophobia of his left eye, which had a visual acuity of 20/15 and no visual field defect. There was no relative afferent pupillary defect. Peripapillary telangiectasias were present in both eyes. Genetic testing revealed LHON mitochondrial DNA mutation 3460G>A (Athena Diagnostics, Marlboro, Mass.). The patient was prescribed idebenone and memantine and re-evaluated at 4 weeks, 6 weeks, and 1 year. Two weeks after vision loss in the right eye, the patient noted mild loss of vision in his left eye (20/25 with a mild central scotoma).
      High-definition OCT (Cirrus HD-OCT Model 4000, Carl Zeiss Meditec, Dublin, Calif.) was used to quantify the thickness of the RNFL and GCC at each visit. Two weeks before symptom onset in the left eye, RNFL swelling was detected (average thickness 132 µm, normal thickness 87–100 µm
      • Akashi A.
      • Kanamori A.
      • Ueda K.
      • Inoue Y.
      • Yamada Y.
      • Nakamura M.
      The ability of SD-OCT to differentiate early glaucoma with high myopia from highly myopic controls and nonhighly myopic controls.
      ), as well as mild overall thickening of the GCC. Immediately after vision loss, there was severe GCC thinning (average thickness 46 µm, normal thickness 75–88 µm
      • Akashi A.
      • Kanamori A.
      • Ueda K.
      • Inoue Y.
      • Yamada Y.
      • Nakamura M.
      The ability of SD-OCT to differentiate early glaucoma with high myopia from highly myopic controls and nonhighly myopic controls.
      ), followed by degeneration of both the RNFL and GCC over the course of 1 year. RNFL and GCC followed a similar course in the right eye over 1 year, consistent with documented progression of LHON (Fig. 1).
      • Barboni P.
      • Savini G.
      • Valentino M.L.
      • et al.
      Retinal nerve fiber layer evaluation by optical coherence tomography in Leber’s hereditary optic neuropathy.
      • Hedges T.R.
      • Gobuty M.
      • Manfready R.A.
      • et al.
      The optical coherence tomographic profile of leber hereditary optic neuropathy.
      Fig. 1
      Fig. 1Staging of Leber’s hereditary optic neuropathy in a 19-year-old male with sequential vision loss. At selected points before and after vision loss for both eyes, we recorded (A) automated visual fields, (B) funduscopic photographs, (C) retinal nerve fibre layer (RNFL) thickness measurements superimposed over normal values, and (D) ganglion cell complex (GCC) layer thickness heat maps. RNFL and GCC layer widths were tracked with respect to disease duration for each eye (E).
      VEP P100 signal amplitudes (RETI-Port/scan, Roland Consult, Brandenburg, Germany) were mildly decreased in the right (affected) eye and normal in the left (unaffected) eye (4 µV OD, 7 µV OS at 60 minutes) at presentation. P100 latency was unaffected (80 ms OD, 106 ms OS at 60 minutes). On pERG, there was slightly decreased amplitude of the N95 component with normal latency. mfERG 1 year after symptom onset showed mildly decreased amplitude of signals bilaterally (Fig. 2).
      Fig. 2
      Fig. 2Functional electrophysiological studies of a 19-year-old male with Leber’s hereditary optic neuropathy. Visual evoked potential (VEP) P100 amplitude was normal 2 weeks before symptom onset (OS) but declined 2 weeks after symptom onset (OD) (A). One-year after symptom onset, there was slightly decreased amplitude of the N95 component on pattern electroretinography (pERG) with normal latency (B) and mild diffuse loss of amplitude in multifocal electroretinography (mfERG) recordings bilaterally (C).
      The patient’s younger brother, an 18-year-old carrier of the same mutation, did not develop vision loss or peripapillary telangiectasias over the course of 1 year. Visual acuities and visual fields remained normal. At 2 visits 6 months apart, OCT did not reveal swelling or degeneration in either RNFL or GCC. pERG showed no abnormalities of the N95 component (Fig. 3).
      Fig. 3
      Fig. 3Representative structural and functional data for an 18-year-old unaffected carrier brother of the described symptomatic patient with Leber’s hereditary optic neuropathy. Studies without abnormal findings in this carrier sibling include visual fields (A), fundus photographs (B), retinal nerve fibre layer recordings superimposed over normal values (average thickness 116 µm OD, 110 µm OS) (C), ganglion cell complex layer thickness heat maps (average thickness 90 µm OD, 92 µm OS) (D), and pattern electroretinography (E).

      Discussion

      We have demonstrated structural changes consistent with functional visual decline and electrophysiological deficits in a patient with LHON. At our first evaluation 2 weeks before vision loss, the RNFL and GCC were thickened, suggesting possible pathologic changes of both axons and ganglion cells at this early stage. It is unknown when the swelling began. The GCC began to thin slightly at the time of vision loss, after which GCC thinning took place at a rate of about 0.6 µm/wk. The RNFL remained swollen through about 6 weeks after vision loss, which was followed by rapid thinning over the course of the 1-year study period. These results suggest that thickening of RNFL or GCC may be a precursor of acute vision loss in LHON, as previously suggested.
      • Hedges T.R.
      • Gobuty M.
      • Manfready R.A.
      • et al.
      The optical coherence tomographic profile of leber hereditary optic neuropathy.
      • Hwang T.J.
      • Karanjia R.
      • Moraes-Filho M.N.
      • et al.
      Natural history of conversion of Leber’s hereditary optic neuropathy.
      VEP signals were normal in the presymptomatic period; P100 amplitudes decreased only after vision loss. One year after symptom onset, pERG showed mildly decreased amplitude of the N95 component, suggesting loss of ganglion cell function. We have noted this finding in other cases of LHON, and thus the phenomenon should be subject to further study. mfERG amplitudes were mildly decreased in both affected eyes, indicating possible outer retinal involvement, as previously reported.
      • Kurtenbach A.
      • Leo-Kottler B.
      • Zrenner E.
      Inner retinal contributions to the multifocal electroretinogram: patients with Leber hereditary optic neuropathy (LHON).
      The patient’s unaffected brother, a carrier of the same mutation, did not demonstrate structural abnormalities on fundoscopy or OCT. Although there has been evidence of RNFL thickening in unaffected male carriers, the finding was not significant for patients with the 3460 mutation.
      • Savini G.
      • Barboni P.
      • Valentino M.L.
      • et al.
      Retinal nerve fiber layer evaluation by optical coherence tomography in unaffected carriers with Leber’s hereditary optic neuropathy mutations.
      Additionally, the pERG abnormalities found in 11778 carriers
      • Guy J.
      • Feuer W.J.
      • Porciatti V.
      • et al.
      Retinal ganglion cell dysfunction in asymptomatic G11778A: Leber hereditary optic neuropathy.
      may not be relevant to the 3460 mutation or may not be a hallmark of LHON. Thus, we found no structural or functional abnormalities for the carrier sibling in our study.

      Disclosure

      The authors have no proprietary or commercial interest in any materials discussed in this article.

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