Visual Outcomes and Optical Coherence
Tomography Biomarkers of Vision
Improvement in Patients With Leber Hereditary
Optic Neuropathy Treated With Idebenone
ENRICO BORRELLI4, ALESSANDRO BERNI4, MARIA LUCIA CASCAVILLA, COSTANZA BARRESI,
MARCO BATTISTA, GIORGIO LARI, MICHELE REIBALDI, FRANCESCO BANDELLO, AND PIERO BARBONI
• PURPOSE: To assess the relationship of demograph-
ics, clinical characteristics and structural optical coher-
ence tomography (OCT) findings to long-term visual out-
comes in patients with Leber hereditary optic neuropathy
(LHON) treated with idebenone.
• DESIGN: Retrospective, interventional, noncompara-
tive clinical cohort study.
• METHODS: In this study, a total of 17 participants (34
eyes) with LHON treated with idebenone therapy within
1 year after disease onset and 2 years (24 months) of reg-
ular follow-ups were retrospectively enrolled. At base-
line, structural OCT volume scans of the macula and
optic nerve were reviewed to measure metrics reflecting
neuronal loss (ie, macular ganglion cell and inner plexi-
form layer [GC-IPL] and peripapillary retinal nerve fiber
layer [RNFL] thicknesses). Stepwise multiple regression
analyses were computed to assess associations between
final best-corrected visual acuity (BCVA) at 2 years and
change in BCVA from baseline at 2 years as dependent
variables with demographics, clinical characteristics, and
OCT metrics at baseline (visit before the initiation of
treatment).
• RESULTS: The BCVA was 1.6±0.8 logMAR (Snellen
VA of ∼20/800) at baseline (visit before the initia-
tion of treatment) and 1.0±0.7 logMAR (Snellen VA
of 20/200) at the 2-year follow-up visit (P < .0001).
Mean±SD change in BCVA from baseline at 2 years
was –51.9%±35.9%. In multivariable analysis, the
strongest associations with final BCVA were with base-
line BCVA (P = .012), superior macular GC-IPL thick-
ness (P = .044), superotemporal macular GC-IPL thick-
ness (P = .010), and inferotemporal macular GC-IPL
thickness (P = .015). Similarly, the strongest associa-
tions with delta BCVA were with superior macular GC-
Accepted for publication November 4, 2022.
From the Vita-Salute San Raffaele University, Milan (E.B., A.B.,
M.L.C., C.B., M.B., G.L., F.B., P.B.); IRCCS San Raffaele Scientific In-
stitute, Milan (E.B., A.B., M.L.C., C.B., M.B., G.L., F.B., P.B.); and De-
partment of Ophthalmology, University of Turin (M.R.), Italy
Inquiries to Enrico Borrelli, Department of Ophthalmology, University
Vita-Salute San Raffaele, Milan, Italy.; e-mail: borrelli.enrico@yahoo.com
4 Enrico Borrelli and Alessandro Berni contributed equally to the work
presented here and should therefore be regarded as equivalent authors.
0002-9394/$36.00 © 2022 ELSEVIER INC. ALL RIGHTS RESERVED.
https://doi.org/10.1016/j.ajo.2022.11.004
IPL thickness (P = .045), superotemporal macular GC-
IPL thickness (P = .047), and inferotemporal macular
GC-IPL thickness (P = .030).
• CONCLUSION: We identified OCT biomarkers associ-
ated with long-term (ie, 2-year) visual outcomes in pa-
tients with LHON treated with idebenone therapy in the
first year after disease onset. Thinning of the GC-IPL in
the superior and temporal parafoveal regions was associ-
ated with worse long-term visual outcomes in these pa-
tients. (Am J Ophthalmol 2023;247: 35–41. © 2022
Elsevier Inc. All rights reserved.)
L
eber hereditary optic neuropathy (LHON) is
one of the most common mitochondrial diseases
and it is caused by mitochondrial DNA (mtDNA)
point mutations involving complex I of the oxidative
phosphorylation chain.1–4 The 3 most common mutations
eventually resulting in LHON are at nucleotide positions
11778/ND4, 3460/ND1, and 14484/ND6. Typically, pa-
tients with LHON may experience a painless, subacute, and
simultaneous or sequential loss of central vision, this often
occurring early in life.2 , 4–6
LHON is noteworthy in its tissue selectivity, as this dis-
ease is mainly limited to injuring retinal ganglion cells and
their axons converging in the optic nerve.1–4 In the early
phases of LHON, the smaller-caliber fibers of the papil-
lomacular bundle are predominantly damaged.7–9 Succes-
sively, the fiber decline may advance and eventually involve
the whole optic nerve.10
A lot of evidence has suggested that idebenone may be
an efficacious and safe therapy in patients with LHON.11
Idebenone is a synthetic analogue of coenzyme Q10 with a
shorter and less lipophilic tail, the latter characteristic al-
lowing an easier penetration of mitochondrial membranes.
Furthermore, the activation of idebenone takes place in the
cytoplasm and is thus dependent on mitochondrial func-
tion. Therefore, the transformation into the reduced form
may allow idebenone to shuttle the electrons directly to
complex III, bypassing the complex I dysfunction that char-
acterizes LHON.12
35
 Idebenone is administered orally and demonstrated to
have a good bioavailability and linear dose-dependent phar-
macokinetics, with a relevant ocular and brain distribu-
tion.13 Importantly, idebenone proved to be an efficacious
therapy in LHON patients with a randomized, double-
blinded, placebo-controlled study.11 In detail, Klopstock
and coauthors recruited 87 subjects with LHON that were
randomized to either idebenone 900 mg per day or placebo
for 24 weeks. In the latter study, idebenone proved to be
an efficacious treatment in maintaining or improving visual
acuity in LHON patients.11
The latter results were further confirmed by Carelli and
colleagues,14 who performed a retrospective study on 103
LHON patients who were followed up for 1 year after the
initiation of visual decline in the second eye. In the lat-
ter study, the quota of patients experiencing a visual re-
covery was greater in the treated group, as compared with
untreated patients. More importantly, an earlier visual im-
provement was associated with a prompt initiation and
longer duration of therapy.14 Finally, the beneficial effect of
idebenone on visual recovery was demonstrated to be still
present even after the discontinuation of therapy.15
Structural optical coherence tomography (OCT) is
widely used as an objective and reproducible imaging tool in
the diagnosis and follow-up of patients with LHON. In de-
tail, structural OCT was employed to describe longitudinal
peripapillary retinal nerve fiber layer (RNFL) and macular
ganglion cell and inner plexiform layer (GC-IPL) thickness
changes in LHON subjects. In LHON, a significant thick-
ening of the peripapillary RNFL may be detected in the
preonset and acute stages of the disease.10 , 16 Subsequently,
structural OCT usually shows a thinning of the peripapil-
lary RNFL as the retinal fibers’ loss prevails on swelling and
proceeds through the acute and dynamic stages until the be-
ginning of the chronic stage at 1 year.10,16,17 Conversely, a
thinning of the macular GC-IPL may be detectable before
the subjective onset of visual loss and progresses until the
end of the acute stage, when it becomes stable.18
What is lacking is information concerning the relation-
ship among the baseline anatomic characteristics detected
with structural OCT, the clinical features of this disease,
and long-term visual outcomes in patients with LHON
treated with idebenone within 1 year after disease onset.
Therefore, in this longitudinal study, we performed an anal-
ysis to assess the presence of clinical biomarkers predicting
the response to idebenone in patients with LHON.
METHODS
• STUDY PARTICIPANTS AND TESTS: The San Raffaele
Ethics Committee was notified about this retrospective co-
hort study. The study adhered to the 1964 Helsinki decla-
ration and its later amendments. Patients granted informed
consent to retrospectively access the data.
36 AMERICAN JOURNAL OF OPHTHALMOLOGY
In this study, patients with a clinical and molecularly
confirmed diagnosis of LHON were identified from the
medical records of a neuro-ophthalmology practice at the
San Raffaele Scientific institute. In details, patients were
included in the initial study cohort if they had history of
LHON treated with idebenone therapy within 1 year af-
ter disease onset. Exclusion criteria were the presence of
any retinal pathology and/or optic nerve disease other than
LHON. To be included, patients were also required to have
a minimum of 2 yearly neuro-ophthalmology visits covering
a study period of 2 years after the initiation of idebenone
therapy. Idebenone was prescribed at 900 mg/d for all pa-
tients except children, who started at 450 mg/d. On the ba-
sis of the presence of side effects, the final dosage was at the
discretion of the treating physician and not lower than 540
mg/d.14
At baseline (visit 0-7 days before the initiation of
idebenone therapy), all patients received a complete oph-
thalmologic examination, including the measurement of
best-corrected visual acuity (BCVA) that was performed us-
ing a Snellen chart and converted to logMAR, as previously
described.19 Furthermore, all subjects underwent an auto-
mated visual field that was performed using a Humphrey
Field Analyzer (Humphrey Systems, Inc) running a 30-2
SITA threshold strategy program.
All subjects also underwent the ZEISS Cirrus 5000 (Carl
Zeiss Meditec). In detail, structural OCT volume scans of
the macula (512 × 128) and optic nerve (200 × 200) were
performed to measure macular GC-IPL and peripapillary
RNFL thicknesses, as previously described.18 , 20–23 In brief,
the ganglion cell analysis (GCA) algorithm (Cirrus OCT
software, version 6.0) was employed to identify and quan-
tify GC-IPL thickness within a circular annulus around the
fovea (dimensions: inner and outer radii of 0.6 and 1.73
mm, respectively; vertical inner and outer radii of 0.5 and
2.0 mm, respectively). The GCA algorithm automatically
recognizes and computes the difference between the RNFL
and inner plexiform layer (IPL) outer boundary segmenta-
tions, yielding a combined thickness of the ganglion cell
and inner plexiform layers (ie, GC-IPL).18 , 21–23
The average and 6-sector (superior [S], superotemporal
[ST], inferotemporal [IT], inferior [I], superonasal [SN], in-
feronasal [IN]) GC-IPL thicknesses were considered for this
analysis. The macula (512 × 128) scan was also employed to
measure the central macular thickness, which was measured
as the difference between the RNFL and retinal pigment
epithelial inner boundary segments within the foveal re-
gion (dimensions: diameter of 1.00 mm). Similarly, the Cir-
rus built-in software identifies and calculates the inner and
outer boundaries of the RNFL in an annular B-scan around
the optic nerve (dimensions: diameter of 3.46 mm), yield-
ing the average and sectorial (superior [S], nasal [N], inferior
[I], and temporal [T]) peripapillary RNFL thicknesses.
Visual acuities at the 2-year follow-up visit (2 years after
the initiation of idebenone therapy) were also considered
in this analysis.
MARCH 2023
 TABLE 1. Characteristics of LHON Patients

Number of eyes enrolled (patients) 34 (17)

Age, years 32.3±17.8

Sex, n (%)
- Male () 15 (88.2)
- Female 2 (11.8)
Mutation, n (%)
- 11778 10 (58.8)
- 3460 4 (23.5)
- 14484 3 (16.7)
Smoking, n (%) 6 (35.3)
Symptomatic disease duration before initiation of treatment, mo 5.3±4.9
Idebenone dose, mg 790.1±248.1

LHON = Leber hereditary optic neuropathy.

Quantitative values are expressed in mean ± SD.

• STATISTICAL ANALYSIS: Statistical calculations were
performed using Statistical Package for Social Sciences
(version 20.0; SPSS Inc).
To detect departures from normal distribution, a Shapiro-
Wilk test was performed for all variables. Means and SDs
were computed for all quantitative variables. Visual acuities
and CV metrics (ie, mean defect) at baseline and 2-year
follow-up visits were compared by conducting paired sam-
ples t test or related-samples Wilcoxon signed rank test.
Baseline clinical and imaging variables were explored
for associations with final BCVA at 2 years and change
in BCVA from baseline at 2 years. Stepwise multiple re-
gression analyses with the above-mentioned outcomes were
computed, with entry selection criterion set at P <.10 and
stay criterion set at P <.05 for variable selection. Measure-
ments of bilateral eyes were nested within subject.
At baseline, the average peripapillary RNFL thickness
was 94.6±32.3 μm, and the average macular GC-IPL thick-
ness was 57.3±11.5 μm. Table 3 summarizes the other struc-
tural parameters in our study cohort of LHON subjects.
• REGRESSION ANALYSIS: Results of linear regressions are
summarized in Table 4.
In multivariable analysis, the strongest associations with
final BCVA were with baseline BCVA (P = .012), supe-
rior macular GC-IPL thickness (P = .044), superotemporal
macular GC-IPL thickness (P = .010), and inferotemporal
macular GC-IPL thickness (P = .015).
Similarly, the strongest associations with delta BCVA
were with superior macular GC-IPL thickness (P = .045),
superotemporal macular GC-IPL thickness (P = .047), and
inferotemporal macular GC-IPL thickness (P = .030).

RESULTS
• CHARACTERISTICS OF PATIENTS INCLUDED IN THE
ANALYSIS: Clinical characteristics of enrolled patients are
presented in Table 1. Of the 17 patients with LHON who
were enrolled (15 males), 34 eyes were included in the anal-
ysis. Mean age was 32.3±17.8 years (range 13-59 years).
Three of 17 patients were younger than 15 years (ie, child-
hood LHON).24 , 25
The BCVA was 1.6±0.8 logMAR (Snellen VA of
∼20/800) at baseline (visit before the initiation of treat-
ment) and 1.0±0.7 logMAR (Snellen VA of 20/200)
at the 2-year follow-up visit (P < .0001) (Table 2).
Mean ± SD change in BCVA from baseline at 2 years
was –51.9%±35.9%. The visual field mean defect was –
18.2±11.6 at baseline and –15.2±9.9 at the 2-year follow-
up visit (P < .0001) (Table 2). Symptomatic disease dura-
tion was 5.3±4.9 months before the baseline visit.
DISCUSSION
In this longitudinal investigation, we explored baseline pre-
dictors of long-term visual outcomes in LHON patients
treated with idebenone within the first year after disease on-
set. Overall, we reported novel OCT biomarkers (ie, GC-
IPL thickness) for visual improvement at 24 months af-
ter the initiation of therapy. Notably, results of the present
study demonstrated that this association is significant in
the superior and temporal parafoveal sectors of the macula,
whereas the nasal and inferior GC-IPL thicknesses seem to
be poorly associated with visual improvement. Among the
demographic and clinical factors, age, sex, and time elapsed
between symptoms’ onset and initiation of therapy did not
significantly impact the 2-year visual outcome.
As asserted above, a lot of evidence has proposed that
idebenone represents an effective and safe treatment in pa-
tients with LHON.11 , 14 Accordingly, our study cohort of

VOL. 247 OCT BIOMARKERS IN LHON TREATED WITH IDEBENONE 37

 TABLE 2. Functional Metrics in LHON Patients at Baseline and Follow-up Visits

Baseline 2-y Follow-Up Visit P Value

BCVA, logMAR 1.6±0.8 1.0±0.7 <.0001

Visual field mean deviation (mean defect) –18.2±11.6 –15.2±9.9 <.0001

BCVA = best corrected visual acuity (logMAR), LHON = Leber hereditary optic neu-
ropathy.
Quantitative values are expressed in mean ± SD.

TABLE 3. OCT Metrics in LHON Patients at Baseline

Average peripapillary RNFL thickness, µm 94.6±32.3

Superior sector peripapillary RNFL thickness, µm 118.8±47.4

Temporal sector peripapillary RNFL thickness, µm 60.6±30.4
Inferior sector peripapillary RNFL thickness, µm 112.8±51.5
Nasal sector peripapillary RNFL thickness, µm 80.0±30.4
Average macular GC-IPL thickness, µm 57.3±11.5
Superior sector macular GC-IPL thickness, µm 59.7±13.8
Superotemporal sector macular GC-IPL thickness, µm 57.9±13.9
Inferotemporal sector macular GC-IPL thickness, µm 56.4±14.6
Inferior sector macular GC-IPL thickness, µm 57.1±12.1
Superonasal sector macular GC-IPL thickness, µm 56.8±12.3
Inferonasal sector macular GC-IPL thickness, µm 55.8±11.8
Optic disc area, mm2 2.1±0.6

GC-IPL = ganglion cell and inner plexiform layer, LHON = Leber

hereditary optic neuropathy, OCT = optical coherence tomography,
RNFL = retinal nerve fiber layer.

LHON patients treated with idebenone within the first year
after disease onset experienced a significant 2-year improve-
ment in visual acuity and visual field.
The introduction of OCT has expanded the characteri-
zation of macular and optic nerve structural modifications
occurring in LHON subjects. In detail, unaffected patients
in the asymptomatic or presymptomatic stages appear to be
characterized by a thickening of the peripapillary RNFL in
the inferior and temporal regions.10 Conversely, structural
OCT during the acute phase demonstrated the presence of
inferior and temporal peripapillary RNFL and nasal macular
GC-IPL thinning—these regions reflecting the topograph-
ical distribution of the papillomacular bundle.18 , 26
Also, in the latter phase, structural OCT usually de-
tects a swelling (ie, thickening) of the superior and nasal
peripapillary RNFL.18 , 26 , 27 The RNFL swelling is likely
to depend on the compensatory increase of mitochondrial
biogenesis and/or axonal stasis along the fibers. Following
the acute stage, a diffuse thinning of the macular GC-IPL
and peripapillary RNFL may be detected in patients with
LHON.10 , 27 , 28
Previous studies have suggested that a cross-sectional as-
sessment of peripapillary RNFL thickness may fail to pro-
vide OCT biomarkers associated with visual outcomes in
patients with LHON.28 Although the RNFL thinning is an
imaging surrogate of optic nerve fibers’ atrophy, a preserved
RNFL thickness indeed may be the result of a combination
of fibers’ swelling and atrophy, rather than an indicator of
true preservation of optic nerve fibers. Therefore, the peri-
papillary RNFL thickness seems to not appropriately reflect
optic nerve atrophy in the earliest stages of LHON disease.
Accordingly, our analysis revealed that peripapillary RNFL
metrics were not associated with better visual outcomes in
patients with LHON treated with idebenone therapy.
Conversely, a previous report has suggested that the sta-
tus of the GC-IPL in the macular region may better re-
flect the amount of preserved ganglion cells and optic nerve
fibers in patients with LHON.28 Accordingly, the present
study highlights the distinctive relationship between inner
retina damage and final visual acuity in LHON patients
treated with idebenone: considering final visual acuity as
the dependent variable, we observed a direct relationship
with variables defining a loss of ganglion cells (ie, macu-
lar GC-IPL thickness), even after accounting for confound-
ing factors, such as age, gene mutation, and symptomatic
disease duration before initiation of treatment, which are
known to modify the visual outcome in these patients.27
Similarly, the change in visual acuity between baseline and
2-year follow-up visits was significantly associated with vari-
ables defining a damage of the inner retina.

38 AMERICAN JOURNAL OF OPHTHALMOLOGY MARCH 2023

 TABLE 4. Regression Analyses Between Final Visual Acuity and Delta Visual Acuity (Dependent Variables) and Clinical and
Structural Parameters in LHON Patients

Final BCVA Delta BCVA

Univariable Analysis Multivariable Analysis Univariable Analysis Multivariable Analysis

β (95% CI) P Value β (95% CI) P Value β (95% CI) P Value β (95% CI) P Value

Age –0.446 .013 –0.088 .659 0.021 .912 — —

(–2.638) (–0.525) (0.111)
Sex: M/F –0.079 .680 — — 0.429 .018 0.123 .508
(–0.417) (2.513) (0.674)
Smoking: Y/N –0.382 .038 –0.039 .801 0.018 .924 — —
(–2.184) (–0.256) (0.096)
Mutation 0.180 .359 — — –0.331 .085 –0.047 .793
(0.933) (–1.789) (–0.266)
Baseline BCVA 0.680 <.0001 0.434 .012 –0.289 .122 — —
(4.912) (2.785) (–1.596)
Symptomatic disease duration before –0.325 .079 –0.205 .341 –0.275 .141 — —
initiation of treatment (–1.820) (–0.976) (–1.516)
Idebenone dose –0.420 .021 –0.319 .090 –0. 210 .264 — —
(–2.450) (–1.785) (–1.139)
Optic disc area 0.479 .007 0.085 .671 –0.087 .646 — —
(2.855) (0.431) (–0.465)
Average peripapillary RNFL thickness 0.022 .907 — — –0.132 .485 — —
(0.118) (–0.707)
Superior sector peripapillary RNFL –0.078 .681 — — –0.125 .510 — —
thickness (–0.416) (–0.668)
Temporal sector peripapillary RNFL –0.090 .638 — — –0.090 .635 — —
thickness (–0.476) (–0.479)
Inferior sector peripapillary RNFL thickness –0.094 .620 — — 0.074 .696 — —
(–0.501) (0.395)
Nasal sector peripapillary RNFL thickness –0.006 .976 — — –0.239 .203 — —
(–0.031) (–1.304)
Average macular GC-IPL thickness 0.385 .036 0.849 .141 0.417 .022 0.918 .092
(2.208) (1.534) (2.425) (1.769)
Superior sector macular GC-IPL thickness 0.378 .040 0.357 .044 0.411 .024 2.536 .045
(2.158) (2.050) (2.387) (2.136)
Superotemporal sector macular GC-IPL 0.476 .008 0.462 .010 0.417 .022 1.171 .047
thickness (2.861) (2.775) (2.429) (2.061)
Inferotemporal sector macular GC-IPL 0.451 .012 0.439 .015 0.539 .002 1.264 .030
thickness (2.676) (2.525) (3.388) (2.333)
Inferior sector macular GC-IPL thickness 0.186 .324 — — 0.412 .024 –0.113 .652
(1.004) (2.392) (–0.458)
Superonasal sector macular GC-IPL 0.240 .202 — — 0.221 .240 — —
thickness (1.307) (1.199)
Inferonasal sector macular GC-IPL 0.135 .477 — — 0.055 .773 — —
thickness (0.720) (0.291)

BCVA = best-corrected visual acuity, GC-IPL = ganglion cell and inner plexiform layer, LHON = Leber hereditary optic neuropathy,
RNFL = retinal nerve fiber layer.

Previous preclinical evidence has suggested that
idebenone may have a protective role against retinal
ganglion cell loss occurring in LHON, and more im-
portantly, this treatment may restore function of spared
ganglion cells. In particular, Heitz and associates27 have as-
sessed the protective effect of idebenone in a mouse model
of LHON, whereby mitochondrial complex I dysfunction
was caused by exposure to rotenone.
In this model, idebenone proved to protect against the
loss of retinal ganglion cells. Also, consistent with this pro-

VOL. 247 OCT BIOMARKERS IN LHON TREATED WITH IDEBENONE 39

tection of retinal integrity, idebenone restored the func-
tional loss of vision in this disease model. Our study seems
to suggest that idebenone may improve visual function in
patients with LHON treated in the first year after disease
onset and that this amelioration is superior in those sub-
jects with a greater amount of spared retinal ganglion cells,
as this treatment may eventually restore function of these
preserved cells.
To provide a detailed quantification of the damage of
the inner retina within the macula, we also performed a
topographic quantitative analysis of the GC-IPL. In this
topographic investigation, we demonstrated that GC-IPL
thicknesses in the inferior and nasal parafoveal regions were
not significantly associated with visual improvement in our
study cohort of LHON patients. These regions correspond
to the upstream portion of the papillomacular bundle where
the mitochondrial dysfunction is known to initially and
mainly affect ganglion cells.18
In a previous OCT report, Balducci and associates18
showed that a thinning of the GC-IPL nasal sector occurs
early in LHON patients and then it progressively extends
following a centrifugal and spiral pattern. Therefore, an
early cell loss in these areas might partially account for the
absence of a significant association between visual acuity
and GC-IPL thickness as most patients starting idebenone
therapy are already characterized by a significant loss of gan-
glion cells in these regions.
Alternatively, with advanced neuronal loss, GC-IPL
thickness may level off, because of the assumed presence
of residual glial or nonneural tissue. Therefore, this “floor
effect” may not allow to appropriately assess the amount of
preserved ganglion cells in these regions, which are charac-
terized by an early neuronal damage. Conversely, our analy-
sis revealed that GC-IPL thickness in the superior and tem-
poral parafoveal regions was significantly associated with
both final visual acuity and 2-year change in visual acuity.
Funding/Support: This study received no funding. Financial Disclosures: The authors indicate no financial support or conflicts of interest. All authors
attest that they meet the current ICMJE criteria for authorship.
Acknowledgment: We thank Leonardo Caporali, IRCCS Istituto delle Scienze Neurologiche di Bologna, Italy, for providing us the LHON gene mutation
analysis.
REFERENCES
1. Carelli V, Ross-Cisneros FN, Sadun AA. Mitochondrial dys-
function as a cause of optic neuropathies. Prog Retin Eye Res.
2004;23(1):53–89. doi:10.1016/j.preteyeres.2003.10.003.
2. Yu-Wai-Man P, Griffiths PG, Chinnery PF. Mitochondrial op-
tic neuropathies - disease mechanisms and therapeutic strate-
gies. Prog Retin Eye Res. 2011;30(2):81–114. doi:10.1016/j.
preteyeres.2010.11.002.
3. Carelli V, La Morgia C, Iommarini L, et al. Mitochondrial
optic neuropathies: how two genomes may kill the same
cell type? Biosci Rep. 2007;27(1-3):173–184. doi:10.1007/
s10540- 007- 9045- 0.
40 AMERICAN JOURNAL OF OPHTHALMOLOGY
A delayed neuronal damage and resulting GC-IPL thin-
ning in these regions might implicate that idebenone has
a better effect in subjects with a greater amount of dys-
functional retinal ganglion cells that have not yet atro-
phied in macular regions outside the papillomacular bun-
dle. Therefore, the stronger association between 2-year vi-
sual improvement and structural damage in the superior and
temporal parafoveal regions might suggest that structural
parameters in these areas are a better reflection of expected
visual outcome in LHON patients treated with idebenone.
Our study does have some limitations including its sam-
ple size. This study, however, does represent the largest set
of OCT data in a somewhat rare study cohort of LHON pa-
tients treated with idebenone. Importantly, spontaneous re-
covery is rare but has been occasionally reported in LHON
subjects.27 , 29 Therefore, we are not able to exclude that vi-
sual improvement in a number of patients was attributable
to spontaneous amelioration (ie, natural history) rather
than treatment effect. Moreover, our study cohort included
patients with childhood-onset LHON, which is known to
be characterized by an overall better prognosis and peculiar
characteristics.24 , 25 However, our results accounted for fac-
tors that are known to be associated with spontaneous re-
covery and better visual prognosis, including age, gene mu-
tation, and sex.24 , 25 , 27 , 29
In conclusion, this study provides OCT biomarkers as-
sociated with long-term (ie, 2-year) visual outcomes in
patients with LHON treated with idebenone therapy in
the first year after disease onset. Thinning of the GC-IPL
in the superior and temporal parafoveal regions was as-
sociated with worse long-term visual outcomes in these
patients. Therefore, topographic macular structural mea-
sures, if replicated in future studies, may prove to be useful
biomarkers for adapting idebenone therapy and monitoring
the efficacy of therapeutic approaches in LHON patients.
4. Newman NJ. Hereditary optic neuropathies: from the
mitochondria to the optic nerve. Am J Ophthalmol.
2005;140(3):517–523. doi:10.1016/j.ajo.2005.03.017.
5. Man PYW, Griffiths PG, Brown DT, Howell N, Turnbull DM,
Chinnery PF. The epidemiology of Leber hereditary optic neu-
ropathy in the North East of England. Am J Hum Genet.
2003;72(2):333–339. doi:10.1086/346066.
6. Hwang TJ, Karanjia R, Moraes-Filho MN, et al. Natural his-
tory of conversion of Leber’s hereditary optic neuropathy: a
prospective case series. Ophthalmology. 2017;124(6):843–850.
doi:10.1016/j.ophtha.2017.01.002.
7. Sadun AA, Win PH, Ross-Cisneros FN, Walker SO,
Carelli V. Leber’s hereditary optic neuropathy differentially
MARCH 2023
 affects smaller axons in the optic nerve. Trans Am Ophthalmol
Soc. 2000;98:223–232. discussion 232-235. Accessed August
6, 2013. http://www.pubmedcentral.nih.gov/articlerender.
fcgi?artid=1298228&tool=pmcentrez&rendertype=abstract .
8. Pan BX, Ross-Cisneros FN, Carelli V, et al. Mathematically
modeling the involvement of axons in Leber’s hereditary op-
tic neuropathy. Invest Ophthalmol Vis Sci. 2012;53(12):7608–
7617. doi:10.1167/iovs.12-10452.
9. Sadun AA, La Morgia C, Carelli V. Mitochondrial optic neu-
ropathies: our travels from bench to bedside and back again.
Clin Exp Ophthalmol. 41(7):702-712. doi:10.1111/ceo.12086
10. Barboni P, Carbonelli M, Savini G, et al. Natural history of
Leber’s hereditary optic neuropathy: longitudinal analysis of
the retinal nerve fiber layer by optical coherence tomography.
Ophthalmology. 2010;117(3):623–627. doi:10.1016/j.ophtha.
2009.07.026.
11. Klopstock T, Yu-Wai-Man P, Dimitriadis K, et al. A random-
ized placebo-controlled trial of idebenone in Leber’s hered-
itary optic neuropathy. Brain. 2011;134(Pt 9):2677–2686.
doi:10.1093/brain/awr170.
12. Giorgio V, Petronilli V, Ghelli A, et al. The effects of
idebenone on mitochondrial bioenergetics. Biochim Biophys
Acta. 2012;1817(2):363–369. doi:10.1016/j.bbabio.2011.10.
012.
13. Kutz K, Drewe J, Vankan P. Pharmacokinetic properties and
metabolism of idebenone. J Neurol. 2009;256(Suppl):31–35.
doi:10.1007/s00415- 009- 1006- z.
14. Carelli V, La Morgia C, Valentino ML, et al. Idebenone
treatment in Leber’s hereditary optic neuropathy. Brain.
2011;134(Pt 9):e188. doi:10.1093/brain/awr180.
15. Klopstock T, Metz G, Yu-Wai-Man P, et al. Persistence of the
treatment effect of idebenone in Leber’s hereditary optic neu-
ropathy. Brain. 2013;136(Pt 2):e230 -e230. doi:10.1093/brain/
aws279.
16. Barboni P, Savini G, Valentino ML, et al. Retinal nerve fiber
layer evaluation by optical coherence tomography in unaf-
fected carriers with Leber’s hereditary optic neuropathy mu-
tations. Ophthalmology. 2005;112(1):127–131. doi:10.1016/j.
ophtha.2004.06.034.
17. Carelli V, Carbonelli M, de Coo IF, et al. Interna-
tional consensus statement on the clinical and therapeu-
tic management of Leber hereditary optic neuropathy. J
Neuro-Ophthalmol. 2017;37(4):371–381. doi:10.1097/WNO.
0000000000000570.
18. Balducci N, Savini G, Cascavilla ML, et al. Macular nerve fi-
bre and ganglion cell layer changes in acute Leber’s hereditary
optic neuropathy. Br J Ophthalmol. 2015;100(9):1232–1237.
doi:10.1136/bjophthalmol- 2015- 307326.
VOL. 247 OCT BIOMARKERS IN LHON TREATED WITH IDEBENONE
19. Holladay JT. Proper method for calculating average vi-
sual acuity. J Refract Surg. 1997;13(4):388–391. doi:10.3928/
1081- 597X- 19970701- 16.
20. Borrelli E, Abdelfattah N, Uji A, Nittala M, Boyer DS,
Sadda SR. Postreceptor neuronal loss in intermediate age-
related macular degeneration. Am J Ophthalmol. 2017;181:1–
11. doi:10.1016/j.ajo.2017.06.005.
21. Mwanza JC, Oakley JD, Budenz DL, Chang RT, Knight OJ,
Feuer WJ. Macular ganglion cell–inner plexiform layer: auto-
mated detection and thickness reproducibility with spectral
domain–optical coherence tomography in glaucoma. Inves-
tig Opthalmology Vis Sci. 2011;52(11):8323. doi:10.1167/iovs.
11-7962.
22. Kim KE, Jeoung JW, Park KH, Kim DM, Kim SH. Diagnostic
classification of macular ganglion cell and retinal nerve fiber
layer analysis: differentiation of false-positives from glaucoma.
Ophthalmology. 2015;122(3):502–510. doi:10.1016/j.ophtha.
2014.09.031.
23. Triolo G, Rabiolo A, Shemonski ND, et al. Optical co-
herence tomography angiography macular and peripapillary
vessel perfusion density in healthy subjects, glaucoma sus-
pects, and glaucoma patients. Invest Ophthalmol Vis Sci.
2017;58(13):5713–5722. doi:10.1167/iovs.17-22865.
24. Barboni P, Savini G, Valentino ML, et al. Leber’s hereditary
optic neuropathy with childhood onset. Invest Ophthalmol Vis
Sci. 2006;47(12):5303–5309. doi:10.1167/iovs.06-0520.
25. Majander A, Bowman R, Poulton J, et al. Childhood-
onset Leber hereditary optic neuropathy. Br J Ophthalmol.
2017;101(11):1505–1509. doi:10.1136/bjophthalmol-2016-
310072.
26. Carbonelli M, La Morgia C, Romagnoli M, et al. Captur-
ing the pattern of transition from carrier to affected in Leber
hereditary optic neuropathy. Am J Ophthalmol. 2022;241:71–
79. doi:10.1016/j.ajo.2022.04.016.
27. Wang D, Liu HL, Du YY, et al. Characterisation of
thickness changes in the peripapillary retinal nerve fibre
layer in patients with Leber’s hereditary optic neuropa-
thy. Br J Ophthalmol. 2021;105(8):1166–1171. doi:10.1136/
bjophthalmol- 2020- 316573.
28. Balducci N, Savini G, Cascavilla ML, et al. Macular nerve fi-
bre and ganglion cell layer changes in acute Leber’s hereditary
optic neuropathy. Br J Ophthalmol. 2016;100(9):1232–1237.
doi:10.1136/bjophthalmol- 2015- 307326.
29. Yu-Wai-Man P, Newman NJ, Carelli V, et al. Natural history of
patients with Leber hereditary optic neuropathy-results from
the REALITY study. Eye (Lond). 2022;36(4):818-826. doi:10.
1038/s41433- 021- 01535- 9.
41