Painless Gradual Visual Loss with a Disc That Looks Different
A 58-year-old woman presents with 6 months of painless, progressive blurring in the left eye. Acuity is 6/6 right and 6/36 left. She notes colours look washed out on the left and that bright lights seem harsh. Pupils: left afferent defect detected with reverse neutral-density filter and with the swinging torch test, though the resting anisocoria is under 1 mm. Fundus: right disc crowded, small cup; left disc also small and crowded, but there is a subtle sector of pallor superotemporally and a few dilated capillaries on the disc surface. Intraocular pressure is 15 mmHg both eyes, gonioscopy open, and there is no relative hypertension. Humphrey 24-2 shows a superior arcuate-like defect in the left eye only. MRI brain and orbits with contrast is reported as normal.
1. Construct a differential diagnosis and explain how the clinical findings argue for or against each entity.
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The key discriminators are laterality, disc appearance, the afferent pupillary defect, and the imaging.
Leber hereditary optic neuropathy (LHON). Strongly favoured. Painless subacute sequential loss, dyschromatopsia out of proportion to acuity, and a small crowded (hyperaemic then atrophic) disc fit. The 'normal' MRI is expected. The sector pallor and telangiectatic capillaries are classic. Against: age 58 is older than the typical male teen/young adult peak, but female and older onset occur, and penetrance is incomplete.
Compressive optic neuropathy (meningioma, aneurysm). The normal contrast MRI makes this much less likely, though a small planum sphenoidale or canalicular lesion can be missed on non-dedicated sequences; a dedicated thin-slice orbital protocol would be needed if suspicion persists.
Non-arteritic anterior ischaemic optic neuropathy. Against: no acute altitudinal field loss, no disc oedema at presentation, and progression over 6 months is atypical. The small cup-to-disc ratio is a risk factor, but the tempo is wrong.
Glaucomatous optic neuropathy. Against: normal pressures, open angles, no cupping, and an afferent defect with profound dyschromatopsia is unusual for glaucoma.
Toxic/nutritional optic neuropathy. Possible but usually bilateral and symmetrical; ask about B12, folate, alcohol, and ethambutol.
Next steps: Humphrey 10-2 for central field, OCT retinal nerve fibre layer and ganglion cell layer, and genetic testing for the three primary mtDNA mutations (m.11778G>A, m.3460G>A, m.14484T>C).
2. The patient asks about her other eye and about her children. How do you counsel her, and what does the mitochondrial genetics mean practically?
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Counsel honestly that LHON is a bilateral disease, and that the second eye becomes involved in most patients, typically within weeks to months, though the interval can be up to years. Because her second eye is currently asymptomatic, she should be warned to check each eye daily and to report any blurring or colour change immediately, as early presentation may allow discussion of investigational therapies.
Genetics: LHON is caused by mitochondrial DNA point mutations, so it is transmitted maternally. All of her children will inherit her mitochondria, but only those with a high heteroplasmic mutant load are at risk. Sons never transmit the mutation; daughters transmit to all their children. Penetrance is incomplete and sex-biased - roughly half of male carriers and about one in ten female carriers lose vision, modulated by age, smoking, alcohol, and other genetic factors. So her sons face a higher risk than her daughters, but no child is certain to be affected.
Practical advice: avoid tobacco and excess alcohol, maintain a healthy diet, and be cautious with agents that stress mitochondrial function. Genetic counselling should be offered to her and to her daughters. Discuss that the visual prognosis varies by mutation, being most favourable for the m.14484T>C mutation. There is no proven treatment, though idebenone is used in some centres; she should understand the evidence is limited. Document the discussion and arrange follow-up with repeat OCT to detect subclinical second-eye involvement.