Test yourself

Pract Neurol: first published as 10.1136/practneurol-2020-002662 on 2 September 2020. Downloaded from http://pn.bmj.com/ on July 13, 2024 at World Health Organisation (HINARI) -
Bilateral visual loss in a 60-year-old
woman
Edward Margolin

Ophthalmology and Vision A 60-year-old woman noticed gradually Arteritic ischaemic optic neuropathy
Sciences, University of Toronto, worsening blurred vision in the right (giant cell arteritis) should also be consid-
Toronto, Canada
eye for several weeks. The patient had ered in anyone over the age of 50 with the
Correspondence to history of anxiety and depression. She new onset of optic neuropathy. It is usually
Edward Margolin, Department had never smoked cigarettes and drank anterior (ie, presents with optic nerve
of Ophthalmology and Visual
alcohol only socially. An optometrist head swelling) and the visual loss is typi-
Sciences, Department of
Medicine, Division of Neurology, had assessed her vision 2 weeks after cally sudden and profound, due to vascu-
Chief of Service, Neuro-­ the symptoms had begun and recorded litis causing non-perfusion of the short
Ophthalmology, University of visual acuity of 6/60 right and 6/6 left, posterior ciliary arteries or central retinal
Toronto, 801 Eglinton Ave West,
Suite 301, Toronto, Canada; ​
with a mild right relative afferent artery.
Edward.​margolin@​uhn.​ca pupillary defect, but normal ophthal- Bilateral sequential demyelinating optic
moscopic examination. One month neuritis is another possibility but is
Accepted 29 July 2020 later, her right eye vision had worsened,
Published Online First uncommon in patients over 50 years of
2 September 2020 with a slowly progressing left eye blurry age and it is rarely sequential and bilateral.

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vision as well. An ophthalmologist Immune-mediated optic neuritis from
recorded vision of counting fingers only antimyelin oligodendrocyte glycoprotein
in the right eye and 6/30 in the left eye. and neuro-myelitis optica antibodies is
There was a mild right relative afferent possible in this case, as the visual loss is
pupillary defect on the right but again usually subacute and frequently bilateral.
ophthalmoscopy was normal bilaterally. Infective optic neuropathy is uncom-
An MR scan of the brain and orbits mon in an immunocompetent host in
without contrast was interpreted as a developed country who is otherwise
normal. well. However, syphilitic optic neuropa-
thy rarely can cause retrobulbar bilateral
QUESTION 1. WHAT IS THE optic neuropathy, although usually with
DIFFERENTIAL DIAGNOSIS FOR THIS intraocular inflammation.
PATIENT'S BILATERALLY DECREASED Infiltrative optic neuropathy is also pos-
VISION? sible, due to haematological and solid
She has severely decreased central visual
malignancies, or granulomatous diseases
acuity in each eye with a mild right relative
such as sarcoidosis and tuberculosis.
afferent pupillary defect but normal
appearance of the optic nerve heads, sug- However, these entities are very uncom-
gesting a bilateral retrobulbar optic neuro- mon and typically the MR scan in inflam-
pathy. Table 1 lists the possible causes of matory and infiltrative optic neuropathies
this with pros and cons for each condition. shows increased signal in the optic nerves
Non-glaucomatous optic neuropathy in on T2-weighted sequences, though this
patients aged over 50 years has several might be mild and difficult to call.
possible causes. Gadolinium enhancement is expected in
Non-arteritic anterior ischaemic optic inflammatory and infiltrative optic neuro-
neuropathy is the most common of these. pathies. In this case, however, the MR scan
However, this can be excluded since non- was done without contrast.
arteritic anterior ischaemic optic neuropa- Autoimmune disorders (such as Behçet’s
© Author(s) (or their disease, Sjögren’s syndrome, systemic
employer(s)) 2021. No
thy requires the presence of a swollen
commercial re-­use. See rights optic nerve, whereas in this case, both lupus erythematosus and antineutrophilic
and permissions. Published optic nerves appeared normal at the time cytoplasmic antibody-associated disor-
by BMJ. ders) very rarely may produce retrobulbar
of her visual loss. Also, the onset of visual
To cite: Margolin E. loss is sudden in this condition whereas optic neuropathy that can be bilateral;
Pract Neurol 2021;21:77–80. here it was of gradual onset. however, there are often systemic

Margolin E. Pract Neurol 2021;21:77–80. doi:10.1136/practneurol-2020-002662 77

Test yourself

Pract Neurol: first published as 10.1136/practneurol-2020-002662 on 2 September 2020. Downloaded from http://pn.bmj.com/ on July 13, 2024 at World Health Organisation (HINARI) -
Table 1 Potential causes of bilateral optic neuropathy
Disease entity Pros Cons
Non-arteritic anterior ischaemic optic neuropathy Most common non- Must have optic nerve head swelling as the presentation
glaucomatous optic with visual loss is acute
neuropathy in patients aged
>50 years
Demyelinating optic neuritis Often retrobulbar Rare after 4th decade, only rarely sequential and
bilateral, usually increased signal on T2 and
enhancement of optic nerve on MR imaging
Infiltrative optic neuropathies Often retrobulbar and bilateral Rare, typically progresses quickly, increased signal on T2
enhancement of optic nerves on MR imaging
Compressive optic neuropathies Often retrobulbar, would Uncommonly bilateral, typically lesions is seen on
typically involve prechiasmatic unenhanced MR imaging
optic nerves if bilateral
Autoimmune optic neuritis (anti-MOG and neuromyelitis Often bilateral and retrobulbar, Typically increased signal/enhancement of involved
optica) not uncommon in older adults optic nerve on MR imaging
Infective optic neuropathy (most commonly secondary to Can be bilateral with Rare in immunocompetent host in developed world
tuberculosis and syphilis) sequential involvement without risk factors and absence of intraocular
inflammation
Autoimmune-associated optic neuropathy (associated Can be bilateral and Rare and typically associated with other local (retinal
with systemic lupus erythematosus, Sjögren’s syndrome, retrobulbar with sequential vasculitis) or systemic symptoms
ANCA-associated vasculitis and others) involvement
Paraneoplastic optic neuropathy Can be bilateral, sequential Associated with vitritis in CRMP-5-associated optic
and retrobulbar neuropathy. If associated with cancer-associated or
melanoma-associated retinopathy, it is accompanied by
retinal arteriolar attenuation and/or pigmentary

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retinopathy
Leber’s hereditary optic neuropathy Typically bilateral with Typically occurs in young men, very rare in older women
sequential involvement
ANCA, antineutrophil cytoplasmic antibody; CRMP-5, collapsin response mediator protein-5; MOG, myelin oligodendrocyte glycoprotein.

symptoms and accompanying retinal vasculitis, and this and she has no relative afferent pupillary defect. There
patient had neither of these. is bilateral optic nerve head pallor and thinning of the
Leber’s hereditary optic neuropathy (LHON) can ganglion cells in the macular complex, the cellular sub-
present sequentially with each optic nerve affected strate for the axons forming the optic nerve. While she
within months of each other but is exceedingly uncom- possibly has an inflammatory optic neuropathy affect-
mon in older women. ing both eyes equally, this would be unlikely to produce
A compressive lesion affecting prechiasmatic por- perfectly symmetric optic neuropathy. Even the differ-
tions of both optic nerves can also produce bilateral ence of 6% in the number of axons in the optic tracts
retrobulbar optic neuropathy, but the lesion would (6% more axons from the nasal retina cross to the
usually be discernable on unenhanced MR imaging. contralateral side at the optic chiasm compared with
The patient underwent neuro-ophthalmologic eva- the number of axons from the ipsilateral temporal
luation 2 months after the onset of the right eye visual retina) is enough to produce a noticeable relative affer-
loss. At that time, she reported further deterioration of ent pupillary defect contralateral to the side of optic
vision in each eye but no systemic symptoms. Her visual tract lesion.1
acuity was now counting fingers in each eye, there was Symmetric optic neuropathy has only a short differ-
no relative afferent pupillary defect and ophthalmo- ential diagnosis, which includes hereditary, toxic and
scopy identified mild temporal pallor of both optic nutritional causes.
nerves with diffuse thinning on ganglion cell analysis Hereditary optic neuropathies. Dominant optic atro-
of the macular complex (figure 1A, B). Formal visual phy is the most common hereditary optic neuropathy,
fields (Humphrey 24-2 algorithm) showed diffuse caused by a mutation in the nuclear gene that encodes
depression in each eye without an identifiable pattern. inner mitochondrial membrane protein. However,
Her neurological examination was normal. patients with this condition experience very insidious
bilateral symmetric visual loss starting in childhood,
QUESTION 2. HAS YOUR DIFFERENTIAL and their final visual acuity usually permits driving up
DIAGNOSIS CHANGED AND WHAT WOULD BE until they are in their fifth decade of life. LHON is the
YOUR MANAGEMENT PLAN NOW? next most common hereditary optic neuropathy, typi-
This woman now has bilateral symmetric optic neuro- cally with sequential involvement of each eye.
pathy: her central visual acuity is the same in both eyes However, it typically affects men in their second or

78 Margolin E. Pract Neurol 2021;21:77–80. doi:10.1136/practneurol-2020-002662

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Pract Neurol: first published as 10.1136/practneurol-2020-002662 on 2 September 2020. Downloaded from http://pn.bmj.com/ on July 13, 2024 at World Health Organisation (HINARI) -
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Figure 1 (A) The optic nerve heads showing symmetric mild temporal optic nerve pallor bilaterally. (B) Ganglion cell analysis of the
macular complex showing severe thinning bilaterally. OD, right eye; OS, left eye.

third decades, with sequential visual loss separated by enhancement. Vitamin B12, folate, and heavy metal
several months. While the sequential nature of this concentrations were normal. Molecular genetics test-
patient’s visual loss fits the presentation of LHON, ing for LHON identified the m.11778 mutation at
she is a woman in her sixth decade making this an homoplasty.
unlikely possibility.
Toxic optic neuropathy has many potential culprits, QUESTION 3. WHAT ADDITIONAL INFORMATION
most commonly being ethambutol, methanol, chloram- WILL YOU OBTAIN ON HISTORY AND WHAT
phenicol, isoniazid, amiodarone, vincristine and various INTERVENTIONS WILL YOU OFFER THIS PATIENT?
heavy metals (lead, mercury, arsenic, etc.). However, Unexpectedly, this woman has an m.11778 mutation
typically, the visual loss is symmetric from the onset. causing LHON, with all of her examined mitochondria
This patient had sequential involvement of the optic exhibiting the mutation. Patients being counselled for
nerves with a relative afferent pupillary defect. a new diagnosis of any mitochondrial disorder should
Nutritional optic neuropathies most commonly be advised about the importance of abstaining from
result from vitamin B12 and folate deficiencies but smoking and alcohol. Binge drinking is particularly
may also present with an insidious onset of symmetric harmful as it induces high oxidative stress on the cells
visual loss and no relative afferent pupillary defect. that are already producing insufficient amount of
This patient does not neatly fit into any of the above- energy and causes further loss of function.
mentioned diagnoses. She should, therefore, be tested for When discussing the results, this patient reported
LHON with molecular DNA testing looking for one of being a lifetime non-smoker but admitted to having
the three most common mutations causing it drunk 3–4 hard liquor drinks a day for the past many
(m.11778, m.14484 and m.3460). Serum concentrations years. We considered this to be a potential cause for her
of B12, folate, and heavy metals should also be checked to phenotypic expression of visual loss, at much older age
identify potentially treatable causes of optic neuropathy. than normally seen in LHON and despite the normally
An MR scan of the orbits with contrast would also be very low (~10%) penetrance of LHON in women.
prudent to see whether optic nerves enhance, indicating While LHON has no effective treatment, several
an inflammatory cause of optic neuropathy. recent clinical trials and a consensus statement by
experts recommend starting treatment with idebenone,
TEST RESULTS which increases mitochondrial ATP synthesis and has
MR scan of the orbits with contrast showed normal- antioxidant properties. This should be started as soon
sized optic nerves bilaterally without abnormal as possible in patients whose visual loss began within

Margolin E. Pract Neurol 2021;21:77–80. doi:10.1136/practneurol-2020-002662 79

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Pract Neurol: first published as 10.1136/practneurol-2020-002662 on 2 September 2020. Downloaded from http://pn.bmj.com/ on July 13, 2024 at World Health Organisation (HINARI) -
the past year, at the dose of 900 mg/day and continued QUESTION 5. ARE THERE ARE ANY NEW
for a year.2 There are no recommendations to use TREATMENTS ON THE HORIZON FOR LHON?
idebenone for patients who have had a visual loss for Several gene therapy trials for LHON are currently
over a year. underway, with some suggesting a modest improve-
ment in central visual acuity and peripheral vision.4
QUESTION 4. WHAT IS THE CLINICAL The patients are injected intravitreally with recom-
PRESENTATION, PATHOPHYSIOLOGY AND binant adeno-associated virus containing DNA
PROGNOSIS OF LHON? encoding human wild-type mitochondrial ND4 pro-
Most patients diagnosed with LHON are young men in tein (the site of the mutation causing LHON) with
their late second and third decades of life (with an the hope of its expression and translation by the
average age of 22 years) presenting with subacute visual nucleus and subsequent integration into
loss in one eye followed by the other eye weeks to mitochondria.
months later. Clinically during the acute stage, the
examination may be normal, with the exception of
mild optic nerve head elevation and sometimes appear- Key points
ance of telangiectatic vessels on optic nerve surface.2
► The differential diagnosis of symmetric optic
LHON affects complex I of the mitochondrial elec-
neuropathy is short and specific: it is either inherited,
tron transport chain, which is responsible for moving
toxic/metabolic or nutritional; all should be tested for
the electrons along the mitochondrial membrane, main-
treatable causes such as vitamin B12 and folate
taining the proton gradient and making ATP in the
deficiencies.
process. Thus, patients with one of the three most com-
► Leber’s hereditary optic neuropathy (LHON) is the
mon LHON mutations—accounting for over 95% of
most common mitochondrial disease; its typical
cases (m.1178G-A, m.14484T-G and m.3460G-A)—
presentation is a visual loss in one eye followed by
do not produce enough ATP to provide for normal
the second eye weeks to months later.

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cellular function. The resulting ischaemia leads to
► Older adults with sequential visual loss and symmetric
increased production of harmful reactive oxygen
optic neuropathy require testing for LHON.
species,2 which eventually causes retinal ganglion cell
► Expert opinion suggests that idebenone 900 mg
death through apoptosis. In LHON, this process affects
per day could be prescribed to all newly diagnosed
mostly small non-myelinated axons of the ganglion cells
patients with LHON for at least a year.
that have the highest energy demand; these are prefer-
entially the small fibres in the papillomacular bundle
responsible for central vision, thus causing central and
caeco-central scotomas and subacute central visual loss. Contributors The sole author of this manuscript prepared it and
While a male-to-female ratio in LHON is typically edited on his own.
reported as 5:1, one recent paper that reviewed a large Funding The author has not declared a specific grant for this
international database of patients with LHON reported research from any funding agency in the public, commercial or
that it is much lower, closer to 31.3 These investigators not-for-profit sectors.
also showed that while most men develop LHON in Competing interests None declared.
their second and third decades of life, women have no Patient consent for publication Consent obtained directly from
age predilection and may develop the disease at any the patient(s).
age, which should prompt the clinician to test women Provenance and peer review Not commissioned. Externally peer
of all ages for LHON in the appropriate clinical con- reviewed by Christian Leuck, Canberra, Australia, and Susan
Mollan, Birmingham, UK.
text. While we do not know the exact mechanism for
decreased disease penetrance in women, possible
explanations include the protective effects of oestro- REFERENCES
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fold increase in the risk of visual loss. 1967;101:393–401. PMID: 6051727 PMCID: PMC1270921.
2 Kisilevsky E, Freund P, Margolin E. Mitochondrial disorders and
The type of mutation has the most influence on visual
the eye. Surv Ophthalmol 2020;65:294–311-.
prognosis with LHON. Those with 11778 mutations
3 Poincenot L, Pearson AL, Karanjia R. Demographics of
typically have poor final visual acuity and almost no a large international population of patients affected by
chance of spontaneous improvement, whereas patients Leber’s hereditary optic neuropathy. Ophthalmology
with the 14484 mutation have the best prognosis, with 2020;127:679–688.
37–65% having some degree of visual recovery within 4 Vignal C, Uretsky S, Fitoussi S, et al. Safety of rAAV2/2-ND4 gene
a year of diagnosis. Progression of visual loss after the therapy for Leber hereditary optic neuropathy. Ophthalmology
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80 Margolin E. Pract Neurol 2021;21:77–80. doi:10.1136/practneurol-2020-002662