Question 1: How would you describe the different clinical stages of LHON?

Clinical stages of LHON can be defined as follows,according to time from onset and clinical investigations:

0. Asymptomatic (mutation carriers)

1. Subacute (-6 months from onset)

2. Dynamic (6–12 months)

3. Chronic (-12 months)

The following clinical variants also can be considered:

1. Slowly progressive, defined according to patients’ char-

acteristics independently from time since disease onset

2. Childhood disease, that is, onset in a patient younger

than 12 years

3. Late onset, that is, onset in a patient older than 45 years

Question 2: Are there any clinical characteristics,algorithms, or investigations to reach a rapid diagnosis of LHON?

Diagnosis of LHON can usually be made based on patient and family clinical history as well as baseline investigations

including neuro-ophthalmological examination and mtDNA genetic testing.

There was a strong consensus.                      

Question 3: Typically, how long does it take from symptom onset to confirmation of diagnosis?

“It can take months to reach a confirmed diagnosis.”

There was a strong consensus.

Question 4: What are the main differential diagnoses?

1. Other optic neuropathies especially optic neuritis (neu-

romyelitis optica), toxic, metabolic, and compressive optic neuropathies

2. Maculopathies

3. Nonorganic visual loss

If further extraocular features are present, consider LHON “Plus”, including LHON/MS-like variant. Consider performing appropriate investigations including brain MRI and laboratory studies.

There was strong consensus.

Question 5: How would you assess a patient’s prognosis?

Does this impact your management?

In LHON, positive prognostic factors are as follows:

1. Younger age

2. Type of mutation (14484/ND6)

However, prognostic factors do not affect management.

There was a strong consensus.

Question 6: Before initiating any treatment, what baseline assessments do you usually perform?

The following examinations should be performed before starting any treatment:

1. Visual acuity (Early Treatment Diabetic Retinopathy Study [ETDRS] charts)

2. Automated visual field test

3. OCT (optic nerve head and RNFL analysis, and macular

ganglion cell analysis)

There was a strong consensus.

Question 7: In subacute/dynamic (,6 months, 6–12 months) patients, at which stage of disease would you

ideally start 900 mg/day treatment?

“Idebenone should be started as soon as possible at 900 mg/day in patients with disease less than 1 year.”

There was a strong consensus with 1 participant in partial disagreement.

Question 8: In chronic cases, do you consider treatment?

There is not enough evidence to recommend treatment in chronic patients between 1 and 5 years (after the second eye onset), and no evidence to recommend treatment in chronic patients>5 years (after the second eye onset). There was a strong consensus, but 2 participants disagreed.

Question 9: What is your suggested frequency of follow-up, would it differ by stage?

The ideal frequency of follow-up is as follows:

1. Approximately every 3 months for subacute and dynamic cases

2. Approximately every 6 months for the second year

3. Once a year thereafter

There was a strong consensus.

Question 10: How would you define a clinically relevant response (recovery of vision) to treatment?

Response should be defined according to:

1. Improvement of 2 lines of BCVA on ETDRS charts (or

from off-chart to on-chart)

2. Automated visual field test (mean deviation)

There was strong consensus with 1 participant in partial disagreement.

Question 11: How long would you treat at 900 mg/day to assess response?

“In subacute/dynamic patients, treatment at 900 mg/day should be continued for at least 1 year to assess the start of therapeutic response or until a plateau in terms of improvement is reached.”

There was strong consensus.

Question 12: Once you have confirmed a favorable clinically relevant outcome, for how long after plateau would you continue treatment?

“One year.”

There was strong consensus, but 2 participants partially disagreed and 1 participant disagreed.

Question 13: If you treat a chronic patient, for how long

you would continue treatment?

“One year.”

Consensus was not reached. Five participants did not vote.

Question 14: For chronic patients, once you have confirmed a favorable clinically relevant outcome, for how long after plateau would you continue treatment?

“One year.”

Not voted because of lack of consensus on statement 13.

Question 15: What assessments do you perform to evaluate response during maintenance phase?

The following examinations should be performed to assess

response during maintenance phase:

1. Best-corrected visual acuity

2. Automated visual field test

There was strong consensus.

Question 16: Do you consider a maintenance dose also for nonresponders?

“In nonresponders, the maintenance dose can be 300 mg/day.”

There was strong disagreement, with 1 participant in agreement.

Question 17: Is it necessary to perform genetic screening for LHON mutation in all maternally related family members?

“No.”

There was a strong consensus.

Question 18: Should all maternally related relatives be clinically screened?

Yes.

Eleven participants disagreed that all maternally related relatives should be screened. There was strong disagreement with 2 participants in agreement.

Question 19: Would you consider treating them?

“Currently, treatment is not recommended for relatives of

a LHON patient, but lifestyle counseling is recommended.”

There was a strong consensus.

Question 20: Are you aware of any algorithm or predictive risk factors that could be used to assess the risk of becoming symptomatic?

Currently, there is no clinical prognostic factor that can be used.

There was strong consensus, with 1 participant in disagreement.

The jury unanimously endorsed the final version of all questions and statements (Table 1).