LESIONS

A Guide to Localisation in Neurology

Painful visual loss

What is the lesion?

The optic nerve can be affected by virtually any of the major categories of lesion. To answer the question of 'What?', we will follow the usual approach and consider timing - the best predictor of the lesion type.

This patient went from having normal vision to blurring and then near-blindness in the left eye all within the space of a few days - an acute tempo. In addition he had pain, which is seen in various optic nerve diseases but not others - this can also help. The other features such as dyschromatopsia, disc swelling and RAPD do not help much - they can be seen in many optic neuropathies.

Vascular damage - ischaemic optic neuropathy - is usually due to microvascular changes associated with cardiovascular disease, particularly diabetes and hypertension, but it can also be seen with vasculitis, so we classify ischaemic optic neuropathy into arteritic and non-arteritic forms. The management differs - the arteritic is very dangerous and warrants aggressive treatment. Both of these cause sudden-onset monocular blindness, which doesn't fit this case. Pain is not usually seen in non-arteritic forms, though there is often headache in arteritic ischaemic optic neuropathy - caused by giant cell arteritis (GCA), which features temporal headache and sometimes pains around the eye.

At the opposite end of the spectrum it's unlikely that this is a tumour - it would have to be very rapidly growing. The main tumours of the optic nerve or its sheath grow slowly. Gliomas are seen mainly in children under 10, are painless, and also tend to cause proptosis. Malignant gliomas do exist, mainly in adults, and can be painful and more rapid, so this is possible, but uncommon. Optic sheath meningioma is mainly seen in women aged 50-60, and progresses slowly; a late clue is tortuous dilated vessels on the disc (optociliary shunts). Other tumour types are rare and most grow slowly, for example schwannomas and haemangioblastomas. Lymphomas can grow in the orbit and compress the nerve though they are typically quite slow-growing; more aggressive types do exist however and grow more quickly.

We need to think about acute causes that lead to blindness in days and cause pain.

Optic neuritis can be seen due to many causes. It is a very likely candidate for this patient's presentation. The tempo - onset over days - is typical, and the other features are consistent- pain on eye movement is frequent in optic neuritis and quite suggestive of this condition.

However, what is not typical is the extreme visual loss. Most optic neuritis-related visual loss doesn't get to this level, and is usually milder. This would place the patient in the category of having atypical optic neuritis. Other markers suggesting an atypical form include bilateral disease, more sustained progression to nadir over several weeks, or lack of recovery - typical forms peak quickly and mostly recover with a good prognosis. Lack of pain is another atypical marker.

Several of these atypical markers can't be determined yet as it's too early to know, but the intensity of the attack does put him in an atypical category, which has implications for considering causes.

A major cause of optic neuritis is multiple sclerosis and many people who develop optic neuritis are at risk of this developing in future. The attacks are not usually this severe however.

Two antibody-mediated autoimmune diseases are the major causes of atypical optic neuritis. Neuromyelitis optica (NMO), caused by anti-aquaporin 4 antibodies, causes severe retrobulbar optic neuritis, typically with longitudinally-extensive lesions that may span several nerve segments and reach the chiasm. MOG antibody disease (MOGAD) also causes severe attacks but typically affect the very anterior nerve, with marked fundus changes. Both can cause bilateral disease, either simultaneously or one after the other - sometimes rapidly involving the second eye. Prompt recognition is crucial in order to prevent further damage - whether to the other eye or other parts of the nervous system, especially the spinal cord.

Other inflammatory diseases are linked to optic neuritis including sarcoidosis, systemic lupus erythematosus (which is often linked to NMO), the paraneoplastic anti-CV2 (i.e. anti-CRMP5) syndrome, and anti-GFAP astrocytopathy - although it is rare in the latter, whereas asymptomatic bilateral optic disc oedema is much commoner.

There are many infectious diseases which can be associated with optic nerve damage. Mechanisms can include direct inflammatory effects on the nerve (i.e. infectious optic neuritis), vascular inflammation (e.g. invasive sino-orbital Aspergillus infections and with Varicella zoster-associated vasculopathy), and extrinsic compression and strangulation of the nerve with meningeal inflammation. Infection-related raised ICP can also cause papilloedema.

Some causes might have clinically evident clues - for example a macular rash in syphilis (a classic cause of optic neuritis), or a more profound illness with meningism and altered mental status in tuberculosis. Some feature co-existing retinal and nerve damage, termed neuroretinitis with visible changes in the retina such as the macular star in cat-scratch disease (caused by Bartonella henselae).

Infectious causes are not always associated with fever, though its presence is a clue. It's useful to consider other features such as any risk factors, particularly travel, animal exposures (cat-scratch disease), tick bites and outdoor hiking (Lyme disease), or recent sinus infections (invasive fungi).

Ultimately however we can't reliably tell that someone does or doesn't have an infectious cause, so we tend to send a screening panel of blood tests to look for markers of various infections.

We shouldn't rule out compression just because tumours felt less likely here. Other lesions can grow and cause mass effect on the optic nerve along its path, for example in the orbit or orbital apex.

Granulomatous inflammation from vasculitis (particularly granulomatosis with polyangiitis) is a consideration, as is Tolosa-Hunt syndrome. Graves disease can cause muscle swelling leading to optic nerve compression - dysthyroid optic neuropathy. Orbital pseudotumour features inflammation which can affect vision. The ophthalmic artery can develop an aneurysm which may rapidly progress the optic nerve.

Pain can be seen in various compressive causes, too.

The optic nerve is large and metabolically-active, so is vulnerable to damage from several toxins.

Several prescribed drugs, including ethambutol, linezolid and amiodarone can damage it. TNF-α inhibitors can occasionally trigger optic neuritis, despite being 'anti-inflammatory'. This patient isn't taking any of these medications.

Non-ethanol alcohols - particularly methanol - cause toxic optic neuropathy, with rapid visual loss. This can in people who consume home-prepared alcoholic drinks ('Moonshine') or accidentally ingest contaminated alcohol containing methanol. Others deliberately drink fluids such as antifreeze and windshield wiper fluid in suicide attempts. Methanol also has systemic toxic properties so there may be additional physiological upset.

'Tobacco ambylopia' is a cause of slowly-progressive visual loss as a result of chemicals in the tobacco smoke, mainly in cigar or pipe smokers, and often linked to co-occurring alcohol excess and nutritional deficiencies.

Besides toxins, metabolic disturbances can cause optic nerve damage. The main one is vitamin B deficiency, particularly B1 but also B6 and B12. Deficiency of vitamins A or E leads to visual loss through retinal damage, a different mechanism.

None of these fit well. Pain would be atypical. However it's always worth asking patients about diet, lifestyle, additional exposures (for example herbal or over-the-counter medications) and remembering that toxins may not be ingested with awareness - or may have been ingested deliberately but not reported.

The optic nerve is involved in various genetic conditions. The usual issue is optic atrophy - a slow problem that develops insidiously rather than causing fulminant and monocular blindness. Conditions include primary optic atrophy and other diseases when optic atrophy is seen as a part of a broader, multi-focal problem set.

However, one genetic disease is an important consideration. Leber's hereditary optic neuropathy (LHON) is a disease caused by a mutation in the mitochondrial DNA, inherited maternally. It manifests more often in young males, despite this not being a sex-linked gene. Monocular visual loss progresses quickly over a subacute tempo, but is painless and irreversible. The other eye then tends to lose vision in the following months. Attacks can be triggered by smoking or alcohol excess.

LHON is possible - although the tempo is faster than usual and the pain makes it unlikely.

The best fit for the tempo and pain is atypical, severe optic neuritis.

The next question is what can be done to help. Evidence from the Optic Neuritis Treatment Trial (ONTT) is that steroids don't actually alter outcomes compared to no steroids - but they do accelerate recovery if given intravenously (IV) - oral steroids are no better than placebo, and seem to increase risk of future attacks. Most patients in the ONTT enjoyed good recovery over several months and in the long-term follow-up studies.

The general consensus is to treat if acuity is below 6/12 (in metres; 20/40 in feet) - as the benefit of accelerating recovery is worth the risks of steroid-related side-effects. Milder attacks don't require steroids and will generally recover. In suspected atypical forms, testing for causes is key, and steroids are needed given the intensity of visual loss or other features (e.g. bilateral disease) - often followed by plasma exchange to promote recovery, as atypical disease is often steroid-refractory.