Leber Hereditary Optic Neuropathy (LHON)

Etiology

LHON was the first disease to be associated with mtDNA point mutations and is, therefore, maternally inherited. Whereas both the father and the mother contribute to the nuclear portion of the zygote, the mother's ovum is virtually the sole provider of the zygote's cytoplasmic contents, which contains several hundred intracytoplasmic mitochondria. "Maternal inheritance" refers to the transmission of the mitochondrial genome from a mother to all her children, with no paternal mtDNA contribution. The mitochondria generate the cellular energy necessary for normal cellular function and maintenance; thus, those cells in tissues particularly reliant on mitochondrial energy production (eg, the central nervous system, including the optic nerve, retinal pigment epithelium, and extraocular muscles) will contain more mitochondria. If a new mutation occurs in the mtDNA and the proportion of mutant mtDNA exceeds a certain tissue-specific threshold, however, the wildtype mtDNA is no longer able to compensate to sustain normal cellular function, and the disease phenotype is expressed.[5][6]

In LHON, mitochondrial mutations affect complex I subunit genes in the respiratory chain leading to selective degeneration of retinal ganglion cells (RGCs) and optic atrophy within a year of disease onset. Three common mtDNA mutations (m.11778G.A>MTND4, m.3460G.A>MT-ND1, m.14484T.C>MT-ND6) account for about 90% of clinical cases in multiple and ethnically divergent pedigrees. These mutations are absent or very rare among normal controls.

Except in rare cases of de novo occurrence of a primary LHON mutation, an mtDNA mutation will be present in all maternally related family members of patients with LHON, even though many will never become symptomatic. Hence, whereas the presence of an mtDNA mutation is necessary for phenotypic expression, it may not be sufficient. Since the amount of mutant mtDNA in the optic nerves of individuals at risk may differ, the degree of tissue heteroplasmy might help explain the variable phenotypes seen in patients whose mitochondrial genotypes measured in blood alone appear similar.[7]

Other genetic factors may influence the phenotypic expression of LHON, such as nuclear genes that regulate the expression of mitochondrial genes. Because of the male predominance of visual loss in LHON, an X-linked vision loss susceptibility gene has been hypothesized. Recent studies have identified a high-risk haplotype at Xp21 associated with a 35-fold increase in vision loss among patients with the 11778 and 14484 mutations.

Immunologic factors have also been suggested, mainly to explain the association of LHON with multiple sclerosis. However, studies have shown the HLA-DR locus is not a major genetic determinant for the development of visual loss.

Internal and external environmental factors may also play a role. Systemic illnesses, nutritional deficiencies, trauma, medications, or toxins that stress or directly or indirectly inhibit mitochondrial metabolism have been proposed to affect the phenotypic expression of the disease.[8][9]

Epidemiology

LHON is estimated to be the most frequent mitochondrial disease, with a prevalence ranging from 1 in 27,000 in North East England to 1 in 45,000 in a meta-analysis of reports in the European population. It has a strong male preponderance (80% to 90%), and the usual age at onset is between 15 to 35 years.

History and Physical

The subset of macular RGCs providing axons for the papillomacular bundle and serving central vision is affected first and preferentially, resulting in a visual loss that typically begins painlessly and centrally in one eye. Some patients complain of a sensation of mist or fog obscuring their vision, whereas others note mild central fading of colors. The second eye is usually affected weeks to months later. In around 97% of patients, the second eye is affected within one year.

Most patients deteriorate to acuities worse than 20/200. Color vision is affected severely, often early in the course, but rarely before the significant visual loss. Pupillary light responses may be relatively preserved when compared with the responses in patients with optic neuropathies from other causes.

Visual field defects are typically central or cecocentral. The scotomas may be relative during the early stages of vision loss but rapidly become large and absolute, measuring at least 25° to 30° in diameter. A sudden appearance of the scotoma is not uncommon. Unaffected eyes may show subtle cecocentral scotomas only to red test objects or as a mild depression on central automated perimetry. Fundus can look normal in 20% to 40% of cases in the active stage of the disease, which can delay diagnosis.[10]

There are specific funduscopic abnormalities that can be seen in patients with LHON, especially during the acute phase when they present with visual loss. These include hyperemia of the optic nerve head, dilation and tortuosity of optic nerve head vessels, retinal and disc hemorrhages, macular edema, exudates, retinal striations, and obscuration of the disc margins in some cases.  

A triad of signs pathognomonic for LHON is circumpapillary telangiectatic microangiopathy, swelling of the nerve fiber layer around the disc (pseudoedema), and absence of leakage from the disc or papillary region on fluorescein angiography (distinguishing LHON from truly edematous discs).

The "classic" LHON ophthalmoscopic appearance may help suggest the diagnosis if recognized in patients or their maternal relatives; however, its absence, even during the period of acute visual loss, does not exclude the diagnosis of LHON. As the disease progresses, the telangiectatic vessels disappear, and the pseudoedema of the disc resolves. Perhaps because of the initial hyperemia, the optic discs of patients with LHON may not appear pale for some time. This feature, coupled with the relatively preserved pupillary responses and the lack of pain, has misdiagnosed nonorganic visual loss in some LHON patients. Eventually, however, optic atrophy with nerve fiber layer dropout most pronounced in the papillomacular bundle will become apparent on the examination.

Recent optical coherence tomography (OCT) and histopathology studies have substantiated a precise pattern in retinal nerve fiber layer (RNFL) loss, disease progression, and natural history. In particular, loss of macular RGCs precedes the clinical disease onset. Clinical stages of LHON can be defined according to the time of onset and clinical investigations. In the asymptomatic phase (mutation carriers), the fundus examination may be normal, or there may be recognizable changes and OCT measurements, including vascular abnormalities (microangiopathy and telangiectatic vessels), hyperemia of the optic disc, and RNFL swelling (pseudoedema) that is detected by OCT as increased thickness of the RNFL in the inferior and temporal quadrants.

The subacute phase is defined as 6 months from the onset of clinical symptoms. As central scotoma develops and central visual acuity starts to deteriorate rapidly, it is at this time that most patients will usually seek medical attention. Visual acuity usually stabilizes within 4 to 6 months of the onset of symptoms. The dynamic phase is from 6 months to 1 year from the onset of symptoms. Clinical metrics such as visual fields and OCT measurements usually plateau one year after onset. At this point, the dynamic phase ends with a transition into the chronic stage of the disease.

There can be variations from the classic clinical course, with some patients demonstrating a slowly progressive variant, and the progression of visual loss is slow and gradual rather than sudden. In the childhood disease variant, the onset of visual loss happens in patients younger than 12 years of age, and in the rare late-onset variant, visual loss occurs after 65 years of age.

Associated Findings

In most patients with LHON, visual dysfunction is the only significant manifestation of the disease. However, some pedigrees have members with associated cardiac conduction abnormalities. "Leber's plus" is defined as the presence of minor neurologic abnormalities in patients with LHON. Furthermore, disease clinically indistinguishable from multiple sclerosis may occur in families with LHON, and an underlying LHON mutation may worsen the outcome of optic neuritis in a patient with multiple sclerosis.

Evaluation

Clinicians should perform the following clinical investigations in all patients suspected of having LHON:

• Visual acuity
• Color vision
• Fundus examination
• Visual field perimetry
• OCT imaging

For childhood disease, they should measure the optic disc vertical diameter on OCT. A larger diameter may be associated with a better visual prognosis. For late-onset LHON cases, it is important to consider toxic exposure (eg, smoking, drinking, and environmental factors).[11][12][13]

The tests to determine optic nerve function, like visually evoked potential (VEP), and retinal status, like electroretinogram (ERG), may be abnormal. The earliest VEP findings are prolonged latency and abnormal morphology of waves. The latency is further prolonged as the disease progresses. Unaffected carriers can also reveal ERG changes like a decrease in amplitude of N95 waveform even in an asymptomatic state. Thus, these modalities help in long-term monitoring.[14]

When any extraocular features are present, an MRI of the brain should be performed. ECG should also be ordered for all patients with LHON, as it may reveal cardiac conduction abnormalities.

Treatment / Management

All patients who harbor an LHON mutation should be strongly advised to:

• Discontinue smoking
• Avoid excessive alcohol intake
• Avoid exposure to solvents and other fumes
• Take daily vitamin supplements.

In 2017, an international consensus statement on the clinical and therapeutic management of LHON was published. Of note, it concluded that prognostic factors should not affect management.

Idebenone is a short-chain synthetic analog of ubiquinone that supports mitochondrial adenosine triphosphate (ATP) synthesis and has antioxidant properties. It is recommended that idebenone be started as soon as possible (at 900 mg/day) in patients with disease still in the subacute/dynamic phase. Treatment should be continued for at least 1 year to assess the therapeutic response. A clinically relevant response (recovery of vision) to treatment should be defined according to an improvement of 2 lines of best-corrected visual acuity (BCVA) on Early Treatment Diabetic Retinopathy Study (ETDRS) charts (or from off-chart to on-chart) and an automated visual field test (mean deviation). Once a favorable clinically relevant outcome has been confirmed, the treatment should be continued for another year.

Follow-up

The ideal recommended frequency of follow-up is approximately every 3 months for subacute and dynamic cases, then approximately every 6 months during the second year after the disease onset, and once a year after that.

Differential Diagnosis

The differential diagnoses for LHON include other optic neuropathies such as:

• Demyelinating optic neuritis
• Neuromyelitis optica spectrum disease
• Toxic optic neuropathy
• Compressive optic neuropathy

In addition, maculopathies and nonorganic vision loss should be considered. Clinical history, symptoms, and imagining should be utilized to differentiate LHON from these other optic neuropathies.

Prognosis

In most patients with LHON, the visual loss remains profound and permanent. However, some spontaneous recovery may occur gradually over 6 months to 1 year after an initial visual loss or may suddenly occur up to 10 years after onset. It may take the form of a gradual clearing of central vision or be restricted to a few central degrees, resulting in a small island of vision within a large central scotoma, which can be demonstrated on visual field testing.[15]

A good visual outcome is strongly correlated with a young age of onset. Most patients whose onset is before 20 years have a final visual acuity better than 20/80. Furthermore, the particular mtDNA mutation also influences prognosis, with the 11778 mutations carrying the worst prognosis for vision (only 4% reported spontaneous recovery) and the 14484 mutations the best (37% to 65% reported spontaneous recovery). The ultimate visual acuities in patients with the 14484 mutations are significantly better than those with the 11778 and 3460 mutations. Recurrences of vision loss are rare among patients, both with and without visual recovery.

Complications

Most patients with LHON will develop optic atrophy at the end of one year. These patients suffer from marked visual impairment in their productive years of life that is irreversible.

The extent of final visual recovery depends greatly on the patient's mutational status, with G11778A carrying the worst overall prognosis. There is also some evidence that patients with the T14484C mutation are more likely to show improvement if the visual loss occurs before the age of 20.