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15.5 Optic Neuritis—Inammation oftheOptic Nerve
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may involve the optic chiasma and even the thalamus. The vision loss in NMO is very severe, and
visual recovery is poor. The damage in NMOSD
is irreversible.
The AQP4 antibodies, once they enter the
CNS tissue, bind with AQP4 at the footplates of
the astrocytes, and activate complement, form a
membrane attack complex, initiate an inammatory reaction, and lead to the destruction of the
neural tissue. Thus, recovery from NMO lesions
is minimal [72].
Treatment ofAQP4-ON andNMOSD
Patients with NMOSD do not respond as well to
intravenous corticosteroids as MS-ON.One may
consider plasmapheresis followed by intravenous
corticosteroids or immunoglobulins, especially
in refractory cases. Various immunomodulators
are used for the prevention of relapses in
NMOSD.Azathioprine, mycophenolate mofetil,
and methotrexate are some of them. Of the US
FDA-approved biological agents in treating
NMOSD, rituximab is the most commonly used.
The other agents are eculizumab, inebilizumab,
and satralizumab. Eculizumab prevents the splitting of Complement 5 into C5a and C5b and thus
prevents the formation of the membrane attack
complex. Inebilizumab destroys AQP4 IgGproducing plasmablast cells. Satralizumab is a
humanized antibody against IL-6. A recent network meta-analysis showed that of the three
agents, eculizumab was more effective in preventing relapses of NMOSD than the other two
suggesting that blocking specically Complement
5 was more effective in preventing relapses of
NMOSD than a more non-specic blockage [73].
The visual eld loss is central but may show
more diffuse eld loss. Isolated optic chiasm or
optic tract involvement is more common in
MOG-ON than in other etiologies [69]. They
may have heterogeneous clinical manifestations
of encephalomyelitis and resemble NMOSD, but
the AQP4 antibodies are absent. The MRI shows
perineural enhancement and extensive longitudinal involvement [74].
Recurrences of MOG-antibody associated
with ON may or may not be accompanied by
CNS inammation. The vision at presentation is
mostly poor, but unlike AQP4-ON, visual recovery is good in most, and the average visual acuity
in the short term may improve to 20/30 [74].
Since it is a chronic relapsing disorder with
cumulative damage to the neural axons, high contrast visual acuity recovery in short-term follow up obtained in clinical settings may not reect the
actual outcome of MOG-IgG+ ON.
The recurrences are more frequent in
MOG-ON compared to the AQP4-ON patients.
In comparison, the AQP4-ON leads to severe
damage in a single attack and relapsing attacks in
MOG-ON cause cumulative damage in the
pRNFL and the GCIPL thickness [75].
Treatment ofMOG-ON
These patients show good responses to corticosteroids. They also show good recovery compared to the AQP4-ON.During the acute attack,
MOG-ON patients require intravenous methylprednisolone or plasma exchange to minimize
neuronal damage. Since it is a relapsing disease,
these patients require long-term immunosuppressive therapy.
15.5.5.2 Myelin Oligodendrocyte
Glycoprotein AntibodyAssociated Optic Neuritis
The MOG-antibody associated with ON
(MOG-ON) runs a relapsing course, which is
painful and associated with ONH swelling. There
is no gender predilection. The median age of presentation is 31 years. Nearly 40% are bilateral.
Most have retroocular pain in the movement of
the eyes. Severe visual loss <6/60 is seen in most.
They show moderate to severe ONH swelling.
15.5.5.3 Collapsin-Response
Mediator Protein-5- (CRMP-
5) Associated Optic Neuritis
Collapsin-response mediator protein-5 (CRMP-
5) IgG antibodies were rst discovered in cancer
patients as a marker of the paraneoplastic syndrome [76]. In the rst large series of CRMP-5positive paraneoplastic syndromes, optic neuritis
was seen in only 7% of patients [77]. More
recently, 38% of the CRMP-5-positive patients
had neuro-ophthalmic manifestations. Of these,
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15 Optic Disc Signs—Cupping, Swelling, Inammation, andPallor
62% had associated cancer, primarily small cell
lung cancers. Women were more commonly
affected. In nearly 3/4th of patients, the eye manifestations preceded cancer diagnosis. More than
80% had optic neuritis with ONH swelling, retinitis, vitritis, or uveitis. Less than 20% had retinitis or uveitis without optic neuritis. None of the
patients had optic nerve enhancement on
MRI. Nearly 40% of patients may show ocular
motility disorders and diplopia [78].
15.6 Optic Disc Pallor (Atrophy)
The normal optic disc is pink due to blood capillaries and shows nely blurred disc margins. It
transmits nearly 1.2 million ganglion cell axons.
However, following several optic nerve disorders
such as optic neuritis, chiasmatic compressive
tumours, ischaemic optic neuropathy, trauma,
papilledema, drugs, and toxins, the axons degenerate, leaving behind a complete or sectoral pallor
of the optic disc (Figs.15.13, 15.14, and 15.15).
As the axons degenerate, these get replaced by
glial tissue, and the capillaries attenuate, causing
disc pallor. Pathologically, the antegrade or
ascending optic atrophy is caused by degeneration of the ganglion cells in the retina seen in
open-angle glaucoma, inherited retinal degenerations, and drug toxicities. Retrograde or descending optic atrophy is classically caused by
chiasmal compression by pituitary tumours and
proceeds towards the eye. There is often a transsynaptic degeneration of axons which can be
de f
Fig. 15.15 A 35-year-old woman presented with visual
loss in the left eye for 2 weeks. She had received
Tacrolimus 1mg twice daily for nephrotic syndrome for 2
years. Visual acuity was 6/6in both eyes. She had a relative afferent pupillary defect in the left eye. The left eye
had optic disc swelling, more remarkable in the upper
pole (a). Humphrey’s visual eld analysis using the 30.2
strategy showed an inferior altitudinal eld defect (b); On
FFA, there was delayed lling (yellow arrow) of the upper
half of the disc (c) with late diffuse staining (d). Tacrolimus
was discontinued, and she was treated with oral cortico-
steroids. She maintained RAPD and 6/6 visual acuity in
this eye. There was a loss of retinal nerve bres along the
upper temporal arcade (arrows, e). The visual eld continued to show an inferior altitudinal defect (f) Reproduced
with permission of the publishers from Gupta M, Bansal
R, Beke N, Gupta A.Tacrolimus-induced unilateral ischaemic optic neuropathy in a non-transplant patient. BMJ
Case Rep. 2012 Aug 21;2012:bcr2012006718. doi:
10.1136/bcr-2012-006718. PMID: 22914240; PMCID:
PMC4544422
15.6 Optic Disc Pallor (Atrophy)
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antegrade when the pathology in the photoreceptors can lead to changes in the visual cortex or
retrograde when a pathology in the visual cortex
results in atrophy of the axons in the eye [79].
Clinically, the optic disc pallor is called primary when the axonal degeneration leaves behind
a pale optic disc with sharp margins. Primary
optic atrophy is usually seen in pituitary tumours,
traumatic optic atrophy, or post-optic neuritis.
Secondary optic atrophy results from optic disc
papilledema or papillitis and is marked by exuberant glial tissue proliferation and indistinct disc
margins. Consecutive optic atrophy results from
retinal pathology like retinal arterial occlusion,
retinitis pigmentosa, and chorioretinal inammations. Of all the etiologies, we shall briey discuss hereditary optic atrophy, Leber’s hereditary
optic neuropathy, dominant hereditary optic atrophy, and chiasmal compression syndromes.
15.6.1 Inherited Optic Neuropathies
Inherited optic neuropathies lead to slow and
symmetrical degeneration of the ganglion cells in
the retina. Unlike other causes of optic atrophy,
they do not show RAPD.Neuroimaging is normal. A Canadian cohort of 97 patients with bilateral optic atrophy, where all the known causes of
optic atrophy had been excluded, was subjected
to 22 nuclear panel NGS and complete mtDNA
sequencing; 20% had a nuclear variant, most of
which were in the OPA1 gene. A nuclear variant
is likely positive in patients with a family history
[74]. Leber’s hereditary optic neuropathy
(LHON) is the most important phenotype of
mtDNA mutation, and autosomal dominant optic
atrophy is the most common phenotype of nuclear
mutation, OPA1, which encodes for a mitochondrial protein. Mitochondria play a crucial role in
maintaining the health of the optic nerve.
15.6.1.1 Leber’s Hereditary Optic
Neuropathy
Leber’s hereditary optic neuropathy (LHON) is
one of the most frequently maternally inherited
mitochondrial genetic disorders seen in 1 per
25,000. It manifests with simultaneous or sequen-
tial (within 1–2months) painless subacute loss of
central vision with dyschromatopsia from 10 to
70, mostly in people under 50. A history of similar vision loss can be elicited in the maternal relatives. The optic disc may be normal on fundoscopy
or show prominent RNFL and peripapillary telangiectatic vessels. The retinal vessels appear
tortuous. Pupillary reactions are normal. The
FFA is normal. The visual evoked potential and
the ERG are normal. Neuroimaging is normal.
On perimetry, they show central or centrocecal
visual eld defects (Fig. 15.16). On OCT, the
GCL shows atrophy. By 6 months, the optic discs
are pale. The visual outcome is poor [80]. There
may be extraocular associations such as MS, parkinsonism, and myelopathy without evidence of
CNS involvement [81]. On OCT, in the early
LHON (< 6 months from onset), the RNFL is
thickened, but in the late atrophic stage of LHON,
there is marked thinning of the RNFL.The temporal bres of the papillomacular bundle are the
rst and most severely affected compared to the
nasal bres of the papillomacular bres
(Figs.15.16 and 15.17) [82].
In LHON, the full eld ERG is normal, but the
ash Visual evoked potentials (VEP) and Pattern
ERG are abnormal and consistent with optic
nerve conduction defects. There may be variably
reduced amplitude in the cone ERG and the
icker ERG suggestive of photoreceptor pathology in some patients with LHON.The SD-OCT
is however, normal [83].
LHON results from point mutations in mitochondrial DNA. The most common mtDNA
mutations are G11778A, T14484C, or
G3460A.In a large cohort of suspected LHON,
29.4% were positive for these three targeted
mutations [84, 85]. Nearly 50% of men and 10%
of women ever get LHON.Most LHON patients
carry homoplasmic, i.e. the mutant alleles;
10–15% may have heteroplasmy with a mixture
of mutant and wild-type alleles. The clinical
manifestations develop depending on when the
mutant allele becomes more dominant. Since not
all people who carry the mutation develop
LHON, environmental factors such as nutritional
factors, smoking, alcohol, and vitamin B deciency may play a role [80]. Despite using vita-
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15 Optic Disc Signs—Cupping, Swelling, Inammation, andPallor
Fig. 15.16 (a–d) A case of Leber’s hereditary optic neu-
ropathy (LHON) (a, b), with the temporal bres of the
papillomacular bundle being the rst and most severely
affected (blue arrows) compared to the nasal bres, better
appreciated on red-free fundus photographs (c, d). (e, h)
OCT (e, f) shows RNFL is thickened in the early LHON
(<6months from onset). Visual elds (g, h) show central
or centrocecal visual eld defects. Images courtesy of Dr.
SS Pandav, Professor and Head, Advanced Eye Centre,
Post Graduate Institute of Medical Education and
Research, Chandigarh, India
15.6 Optic Disc Pallor (Atrophy)
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f
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Fig. 15.16 (continued)
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Fig. 15.16 (continued)
15 Optic Disc Signs—Cupping, Swelling, Inammation, andPallor
min cocktails, there has been no proven therapy
for LHON.Gene therapy has reached the stage of
conducting clinical trials [84, 85].
On OCT, it preferentially involves the small
bres of papillomacular bundles. On SD-OCT,
there was a signicant decrease in the overall
cRNFL thickness and more so in the temporal and
15.6.1.2 Dominant Optic Atrophy
Dominant optic atrophy (DOA) is among the
most common inherited optic neuropathy characterized by the progressive loss of ganglion cells,
ultimately leading to temporal optic atrophy. It
starts insidiously in childhood and eventually
leads to blindness. The patients show centrocecal
scotomas and loss of colour vision. However, it
runs a variable course even in the same families.
Most cases are reported with a mutation in OPA1
located on 3q28-q29. This gene encodes for a
mitochondrial protein. This gene is involved in
oxidative phosphorylation and maintenance of
mtDNA.All cells express OPA1 genes, but the
mutation in this gene affects only the RGC and
interferes with the transmission of signals. The
small cell RGCs in the papillomacular bundles
get affected due to low energy reserves in these
cells. A mutation results in oxidative stress resulting in apoptosis of the RGCs [86].
inferior sectors. The macular GCIPL thickness is
reduced in all sectors, but more so in the supero and
infero nasal sectors indicating loss of papillomacular bundles. The rst change occurs in the GCL and
is followed by the loss of RNFL.Compared to the
LHON, the centrocecal scotomas are smaller in
dominant optic atrophy [87].
Long-term follow-up in some patients with
DOA with OPA1 mutations shows conephotoreceptor degeneration and abnormal photic
cone response ERG.However, outer photoreceptor degeneration is more evident in patients of
DOA with optic atrophy type 13 mediated by a
mutation in SSBP1 [83].
There is no proven treatment in DOA. The
treatment options are vitamins B12 and C, lutein
supplements that reduce the optic nerve’s oxidative stress, and idebenone- a ubiquinone analogue. Gene therapy is a promising option in the
future.
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a
b
c
Fig. 15.17 A 44-year-old man presented with a blurring
of vision in the right eye three days following an attack of
a migraine. Visual acuity was 6/18. The right eye showed
mild optic disc edema with obscuration of the cup (a). The
left eye was normal with a normal cup (b). Two months
later, the optic disc edema in the right eye resolved, and
the optic cup became visible (c). Note loss of the inferotemporal papillomacular nerve bres (blue arrows in c).
15.6.2 Chiasmal Compression
Syndrome
The optic chiasm lies above the sella turcica, harbouring the pituitary gland. The anterior part of
the third ventricle lies above the chiasm. Nearly
53% of the axons from the nasal half of each retina, projecting to the temporal eld of vision,
decussate in the chiasm. The pathologies affecting the chiasm most commonly produce visual
symptoms. Several pathologies can cause chiasmal syndrome by (1). intrinsic pathologies
involving the chiasm’s substance include demy-
The corresponding central scotoma (d) in the upper temporal quadrant did not improve (e). He was not tested for
mtDNA mutations. The clinical picture was highly suggestive of Leber’s hereditary optic neuropathy. Image
courtesy of Dr. SS Pandav, Professor and Head, Advanced
Eye Centre, Post Graduate Institute of Medical Education
and Research, Chandigarh, India
elinating disorders like MS, inammatory or
inltrative disorders, neurobromatosis, syphilis,
tuberculosis, or Sarcoidosis; (2). The most common extrinsic lesions that cause compression are
pituitary adenoma, craniopharyngioma, parasellar meningioma, and parasellar internal carotid
artery aneurysm.
15.6.2.1 Pituitary Adenomas
Pituitary adenomas are the most common cause
of the chiasmal syndrome. They need to grow to
a large size before they can compress the chiasm
from below. If the chiasm is placed normally, the
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Fig. 15.17 (continued)
15 Optic Disc Signs—Cupping, Swelling, Inammation, andPallor
crossing bres from the retina (projecting to the
temporal eld in both eyes) are affected. As the
bres from the lower nasal sector cross on the
undersurface of the chiasm, these are affected
rst and produce bitemporal superior eld
defects, which progress clockwise in the right
follow-up compared to 88% with RNFL loss.
Maximum improvement occurs between 6 and
10weeks of surgery [88]. Moreover, the binasal
GCIPL thinning may precede the onset of visual
elds, which appears to be a less sensitive tool
than OCT [89–91].
temporal eld and anticlockwise in the left temporal eld. Patients suffer from blindness temporal to the point of xation, and the earliest
symptom may be bumping into objects. The
visual eld is charted on Humphrey’s VF 24.2.
The earliest defect may be depression of the sensitivity by ≥2Dbs. Depending upon the xation
of the chiasm, the optic nerves or even the optic
tracts may be affected.
On OCT, there is a characteristic binasal loss
of the bres in the papillomacular bundle
(between the foveal centre and the optic disc)
with preservation of the upper and lower temporal arcuate bres, which do not cross in the chiasma and remain preserved for a long time. The
OCT may detect loss of crossing axons even
before the perimetric changes can be demonstrated [44, 45]. RNFL thinning is a prognosis
marker for visual recovery following the decompression of pituitary tumours. More than 97.5%
recovered ≥6/12 visual acuity at 9–15months of
15.6.2.2 Craniopharyngiomas
Craniopharyngiomas are either cystic or solid
benign tumours of childhood between the age of
5 and 14 years and account for 10–15% of all
pituitary tumours and ~ 6% of all childhood
intracranial space-occupying lesions. In adults,
these may arise from 50 to 74 years. These
tumours arise from the epithelial remnants of the
Rathke’s pouch (craniopharyngeal duct) and may
have intrasellar or suprasellar growth. The craniopharyngiomas may be adamantinomatous
(ACP) or papillary (PCP); the former are primarily cystic and may be seen in childhood or later,
and the latter is solid and seen only in adults [92].
The diagnosis is often delayed. The common
symptoms include headache, imbalance, slow
growth, symptoms of diabetes insipidus, and
vision defects. The symptoms arise from the
compression of the pituitary gland. https://rare-
diseases.org/rare- diseases/craniopharyngioma/
15.6 Optic Disc Pallor (Atrophy)
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These do not usually cause erosion of the sella
turcica. In children, these may produce raised
ICP and papilledema. In adults, these are slowgrowing, solid tumours that compress the optic
chiasm from above and behind and present with
optic atrophy. These tend to produce bitemporal
eld defects that initiate in the lower temporal
quadrants and are asymmetric. On CT scans,
90% of ACP show calcication. MRI shows these
as cauliower-type lesions, enhancement in 90%,
and cystic in 90% [92]. Apart from neuroimaging, the functioning of the pituitary gland is evaluated by testing for growth hormone, insulin-like
growth factor-1, prolactin, cortisol, folliclestimulating hormone, luteinizing hormone,
thyroid stimulating hormone, cortisol, testosterone, and estradiol. The extent of hypothalamus
damage is predictive of hypothalamic obesity in
these patients [93].
15.6.2.3 Meningiomas
Meningiomas are the dura mater’s most common,
slow-growing primary CNS tumours. These
tumours affect women, most commonly between
35 and 60years. These may involve afferent and
efferent visual pathways. The symptoms depend
upon the site of involvement. Meningiomas from
tuberculum sellae, anterior clinoid, dorsum clivus, and the parasellar dura often affect the chiasm and the optic nerve and produce asymmetric
perimetry changes. Patients usually complain of
progressive loss of vision and present with
chronic papilledema or optic atrophy. (Fig.15.18).
The presence of refractile bodies in the ONH in
these patients indicates prolonged optic disc
edema. The most common differential diagnosis
is optic neuritis. Any patient with suspected optic
neuritis who does not improve vision by 2 weeks
should be strongly suspected of harbouring
suprasellar meningioma. The meningiomas arising from the inner third of the sphenoidal ridge
produce visual symptoms and paresis of extraocular muscles by compressing on the structures
passing through the superior orbital ssure. The
meningiomas may present with primary optic
atrophy if involving the optic nerve, optic chiasm, or papilledema from raised ICP. Opto-
ciliary shunt vessels on an atrophic optic disc
highly suggest a long-standing perioptic meningioma [94, 95]. There are no specic tests for
meningiomas, and they need to undergo a complete neuro-ophthalmic examination, including
recording of pupil reactions, visual acuity, colour
vision, perimetry, and OCT.Neuroimaging provides the diagnosis (Fig.15.18).
15.6.3 Ischaemic Optic Neuropathies
(ION)
Sudden loss of vision in an older adult (>
50 years) due to optic nerve ischaemia is not
uncommon who report to the eye emergency.
These are broadly classied into: (1). arteritic
anterior ischaemic optic neuropathy (A-AION);
(2). Non-arteritic ischaemic optic neuropathy is
further divided into (a). anterior and (b). posterior. The ION must be differentiated from demyelinating optic neuropathies (multiple sclerosis)
seen primarily in young women (<50) who also
present with sudden acute or subacute vision loss
associated with pain in the movement of eyes.
The MS-ON runs a relapsing-remitting course,
showing disseminated CNS and Spinal involvement in space and time.
15.6.3.1 Nonarteritic Anterior
Ischaemic Optic Neuropathy
NAION accounts for nearly 90% of all optic neuropathies. It is seen more commonly in apparently healthy-looking men >50years.
15.6.3.2 Risk Factors forNAION
The signicant risk factors are hypertension
(50%), diabetes mellitus (25%), coronary artery
disease, dyslipidemia, and smoking [96]. The
relative risk of obstructive sleep apnea in patients
with NAION is 4.9 compared to the normal population [97, 98]. Non-compliance with continuous positive airway pressure increases the risk of
developing NAION in the fellow eye. Notably,
there is a signicant association between OSA,
glaucoma, and stroke [99]. OSA should be considered in all patients with NAION, especially
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15 Optic Disc Signs—Cupping, Swelling, Inammation, andPallor
d
g
Fig. 15.18 A 28-year-old man with ankylosing spondylitis remained under active follow-up for 31 years with
recurrent acute anterior uveitis in both eyes, which remitted and returned to normal vision after each attack. He
maintained a visual acuity of 6/6in both eyes. At the age
of 59years, he complained of visual loss in the left eye
without concurrent uveitis. His visual acuity was 6/6 and
6/12 in the right and left eyes, respectively. The OCT
examination of the left eye ruled out a suspected cystoid
macular edema (a). He returned 1 year later with a normallooking optic disc (b and c), although there was a further
e
f
hi
decline in visual acuity in the left eye. VA in the left eye
had dropped to nger counting at 2.5m. Six months later,
he had no light perception in the left eye. The visual eld
was possible only in the right eye, but a superior temporal
quadrantanopia was overlooked (d). He returned after 1
year when temporal optic disc pallor L>R was noted (e
and f). The Visual Field showed a right-eye temporal
hemianopic defect that progressed into the lower nasal
quadrant (g, cf. d). MRI revealed a large suprasellar
meningioma that extended into the sella turcica (h and i)
the young [100]. The possible mechanism of
NAION on OSA is cerebral venous dilatation and
increased ICP.
The blood supply in the prelaminar ONH is
drawn from the peripapillary short ciliary vessels. The ciliary supply is strictly an end-arterial
supply. On FFA, the optic disc can be frequently
seen in the watershed zone, making them vulnerable to hemodynamic variations. Patients on oral
anti-hypertensive drugs have a dip in their noc-
turnal blood pressure, which affects optic disc
perfusion in patients who are already at risk
[101]. NAION patients with multifactorial risk
factors also risk developing cerebrovascular accidents [102]. A low perfusion pressure during
sleep at night in patients at risk precipitates an
attack of NAION. Other risk factors include
vasoconstrictors used as nasal decongestants
[103], amiodarone [104], and phosphodiesterase
type5 inhibitors [105].
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