Susan Whitmer
Margaret E. M. Scott

BASICS

DESCRIPTION

• Leber hereditary optic neuropathy (LHON) is usually a unilateral acute or subacute painless profound visual loss (20/200 or worse), followed in weeks to months by loss of vision in the fellow eye (50% of cases in 2–3 months).

• It usually starts as a central scotoma that becomes larger and obscures vision.

• It is caused by optic nerve dysfunction resulting from maternally inherited mitochondrial DNA (mtDNA) mutations.

• Predominantly in males, mean onset is 18–35 years of age (80–90%), but the age of onset can be early or late in life.

EPIDEMIOLOGY

Incidence

Estimated to be 1:30,000 to 1:50,000 in European populations

Prevalence

1:8,500 in the USA

RISK FACTORS

• Maternal carrier with known mtDNA mutation

• Excessive smoking and alcohol consumption have been linked to higher rates of visual loss in susceptible individuals.

Genetics

• Maternally inherited mtDNA mutation

• “Primary mutations” (single mutation sufficient to cause disease) are G3460A, G11778A, and T14484C accounting for 95% of LHON cases.

• G11778A accounts for 50%.

• >18 mutations have been reported.

• Many sporadic and singleton cases have been reported.

• Risk of visual loss from all mutations is 46% for men and 11% for women.

• ∼15% of LHON patients demonstrate heteroplasmy (mutant and normal mtDNA will coexist); this may explain the disease threshold with more mutant alleles leading to higher rates of disease and transmission in susceptible individuals.

• Although the rates of homoplasmy or heteroplasmy are measured, they may not directly correlate to levels at the optic nerve.

GENERAL PREVENTION

• Avoid excessive use of tobacco and alcohol if there is a known maternal family member with the disease or carrier state.

• Avoid cyanide-containing products, medications with mitochondrial toxicity, and environmental toxins especially in the acute phase of the disease.

PATHOPHYSIOLOGY

• Each mtDNA mutation affects a subunit of NADH dehydrogenase in the oxidative phosphorylation pathway, which supplies energy to cells.

– It is thought that these mutations cause LHON because of the increased energy requirement of the optic nerve.

– The leading theory is that disease results when some individually determined minimal energy requirement threshold is breeched.

ETIOLOGY

First described in 1871 by Theodor Leber, Professor of Ophthalmology at the University of Gottingen

COMMONLY ASSOCIATED CONDITIONS

• Visual dysfunction is usually the only manifestation of the disease. However, cardiac conduction abnormalities and other conditions can rarely manifest.

– Preexcitation syndromes, Wolf–Parkinson–White, Lown–Ganong–Levine, and prolonged QT interval (rare)

– Palpitations, syncope, and sudden death have also been reported (rare)

– Additional neurologic abnormalities have also been reported (rare)

– Deafness, dystonia, hyperreflexia, cerebellar ataxia, tremor, movement disorders, muscle wasting, gaze evoked nystagmus

DIAGNOSIS

HISTORY

• At onset most patients complain of painless central vision loss in one eye.

• Patients may complain of the sensation of a blur that obscures vision, or loss of color perception.

• Patients may have associated headache, eye discomfort, flashes of light, color disturbance, limb paresthesias, or dizziness.

• Pedigree analysis may reveal maternal male relatives with profound visual loss.

PHYSICAL EXAM

• Color vision often affected earlier than visual acuity

• Central visual field defects

• Decreased visual acuity usually <20/200

• The classic signs on exam are circumpapillary telangiectatic microangiopathy, nerve fiber layer swelling around the disc, and absence of leakage from the disc on fluorescein angiography; however, these signs may not be seen.

• The classic LHON findings may assist in diagnosis, but their presence is not required for diagnosis.

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

Genetic testing for mtDNA mutations (see the “Genetics” section)

Follow-up & special considerations

• EKGs can reveal cardiac conduction abnormalities present in some forms of LHON.

• CSF analysis is normal; however, a Leber-plus disease has been described in patients with a multiple sclerosis-like syndrome.

• Formal color testing with D-15 panel and Farnsworth Munsell 100 Hue tests can show optic nerve dysfunction before visual loss.

• Pattern reversal visual evoked potentials (VEPs) may be absent or show prolonged latencies and decreased amplitudes.

Imaging

Initial approach

• Fluorescein angiography can confirm LHON funduscopic features and lack of disc leakage.

• Orbital ultrasound, CT, and MRI can show distended optic nerve sheaths.

Follow-up & special considerations

• Patients with LHON and carriers may show impaired mitochondrial metabolism within limb muscle and occipital lobes on Phosphorus-31 MRI.

• Abnormal lactate production with exercise may be seen in both LHON patients and carriers.

Diagnostic Procedures/Other

Genetic testing

Pathological Findings

Muscle biopsies fail to show morphologic changes of mitochondria and are therefore thought to have limited value.

DIFFERENTIAL DIAGNOSIS

• Other inherited optic neuropathies: Dominant optic neuropathy, Wolfram syndrome

• Acquired optic neuropathies: Tobacco–alcohol amblyopia

• Multiple sclerosis

• Leber’s-Plus

TREATMENT

MEDICATION

First Line

As of 2010 there is no evidence supporting any intervention in the management of mitochondrial disorders.

Second Line

Studies are ongoing in gene therapy.

ADDITIONAL TREATMENT

General Measures

Four main categories

• Vitamins and cofactors (Coenzyme Q10(CoQ10)) (doses up to 3000 mg daily, typically <400 mg daily), folic acid, vitamin B12, thiamine, riboflavin (100 mg daily), l-carnitine (3 g daily), and creatine (3 g b.i.d.)

• Electron acceptors (vitamin C (4 g daily), menadiol (40 mg daily))

• Free radical scavengers (CoQ10, idebenone (75 mg/kg daily), alpha-lipoic acid (600 mg daily), and vitamin E (400 IU daily))

• Inhibitors of toxic metabolites (dichloroacetate DCA)

Issues for Referral

Patients suspected of having LHON should be followed by a neuro-ophthalmologist.

SURGERY/OTHER PROCEDURES

• Optic nerve sheath decompression showed no improvement.

• Older literature suggested that craniotomy with lysis of chiasmal arachnoid adhesions resulted in visual improvement.

– This study has not been repeated and the distance from the site of involvement, at the retinal ganglion cells, makes it difficult to support in light of known spontaneous recovery.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

Frequent follow-up for visual acuity can indicate regression of the disease.

DIET

• A balanced diet rich in antioxidants, for example, vitamins A, C, and E, selenium, and zinc, is recommended.

• Patients have been treated with antioxidant dietary supplements.

PATIENT EDUCATION

• Low vision assistance can help patients use vision that remains intact, usually peripheral.

• Genetic counseling is crucial once the diagnosis has been made. This affords understanding of disease transmission. It is critical for female carriers to be identified and educated.

PROGNOSIS

• Rates of spontaneous recovery vary by mutation.

• Patients with 14484 have 37–71% chance of some recovery.

• 11778 typically shows the worst prognosis, spontaneous recovery 4%.

• Other favorable prognostic factors are age of onset <20 (better <10) and larger optic disc vertical diameter on OCT.

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