Uttaranchal Journal of Ophthalmology 2020

UTTARANCHAL JOURNAL OF OPHTHALMOLOGY

ISSN 0973-3191

An annual publication of
Uttarakhand State Ophthalmological Society (UKSOS)

Volume 14, Issue 1, November 2020
Editor: Dr Anupam

UTTARANCHAL JOURNAL OF OPHTHALMOLOGY

VOLUME 14, November 2020

ISSN 0973-3191

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 2

UTTARAKHAND STATE OPHTHALMOLOGICAL SOCIETY (UKSOS) 2020

Patrons
Dr SD Vijay
Dr MC Luthra
Dr RC Nagpal

President President Elect Immediate past President
Dr Jaideep Dutta Dr Harsh Bahadur Dr Surajit Das

Secretary Treasurer Journal Committee
Dr Satanshu Mathur Dr Amit Singh Dr Anupam (Chairman)
Dr Sushoban Das Gupta

Dr Nutan Darda Jain

Joint Secretaries Advisory Committee Scientific Committee Proceeding Committee
Dr Renu Dhasmana Dr RN Singh (Chairman) Dr Vinod Arora Dr Manisha Gupta
Dr Nitin Mehrotra (Chairman) (Chairman)
Dr RN Mehrotra
Dr RJK Singh Dr Mayank S Pangtey Dr Sangeeta Jain
Dr BK Oli Dr GS Titiyal Dr Vinita Gupta

Dr Ajai Agrawal
Dr Vipul Arora

Dr Asif

Senior Vice President Junior Vice President
Dr Sanjeev Kumar Mittal Dr AK Saraswat

Awards Committee Academics and Research Committee
Dr Gaurav Luthra (Chairman) Dr Saurabh Luthra (Chairman)
Dr Rajesh Tiwari
Dr Ashok Garg Dr Gopal Agarwal
Dr CS Grover Dr Sanjay Sethi
Dr Deepesh Arora

Executive Committee Members
Dr D P Kar
Dr AK Gupta

Dr Amit Maitreya Dr Naveen Sharma
Dr Anurag Garg Dr Smitha Mehra
Dr BC Ramola Dr Siddharth Pandey
Dr Dinesh SIngh Dr Udai Shankar

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 3

Content Pages
5-7
UTTARANCHAL JOURNAL OF OPHTHALMOLOGY
8-14
VOLUME 14, November 2020 15-29
30-39
EDITORIAL 40-51
REVIEW ARTICLES 52-57

• Central Serous Chorioretinopathy (CSCR): A brief update 58-62
Dr Nisheeta Patnaik, Dr Ajai Agrawal, Dr Raghavendra Mareguddi, Dr
Thounaojam Samita Devi, Dr Gitanjali Sood, Dr Ramanuj Samanta 63-67

• An Insight to keratoconus: A corneal ectasia 68-73
Dr Navjot Kaur, Dr Anuradha Raj, Dr Nikhil Agrawal
74-78
• Ocular Adverse Effects caused by systemic drug therapy – A review 79-81
Dr Gauri Mittal, Dr Sucharita Das, Dr Manisha Bisht 82-90
91-92
• Toxic Optic Neuropathy: A diagnostic dilemma
Dr Nidhi Paharia, Dr Anuradha Raj, Dr Nikhil Agrawal

• Primary Vitreoretinal Lymphoma
Dr Shrinkhal, Dr Devesh Kumawat, Dr Raghavendra R Mareguddi, Dr
Achala Ramawat, Dr Namrata Modi, Dr Ajai Agrawal, Dr Anupam
Singh

CASE REPORTS
• Abnormal Medial Rectus insertion in a case of autosomal recessive
cornea plana
Dr Mahsa Jamil, Dr Rakesh Panyala, Dr Achala Ramawat, Dr
Raghavendra R Mareguddi, Dr Ashem Devyanada Devi, Dr Anupam
Singh

• A rare case report of intraconal cavernous hemangioma in association
with hypothyroidism
Dr Shalaka Waghamare, Dr Rakesh Panyala, Dr Mohd Ghaniul Hasan,
Dr Achala Ramawat, Dr Ashem Devyanada Devi, Dr Srishti Sharma,
Dr Anupam Singh

• A case of Endogenous Endophthalmitis in a young woman following
typhoid fever
Dr Achala Ramawat, Dr Prateek Nishant, Dr Himanshi Aggarwal, Dr
Gitanjali Sood, Dr Anupam Singh, Dr Ramanuj Samanta

• Traumatic optic nerve head avulsion following blunt ocular trauma
Dr Preeti Yadav, Dr Rupal Verma, Dr Neeraj Saraswat, Dr Kavya
Subramanian, Dr Sanjeev Kumar Mittal

PHOTO ESSAY
• Management of a case of vasculitic combined retinal detachment

Dr Himanshi Aggrawal, Dr Neeraj Kumar Saraswat, Dr Achala Ramawat, Dr
Ramanuj Samanta
RESIDENTS CORNER
Instructions to Authors

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 4

EDITORIAL

CHANGES IN OPHTHALMIC PRACTICES DURING THE COVID-19
PANDEMIC: NEED OF THE HOUR

The world has witnessed extraordinary can be minimized and patients requiring
changes in the healthcare due to the COVID- emergent care be directed in time. Triage
19 pandemic. The unexpected measures of should be done by an ophthalmologist or a
lockdown and quarantine to control the trained ophthalmic technician or an
pandemic has proved to be major challenge optometrist. At present it is recommended
of public health at international front. No one that all ophthalmologists provide only
related to healthcare was untouched which emergent care and reschedule all elective
include even ophthalmologists. The proximity OPD visits and procedures after screening of
and close working contact between the the patient for COVID 19. Cases that can be
patient and ophthalmologist to examine the postponed for more than 4 weeks without
eye is a unique challenge that is thought as a considerable risk of loss of vision, general
bidirectional risk to both the patient and health and functioning should qualify as
ophthalmologist. This led to suspension of "elective".
routine care, non-emergency surgery and
follow up of various conditions. Screening

But at the same time postponing the The hospitals/clinics should have efficient
healthcare cannot be an alternative and thus control system at the point of entry so that
it is important to understand that during only the patient and one accompanying
such uncertain times we need to adapt to the attendant are allowed inside the healthcare
needs of public and achieve a professional facility. Apart from the Personal Protective
and ethical balance such that we continue Equipment (PPE) for health care workers,
our services for ophthalmic emergencies even the entrants are expected to wear
without becoming hotspots for viral masks. The hand sanitization should also be
transmission. Keeping this in mind, I wish to assured at the point of entry.
highlight the changes in Ophthalmology
practices during recent times. Precautions at ophthalmic
evaluation and OPD procedures
Ophthalmic Emergency Practice
• Protections for head, mouth, nose,
The most important focus is to have a smart and eye (with a surgical cap, three-
triage team so that vision loss to the patient

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 5

ply surgical mask, goggles/face Telemedicine and online
consultation
shield) for the examiner and a three-
The telemedicine facility is the new normal
ply surgical mask for the patient. and thus wherever possible should be utilized
while following the AIOS guidelines. Online
Masks should be changed every 6 consultation platforms like eSanjeevani
portal which is approved by the government
hours or immediately when of India (GOI) are successful alternatives for
follow up advises and minor ophthalmic
contaminated or wet. complaints.

• Slit-lamp barriers or breath shields Precautions at Operating Room
procedures/surgeries
are must while examination. It should
All procedures and surgery on a COVID-19
be assured that contact parts of the patient is being deferred until the patient
recovers, unless deferral of treatment by 2
slit lamp be cleaned by alcohol wipes weeks has a potential risk for loss of vision,
eye, or life. Such mandatory surgeries
after examining every patient. The should be performed in a multispecialty
hospital approved by the GOI for COVID-19
barriers should be changed for each treatment following all standard protocols
and prophylaxis.
patient. The proper washing drying, Ophthalmic procedures on a non COVID
suspect should be done after the patient is
and sanitization of reusable barriers tested negative on RTPCR.

should be assured. Duty Roster

• Alcohol-based hand sanitizer must be The duty roster should be such that the
manpower is optimally utilized. It has been
used before and after examining each suggested that only one-third to one-half
staff is working at any given time. This
patient. practice will benefit at multiple levels as it
will avoid the crowding in the health care
• Disinfection (using standard

protocols) of all instruments, and

probes used in direct contact to the

patient's tear film and ocular surface

before re-use.

• Retinal examination should preferably

be done with an indirect

ophthalmoscope. Direct

ophthalmoscopy should be avoided.

• All patients with conjunctivitis be

treated as COVID-19 suspects and

should be examined in isolation, with

slit lamp breath shields, using N95

mask and disposable gloves.

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 6

areas and thus help in social distancing. But place. So, preparedness is the “key” for
the key highlight of adopting this norm is to providing OPD and surgical services.
protect the health care providers as it will Some of the changes introduced today may
ensure their availability in future, which will restructure our ophthalmology practice
ensure a functioning health system. forever. But not all changes are good, thus
The fight against SARS-CoV-2 virus seems to generating evidence for what worked and
be a long one and it is sure to redefine the what did not is also important.
ophthalmology care even if the vaccine Everything is temporary, every phase comes
becomes a reality. With reopening of the to an end. This phase too shall pass. Let’s
economy, it becomes all the more important think positive and hope to remain safe and
that we have strict operating procedures in well.

Best Wishes.

Dr Anupam
Editor in chief, UJO
Additional Professor
Ophthalmology, AIIMS Rishikesh
Email - [email protected]

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 7

Review Article

CENTRAL SEROUS CHORIORETINOPATHY (CSCR): A BRIEF UPDATE

Dr Nisheeta Patnaik, Dr Ajai Agrawal, Dr Raghavendra Mareguddi, Dr Thounaojam Samita Devi,
Dr Gitanjali Sood, Dr Ramanuj Samanta

ABSTRACT macular serous detachments. Gass in 1967,
subsequently described its pathogenesis and
Central serous chorioretinopathy (CSCR) is a termed it as ‘Idiopathic Central Serous
common cause of vision loss, primarily Chorioretinopathy’.
affecting men of 30-40 years of age. In this
review, we aim to update the risk factors, CSCR is common in Asians and whites. It
pathogenesis, and diagnosis of CSCR. This generally affects males in their 4th – 5th
review also provides a comprehensive decades.2 Patients usually present with
overview of current treatment options such as complaints of blurred vision, metamorphopsia,
focal laser, photodynamic therapy, micropulse alteration in contrast sensitivity, and relative
diode laser, role of anti-VEGF and oral central scotoma. Raised endogenous cortisol
mineralocorticoid antagonist, as well as newer levels as in cases of Cushing’s disease,
pharmacological options. pregnancy, and exogenous steroids have a
positive correlation with the development of
Key Words: Central Serous CSCR.3 Exogenously administered steroids in
the form of systemic, intranasal, topical,
Chorioretinopathy, Pachychoroid, Micropulse dermatological as well as intravitreal routes
laser, Photodynamic Therapy, Serous PED have been associated with CSCR. Type-A and
maladaptive personality traits have elevated
DISCUSSION levels of corticosteroids and catecholamines,
increasing their risk of developing the
Central serous chorioretinopathy (CSCR) is a disease.4Other risk factors include Helicobacter
common idiopathic self-limiting disease pylori infection, systemic hypertension,
characterized by localized serous neurosensory coronary heart disease, obstructive sleep
detachment (NSD),with or without associated apnoea, and hyperopia. 5
pigment epithelial detachment(PED). It ranks
fourth amongst the common vision- Recently, a genetic link is being explored for
threatening retinopathy after age-related
macular degeneration, diabetic retinopathy, familial CSCR. Single nucleotide
and retinal vascular occlusions.1
polymorphisms (SNPs) in the genes involved
It was first described by Von Graefe as ‘central
recurrent retinitis’ in 1866, noticing recurrent in the complement system, including CFH

encoding complement factor H, the C4B, and

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 8

NR3C2 gene are being evaluated for possible Fundus fluorescence angiography (FFA)
involvement.6 If left untreated, around 50% of classically shows small hyper-fluorescent RPE
these patients will have at least one defect in the early phase, followed by the
recurrence with a one-year recurrence rate passage of dye into subretinal space first
ranging from 30-51%.7 vertically and then laterally giving rise to a
‘smoke-stack’ appearance. Another type of
CSCR is considered as a part of the leakage is ‘ink-blot appearance’, where focal
pachychoroid spectrum of diseases currently. leak increases in size centrifugally in
The pathophysiology is poorly understood but subsequent phases of the angiogram. ICGA
lies primarily in the choroid. Choroidal hyper- shows more extensive areas of hyper-
fluorescence on Indocyanine Green fluorescence corroborating the fact that the
Angiography (ICGA) supports this hypothesis.8 pathology lies at the level of the choroid.
Pathological processes which lead to choroidal
dysfunction include choroidal stasis, Optical Coherence Tomography (OCT) is a
ischaemia, inflammation, and abnormalities in good modality to quantify the subretinal fluid
the complement system.9 This leads to (SRF) and follow its progression. Larger
hyperpermeability of the choroidal vasculature accumulation of subretinal fluid has been
and increased hydrostatic pressure, causing a associated with poorer visual gain.15 Subretinal
breach in the retinal pigment epithelium (RPE) hyper-reflective dots represent macrophages
barrier, allowing the formation of PED and or plasma proteins from inflammatory debris,
NSD.10 This is further supported by Optical or fibrin clots from fibrinogen leakage through
Coherence Tomography angiography (OCTA) a RPE breach. 16
studies showing increased signal intensity and
thicker choriocapillaris vasculature.11 Serous PED is seen as a smooth domed

The hallmark of CSCR is a sharply demarcated elevation of the RPE, with a sharp angle over
area of NSD over the posterior pole containing
clear or turbid subretinal fluid.12-13 The fluid an optically empty space bound by an intact
and fibrin may dissolve with time but may
cause subretinal fibrosis leading to permanent Bruch’s membrane. Another common cause of
low vision. Duration of subretinal fluid does not
seem to correlate with diminution of vision serous PED is age-related macular
always, as cases with quick recoveries have
led to permanent photoreceptor damage degeneration (AMD). Certain OCT
also.14
characteristics help distinguish the two. PED in

AMD may be associated with the simultaneous

presence of intraretinal fluid, greater PED

height, and alterations of the highly reflective

line (irregularity, thickening, and attenuation)

as seen on OCT. 17

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 9

Advances in spectral-domain OCT (SD-OCT) Fundus autofluorescence (FAF) is based on the
particularly enhanced depth imaging (EDI) has accumulation of fluorophores. The
provided more insight into choroidal autofluorescence pattern of CSCR describes
morphology. Along with the thickness of the the status of the RPE and chronicity of the
choroid, EDI-OCT is used to study the disease.21 FAF shows areas of hypo-
morphology of the choroidal vasculature. On autofluorescence corresponding to the areas of
EDI-OCT, eyes with CSCR have shown a leakage of FFA demonstrating the RPE
choroidal thickness of 2-3 times that of abnormalities.
normal. Increased choroidal vascularity,
luminal dilation of outer choroidal vessels, and The aim of treatment is the preservation of the
increased hyper-reflectivity in inner choroid neurosensory retina, early resolution of the
have also been demonstrated. Fellow eyes of NSD, and prevention of recurrences. Due to
CSCR may also show an increase in choroidal the high rate of spontaneous resolution of
thickness and vascularity.12 acute CSCR, the usual first-line management
is observation for 3-4 months in most cases.
Choroidal neovascularisation (CNV) secondary
to chronic CSCR is difficult to diagnose with Several indications of early treatment include
conventional techniques due to overlapping one-eyed patient, a professional requirement,
patterns of both pathologies.18 Swept-source recurrent and/or chronic CSCR, prior history of
OCT (SS-OCT) also showed inconclusive CSCR in the fellow eye. Other indicators of
results due to backscattering light intensity of prolonged CSCR, that may need treatment are
the RPE deposits that are similar to those of subfoveal choroidal thickness > 500 µm, PED
fibrovascular or neovascular CNV. SS-OCTA height > 50 µm, age of presentation at 40
helps to differentiate the two in such years or older, fibrinous debris in the SRF and
scenarios. It is a non-invasive modality, large amounts of SRF. 22-24
includes a blood flow detection algorithm, and
is capable of visualizing the superficial retinal Conventionally, the intervention of choice for
capillaries and FAZ, inner and outer retinal CSCR has been focal laser.25 FFA guided laser
vascular plexuses, choriocapillaris, and larger treatment targets the focal leakage points.
choroidal vessels.19 Additionally, SS-OCTA uses This treatment modality must be limited to
the features of SS-OCT allowing deeper extrafoveal leakage sites and has several
penetration, superior axial resolution, and potential side effects such as vision loss,
generation of ultrahigh-definition B-scan scotomas, and risk of CNV formation. Although
images of the retinal microstructure. 20 laser photocoagulation may hasten the
resolution of CSCR, the final visual outcome is

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 10

similar when compared to the patients who did anti-VEGF (vascular endothelial growth factor)
not undergo any intervention. 26 compounds such as bevacizumab,
ranibizumab, and aflibercept are possible
Micropulse diode laser induces subtle effects treatment modalities.32-33However, a meta-
as compared to laser photocoagulation. It can analysis failed to confirm the benefits of anti-
selectively target the RPE while preserving the VEGFs in acute CSCR, although the authors
photoreceptors. When applied in a sub- suggested its usefulness in certain subtypes of
threshold dose, it is believed to increase the chronic CSCR.34Given the limited data on
expression of heat shock proteins, which might efficacy, the use of anti-VEGF in CSCR should
restore cellular function.27-28 Moreover, it can be limited to patients with CSCR with CNV
be used for sub-foveal leaks also. and/or polypoidal choroidal vasculopathy.

In photodynamic therapy (PDT), the Elevated cortisol levels and mineralocorticoid
benzoporphyrin derivate verteporfin is used receptor dysfunctions have been reported in
due to its high affinity for the RPE. Free several CSCR cases. Few studies with
radicals produced in the choriocapillaris cause mineralocorticoid receptor antagonists -
vascular endothelium damage. Subsequently, eplerenone and spironolactone have shown
vessels in the capillary bed underlying the promising results in CSCR patients, especially
damaged RPE undergo remodelling.29 in chronic cases.35 It is important to monitor
Compared to photocoagulation, PDT induces cardiac and renal functions prior to and during
less destructive changes to the RPE.30 this treatment.
However, diffuse application of PDT has been
associated with alteration in choroidal Other modalities such as antioxidants, aspirin,
pigmentation, RPE atrophy, choriocapillaris beta-blockers, carbonic anhydrase inhibitors,
nonperfusion, and possible choroidal ketoconazole, melatonin, methotrexate, and
neovascularisation. There is a 4% risk of acute rifampicin have been explored but warrant
severe visual decline after PDT therapy. further studies for conclusive efficacy and
Transient choroidal ischemia has also been potential side effect profile.
reported.31 The ischemic change in these eyes
does not leave permanent damage most of the To conclude, the pathophysiology of CSCR is
time but has led to newer low dose and low often multifactorial. It remains one of the
fluence PDT. Low-dose PDT uses a half dose of common causes of the diminution of vision
verteporfin (3 mg/m2). affecting the younger population. It is
important to counsel the patient well, deal
As the primary pathology of CSCR lies in the with external risk factors, and also keep in
choroidal vasculature, intravitreal injections of mind the cases that require intervention. With

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 11

the recent improvement in imaging modalities, psychological morbidity and coping
the patients should be subjected to ancillary
investigations promptly. While first line of strategies in chronic central serous
treatment still lies in observation, newer
modalities such as micropulse laser, and many chorioretinopathy.
oral medications such as eplerenone should be
kept in mind. ActaOphthalmologica. 2018;97(4):572-

CONFLICT OF INTEREST – None 579.

FINANCIAL INTEREST – None 5. Chatziralli I, Kabanarou S, Parikakis E,

Chatzirallis A, Xirou T, Mitropoulos P.

Risk Factors for Central Serous

Chorioretinopathy: Multivariate

Approach in a Case-Control Study.

Current Eye Research.

2017;42(7):1069-1073.

6. vanDijk E, Schellevis R, Breukink M,

Mohabati D, Dijkman G, Keunen J et al.

Correspondence Address Familial Central Serous

Dr. Ramanuj Samanta Chorioretinopathy. Retina.
Assistant Professor; Department of Ophthalmology
All India Institute of Medical Sciences, 2019;39(2):398-407.
Rishikesh, Uttarakhand, India, 249203.
E-mail: [email protected] 7. Matet A, Daruich A, Zola M, Behar-
Phone Number: +9188722932345
Cohen F. Risk Factors For Recurrences

Of Central Serous Chorioretinopathy.

Retina. 2018;38(7):1403-1414.

8. Spaide R, Campeas L, Haas A, Yannuzzi

L, Fisher Y, Guyer D et al. Central

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UJO 2020 Volume 14, Issue 1 | November 2020 | Page 14

Review Article

AN INSIGHT TO KERATOCONUS: A CORNEAL ECTASIA

Dr Navjot Kaur, Dr Anuradha Raj, Dr Nikhil Agrawal

ABSTRACT Keywords: Keratoconus, Pachymetry,

Keratoconus is a bilateral progressive disease Rigid gas permeable lenses, Corneal
of corneal steepening and thinning. Ocular tomography, Collagen cross linking.

allergy and eye rubbing play a major role in INTRODUCTION

its pathogenesis. The diagnosis of

keratoconus is made first on the basis of high Keratoconus (KC) is a chronic, bilateral,

index of clinical suspicion. Then, careful degenerative, non-inflammatory disease of

evaluation using various diagnostic and the cornea, characterized by progressive

imaging tools including biomicroscopy, steepening, thinning, and apical scarring.

keratometry, keratoscopy, corneal Prevalence rates vary from 20 in 100,0001,2

topography and tomography, corneal to 1 in 500,000.3 Keratoconus was first

biomechanics, wave front analysis, specular described by John Nottingham.4 It is a

microscopy, confocal microscopy and anterior multifactorial disease; genetic,

segment OCT is done to aid in diagnosis. In environmental, and biochemical factors play

early stages, it is managed with spectacles important roles. Inheritance can be an

and contact lenses. Progression of autosomal recessive or dominant.1 Ocular

keratoconus can be hampered with corneal allergy plays a major role in pathogenesis.

collagen cross-linking. In later stages, optical Allergic conditions include vernal

optimization can be done with the help of keratoconjunctivitis (VKC), atopic

intracorneal ring segments (ICRS), toric keratoconjunctivitis and seasonal or

phakic intraocular lenses (tp-IOLs) and deep perennial allergic keratoconjunctivitis.

anterior lamellar keratoplasty (DALK) or Increased proteases, protease activity, and

penetrating keratoplasty (PK). Various above inflammatory molecules like histamines, TNF

said techniques can be combined to achieve alpha, IL-6 and metalloproteinases play an

best unaided visual acuity and regularize the important part in the pathogenesis of KC.5

cornea. Bowman membrane transplantation The Collaborative Longitudinal Evaluation of

and keraflex are newer techniques to Keratoconus (CLEK) study found that the

strengthen the cornea and correct irregular incidence of atopic disease was 53% in over

astigmatism. 1200 keratoconus patients.6 The Dundee

University Scottish Keratoconus study

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 15

(DUSKS) of 200 patients found that only inflammatory in nature, but it should be
reconsidered in light of the cytokine
11% of patients reported never rubbing their imbalance in the corneas of keratoconus
patients.9
eyes and 48% reported frequent eye rubbing
CLASSIFICATIONS
and reported atopic diseases including
Morphologically, keratoconus has three
asthma in 23%, eczema in 14%, and hay different types of cones (Table 1). Buxton et
al 10, have classified keratoconus based on
fever in 30% of the KC patients.7 It is found the keratometry: Mild if less than 45.00 D,
moderate if >45.00 D and <52.00 D,
to be associated with retinitis pigmentosa, advanced if > 52.00 D and < 62 D, and
severe if > 62.00 D. First classification was
Leber’s congenital amaurosis, blue sclera, proposed by Amsler11, later modified by
Krumeich et al.12 (Table 2). Alio and
congenital cataract, aniridia, Fuchs Shabayek13 did another modification to
Amsler-Krumeich grading system, that is,
dystrophy, posterior polymorphous they added root mean square of coma-like
aberrations (Table 3). Belin and Duncan (14)
dystrophy, granular dystrophy and lattice used anterior radius of curvature, posterior
radius of curvature, thinnest pachymetry and
dystrophy. Systemic associations include distance visual acuity to propose a
keratoconus classification (Table 4).
Marfan’s syndrome, Ehlers-Danlos syndrome,

osteogenesis imperfecta, congenital hip

dysplasia, Rieger’s syndrome, Crouzon’s

syndrome, floppy eyelid syndrome, Down’s

syndrome, Turners syndrome, atopic

dermatitis and mitral valve prolapse.

Recently, it has been found that the patients

with KC had lower serum vitamin D levels

than those of age- and sex-matched healthy

controls.8 Perhaps the classic definition of

keratoconus considered it as non-

TABLE 1: MORPHOLOGICAL CLASSIFICATION OF KERATOCONUS

Type Size (mm) Displacement Contact lens fitting
Nipple Good
Oval <5 Usually infero-nasal Fair
Globus Poor
5-6 Usually infero-temporal

>6 Generalized

TABLE 2: AMSLER-KRUMEICH CLASSIFICATION OF KERATOCONUS

Severity Mean central K (D) Thickness (µm) Spherical Cornea
4 Central scars
equivalent (D)

>55 <200 Not measurable

3 53–55 300–400 > −8 No central scars

2 <53 401–500 [−5, −8] No central scars

1 <48 >500 < −5 No central scars

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 16

TABLE 3: ALIO-SHABAYEK CLASSIFICATION OF KERATOCONUS

Severity Mean Thickness Spherical RMS of Cornea
central
4 K (D) (µm equivalent coma-like Central scars
3 No central scars
2 >55 (D) aberration (µm) No central scars
1 No central scars
53–55 <200 Not >4.5

measurable

300–400 > −8 >3.5 to ≤4.5

<53 401–500 [−5, −8] >2.5 to ≤3.5

<48 >500 < −5 1.5–2.5

TABLE 4: ABCD CLASSIFICATION

A BC D
ARC BDVA
>7.25 PRC Thinnest =20/20 Scar
>7.05 <20/20 -
Stage 0 >6.35 >5.90 >490 <20/40
Stage 1 >6.15 <20/100 -,+,++
Stage 2 <6.15 >5.70 >450 <20/400 -,+,++
Stage 3 -,+,++
Stage 4 >5.15 >400 -,+,++

>4.95 >300

<4.95 <300

DIAGNOSIS findings includes stromal thinning usually
infero-nasally but may be infero-temporally,
The diagnosis of keratoconus is made first on ectasia, posterior stress lines (Vogt’s striae),
iron ring (Fleischer ring), prominent corneal
the basis of high clinical suspicion and then nerves and subepithelial scar resulting from
ruptures in Bowman's layer (Figure 1). In
on careful evaluation using various diagnostic more advanced cases, deeper opacities can
be seen at the apex of the cone resulting
and imaging tools including biomicroscopy, from healed acute cornea hydrops due to
ruptures in the Descemet membrane. Other
keratometry, keratoscopy, corneal signs are scissoring on retinoscopy and Oil
droplet sign (“Charleaux”) on retro
topography and tomography, corneal illumination.

biomechanics, wave-front analysis, specular

microscopy and confocal microscopy and

anterior segment OCT.

1. Slit lamp examination: On external
examination, Munson’s sign and Rizzuti
phenomenon may be present. Slit-lamp

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 17

AB

Figure1: Slit lamp photo showing subepithelial apical scar on diffuse illumination (A), thinning and ectasia (B) on
parallelepiped slit.

2. Keratometry: It is a widely available tool Placido-based videokeratoscopy, displaying
for measuring corneal curvature. Inferior color-coded maps and quantitative data of
corneal steepening is an early sign of the front surface of the cornea.
keratoconus. There are patients with steep
corneas and high astigmatic errors who do 6. Corneal tomography: The term
not have keratoconus and, vice versa, “tomography” also derives from the Greek,
patients with keratoconus who have normal as the combination of “tomos” (to cut or
central curvature power. section) and “graphein” (to write). It is the
three-dimensional reconstruction of the
3. Photokeratoscopy: Compression of cornea characterizing the elevation of the
mires inferiorly (“egg-shaped” mires), also front and back surfaces of the cornea along
known as kerato-kyphosis indicating with pachymetric mapping15. Different
steepening. technologies, such as horizontal slit
scanning, rotational Scheimpflug, very-high
4. Videokeratoscopy: Localized increased frequency ultrasound, and optical coherence
surface power, inferior superior dioptric tomography (OCT) are available in many
asymmetry and relative skewing of the commercial instruments (Figure 2).
steepest radial axes above and below the
horizontal meridian. Curvature maps: Rabinowitz criteria 17:

5. Corneal topography: “Topography” a. Corneal power value greater than 47.2 D
derives from Greek words “topo” (to place)
and “graphein” (to write), which means to b. Inferior/superior dioptric asymmetry (I-S
describe a place. The term “corneal value) over 1.2
topography” has been used for the
reconstruction of the anterior corneal c. Sim-K astigmatism greater than 1.5 D,
surface15 Stephen D. Klyce16, developed
algorithms for surface reconstruction using d. Skewed radial axes (SRAX) greater than
21 degrees

Elevation maps: Abnormal values are > 12 inferior thicknes at the central 5-mm circle ≥
µm and > 15 µm on the anterior and 30 µm is considered abnormal.18
posterior elevation maps respectively at
5mm circle on BFTE mode.18 Thickness profile: The corneal thickness
spatial profile (CTSP) describes the average
Thickness maps: Thinning is defined as progression of thickness starting from the TL
corneal thickness < 470 µm with normal to corneal periphery in relation to zones
tomography or < 500 µm with abnormal concentric with the TL. Percentage thickness
tomography. Y Co-ordinates ≤500 µm is increase (PTI) percentage of progression of
considered as normal, between –500 to– the same. The normal profile follows the
1000 µm is suspicious and ≥1000 µm is course of the normative black dotted curves,
abnormal. Difference between pachymetry at with an average of 0.8–1.1. Quick Slop is
apex and thinnest location >10 µm is when it leaves its course before the 6-mm
abnormal. Difference between superior and zone. S-shape is another abnormal profile
seen in keratoconus.18

Figure 2: Pentacam
showing extreme corneal
steepening with eccentric
corneal thinning with
elevation on anterior and
posterior elevation floats.

7. Biomechanical measurement: The Applanation pressure is recorded at two
points: when the cornea is bending inward
Ocular Response Analyzer is used for and when the cornea is returning to its
measuring biomechanical properties of the normal state and the difference in the
cornea in response to an air puff.

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 19

applanation pressure at these two points is 10. Confocal microscopy: Confocal
termed corneal hysteresis. Keratoconus microscopy shows: elongated, exfoliating
patients have statistically lower hysteresis superficial epithelial cells; wide wing and
than normal patients. Corneal hysteresis and basal epithelial cells; prominent, thickened
corneal resistance factor were poor sub-basal nerves; thinning of the stroma;
parameters for discriminating between mild increased stromal haze and reflectivity due
keratoconus and normal corneas.19 scarring; structurally abnormal anterior
stromal keratocyte nuclei; lower densities of
8. Wavefront analysis: Gobbe and anterior and posterior stromal keratocytes;
coworkers showed that to differentiate folds in the anterior, mid, and posterior
between suspected KC and normal corneas stroma; folds in Descemet’s membrane;
vertical was coma with a specificity of 71.9 pleomorphism and polymegathism of
% and sensitivity of 89.3 % was the best endothelial cells and increased endothelial
detector.20 There were significantly more cell density.24
total ocular higher-order (HOA) aberrations
and coma was found to be 2.32 times higher 11. Anterior segment OCT Pachymetry:
than spherical-like aberrations in keratoconic The 5 diagnostic parameters are25;
eyes.21
a. Minimum-median.
9. Specular microscopy: There is a
significant increase in polymegathism and b. The I-S: The average thickness of the
pleomorphism compared with normal inferior (I) octant minus that of the superior
controls and a significant decrease in (S) octant.
hexagonality in the keratoconic cornea.
These changes are due to contact lens use c. The IT-SN: The average thickness of the
and are reversible on discontinuation.22 IT octant minus that of the SN octant.
Keratoconus is also associated with corneal
guttata.23 d. Minimum thickness 470µm

e. Vertical location of the minimum (Fig 3).

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 20

Figure 3: Pachymetry scan on
anterior segment optical
coherence tomography showing
diagnostic parameters for
Keratoconus

12. Corneal epithelial mapping with MANAGEMENT

segmental OCT: The epithelial pattern

found in keratoconic eyes is distinct, known Management of KC can be classified into 3

as the “doughnut pattern”. Corneal types: Corneal strengthening techniques,

epithelium undergoes compensatory Optical optimization techniques and

changes. The epithelium appears to remodel Combined techniques. Corneal collagen

to reduce the anterior stromal surface cross-linking (C3R) is used to strengthen the

protrusion and to smoothen the anterior cornea. Optical rehabilitation can be achieved

corneal surface by thinning over the cone with the help of spectacles, contact lenses,

and thickening around the cone. The intracorneal ring segments (ICRS), toric

difference between the thinnest and thickest phakic intraocular lenses (tp-IOLs) and deep

epithelium increases with advancing disease. anterior lamellar keratoplasty (DALK) or

Thus, epithelial thickness profile changes penetrating keratoplasty (PK). Various

with the progression of the disorder.26 refractive procedures can be combined with

C3R like LASIK, PRK, PTK, tp-IOLs or ICRS,

termed as C3R plus to achieve best

uncorrected visual activity. Recently,

Bowman membrane transplantation,

introduced to restore the corneal anatomy, intolerance may occur at which time RGP
stabilizes the corneal structure, flattens the lenses are needed.
surface, and arrests progression.
c. Rose K lenses: These are unique
1. Spectacles: Spectacles can suffice to keratoconus lenses designed with complex
correct for the regular astigmatism and the computer-generated peripheral curves based
very low amounts of irregular astigmatism in on data collected by Dr Paul Rose of
few cases. Even, in moderate cases Hamilton, New Zealand. Standard lenses with
spectacles can be the best choice if disease is fixed optical zones do not fit the cone of
stable. keratoconus patients due to undue pooling of
tear film underneath the contact lens. These
2. Contact lenses: Contact lenses provide a are specially designed with small optic zone
regular refracting surface over the cone by diameter to fit the cone. Rose K2 lenses have
bridging the gap between the irregular aspheric back surface. Rose K2 NC (nipple
corneal surface and the smooth regular inner cone), Rose K2 IC (irregular cornea), Rose
surface of contact lens by tear fluid, thereby K2 PG (post graft) and Rose K2 XL (semi-
creating the effect of a smoother cornea. scleral) are different varieties of lens designs
Various types of contact lenses are available fitted according to corneal topography.
in the market; soft/soft toric, rigid gas
permeable, rose-k lenses, hybrid, piggyback d. Piggyback lenses: Rigid gas permeable
and scleral lenes.27 lenses are worn over the soft contact lens in
this combination system. Indications include
a. Soft/soft toric contact lenses: These have RGP intolerance, unstable RGP and recurrent
very limited role in keratoconus. Indications corneal abrasion and scarring with RGP.
include very early keratoconus, glasses over
contact lenses, RGP intolerance and with e. Hybrid lenses: These lenses have a rigid
piggyback lenses. lens in the centre and a soft skirt in the
periphery. The diameter of the lens is 14.5
b. Rigid gas permeable lenses: Corneal RGP mm. These lenses are fitted with no or
lens is the first lens of choice for visual minimal apical touch in the central cornea.
improvement in keratoconus. The three Indications are same as piggy back lenses.
different types of contact lens fitting include The vault can vary between 100-600
apical clearance, apical bearing or three point microns.
touch. The three point touch is the most
widely accepted one. When the cylindrical f. Scleral lenses: These lenses vault the
power increases beyond 3.0 D, visual cornea and rest over the sclera with diameter

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 22

of 20-24mm. Mini scleral lenses have (f) Corneal ectasia after refractive surgery
diameter of 14-17mm. Intolerance to other
lenses, VKC, scar and advanced keratoconus The original Dresden protocol used an energy
are some of the indications of scleral lenses. dose of 5.6 J/cm2 with an intensity of 3
PROSE (Prosthetic Replacement of the Ocular mW/cm2 for an exposure time of 30 min.30 It
Surface Ecosystem, Boston Foundation for requires epithelial removal to allow sufficient
Sight, Needham Heights, Boston, MA, USA) penetration of the riboflavin molecules (Epi-
are customised non-fenestrated scleral OFF technique). Riboflavin 0.1% is a
contact lenses. photosensitizer which is instilled every 2 min
for 30 min. Central 8 mm of the cornea is
3. Corneal collagen cross-linking: C3R is irradiated with UV-light of a wave length of
a novel approach that aims at increasing the 370 nm and intensity of 3 mW/cm2 for 30
mechanical and biochemical stability of the min and riboflavin is applied every 5 min.
stromal tissue. The principle of this Effective C3R happens only if oxygen, UV
treatment is to create additional chemical light, and riboflavin are available in sufficient
bonds inside the corneal stroma by means of concentration.
photopolymerization using Riboflavin and
Ultraviolet A. The effects of cross-linking are The minimum corneal thickness required for
localized to the anterior 300 µm of the C3R treatment is 400 µm without the
stroma28 and it increases biomechanical epithelium. However, many techniques have
strength by 328.9% in human cornea.29 been developed to treat thinner corneas.
Indications are: These include transepithelial or epithelium-on
(Epi-On C3R), use of hypo-osmolar
(a) Documented progression of KC (Change preparations of riboflavin to produce corneal
of K-max by > 1 D, Thinning of the cornea swelling31, pachymetry- guided epithelial
by > 30, Increase of topographical debridement, soft contact lens assisted C3R,
astigmatism by > 1 D over 1 year) and tissue augmented C3R. Methods to
enhance penetration through intact
(b) KC with age under 20 years old epithelium include the use of topical
anaesthetics, longer application of riboflavin,
(c) Pellucid marginal degeneration iontophoresis32, and benzalkonium chloride-
EDTA (BAC-EDTA) riboflavin-UVA Epi-On.33
(d) To stabilize or to prepare the cornea with
KC before Photo refractive keratectomy Accelerated protocols: According to the
(PRK) photochemical law of reciprocity (Bunsen-
Roscoe law), the same photochemical effect
(e) Forme fruste KC before PRK

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 23

can be achieved with reduced irradiation time stromal ablation (maximum 50 µm) and
with increased irradiation intensity.34 3-min irradiation at higher fluence (10mW/cm2).38
irradiation at 30 mW/cm2, 5-min irradiation Minimum thickness required for this
at 18.0 mW/cm2, and 10-min irradiation at procedure is 450 µm.
9.0 mW/cm2 should provide the same effect
obtained with a 30-min irradiation at 3.0 C3R with PTK: Combined transepithelial
mW/cm2, all delivering 5.4 J/cm2 of phototherapeutic keratectomy and corneal
fluence.35 Only last two protocols are collagen crosslinking for ectatic disorders is
commonly used. The biomechanical effect known as cretan protocol.39 It resulted in
decreases with higher radiation energy and better visual, refractive, and keratometric
less time with even no effect at a cut-off of outcomes compared with mechanical
45 mW/cm2 respectively.36 These results epithelial debridement over a long-term
confirmed that intrastromal oxygen diffusion follow-up.40
capacity and increased oxygen consumption
associated with higher irradiances may be a It results in reduction of K-max by 1.0–2.0
limiting factor leading to reduced treatment D, stability that is statistically proven over 48
efficiency.36 months,1–2 line gain in BSCVA and low-to
moderate haze up to 6 months post surgery.
Pulsed Accelerated Cross-Linking: It has C3R is contraindicated in Corneal thickness <
been evidenced that the corneal cross-linking 400 µm, K-max > 58 D, high visual
is an oxygen-dependent reaction. In expectations, corneal epithelial healing
accelerated protocols, depletion of oxygen disorders, previous herpes keratitis, corneal
occurs, thereby compromising the corneal melting disorders (RA), pregnancy, eye
collagen covalent bond formation and hence rubbing habits and corneal scarring.
its effectiveness. Pulsing the UV light during
crosslinking treatment seems to allow the 4. Intrastromal Corneal Ring Segments
achievement of an additional oxygen (ICRS): These tiny ring segments are made
concentration and give a better functional of biocompatible polymethylmethacrylate. It
outcome compared to continuous light is based on Barraquer thickness law which
procedure.37 states that when a material is added to the
periphery of the cornea or an equal amount
C3R with PRK: The procedure known as the of material is removed from the central area,
Athens Protocol involves sequentially a flattening effect is achieved. In contrast,
excimer-laser epithelial debridement (50 when a material is added to the centre or
µm), partial topography-guided excimer laser removed from the corneal periphery, the
surface curvature is steepened. The smaller

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 24

the diameter, the greater the correction and the treatment of keratoconus because of its
the greater the thickness, the greater the low risk of rejection and complications.42
correction. Various types of ICRS are ferrara Currently trends are towards femtosecond
rings, keraring and intrastromal rings (Table laser assisted DALK (F- DALK). The mean
5). Indication is mild to moderate keratometry and apical keratometry values
keratoconus with contact lens intolerance, were significantly greater for manual DALK
corneal thickness > 350 µm at the thinnest than F-DALK, while the keratometric
location, maximal K-reading < 60 D, astigmatism was similar.43
refractive error (S.E) ≤ 6 D, clear cornea
with no central scars or stress lines and 6.Toric phakic intraocular lenses (tp-
thickness at incision site ≥ 450µ. The devices IOL): These are alternative resort to
are inserted into stromal tunnels which can keratoplasty for higher spherical
fashioned manually using a handheld equivalent. They offer correction of higher
diamond blade or automatically using a spherical equivalent than ICRS and have a
femtosecond laser. ICRS are contraindicated much faster rehabilitation than corneal
in high visual expectations, uncontrolled transplantation. Contact lens intolerance with
autoimmune disease, pregnancy and during a clear cornea and stable refraction along
nursing, continuous eye rubbing habits, with deep anterior chambers (AC) are good
corneal thickness < 350 µm at the thinnest candidates for phakic IOLs. They are less
location, maximal K-reading > 65 D and suitable in presence of high irregular
corneal scarring. astigmatism. Toric ICL implantation was
effective, predictable and safe to correct
5. Keratoplasty: DALK and PK are the last refractive error and improve visual acuity in
resort for the management of KC. Anterior patients with stable KC.44 In cases of
corneal scars, advanced disease with stress progressive keratoconus, C3R is first done to
lines and clear cornea, K-max > 60D, stabilize cornea then at second stage tp-IOL
thinnest location < 350 µm and very high can be done.45 ICRS can be combined with
refractive error (sphere > −6 and/or cylinder tp-IOL, in cases of decentered cone.46
> −6) are indications for DALK. PK is Complications include risk of endothelial cell
indicated when there is posterior corneal scar loss and significant pigment dispersion with
due to healed hydrops. There is reduced anterior chamber IOLs and development of
rejection and refractive astigmatism with anterior subcapsular cataract, rotation of
DALK but better visual outcomes with PK.41 toric ICL and glaucoma in cases of posterior
But still, deep anterior lamellar keratoplasty chamber IOLs.
is preferred over penetrating keratoplasty for

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 25

TABLE 5: CHARACTERISTICS OF ICRS IMPLANTS

Characteristics INTACS Ferrara Ring Keraring
Arc Length (degrees) 90,120,160,210,240
Cross section 150 160 Triangular
Thickness (mm) 0.15-0.30
Hexagonal Triangular (0.05 increments)
Inner Radius (mm) 5.0
Outer Radius (mm) 0.25-0.45 0.20-0.35 6.0

(0.05 increments) (0.05 increments)

6.77 4.40

8.10 5.60

7. Bowman membrane transplantation: extensively studied and various protocols
Van Dijk et al introduced the idea of an
isolated Bowman layer inlay into a manually have been made to improve its efficacy. In
dissected mid-stromal pocket in advanced
keratoconus. It helps to restore the corneal advanced cases, it can be best dealt with tp-
anatomy, stabilize the corneal structure,
flatten the surface, and arrest IOL and keratoplasty. Refractive procedures,
progression. Bowman layer transplantation
seems to be a promising, minimally invasive like PRK, PTK and tp-IOL have been
technique for advanced keratoconus with a
reported 5-year success rate of 84%.47 successfully combined with C3R in cases of

8. Keraflex: It is a new method for progressive keratoconus to achieve regular
keratoconus treatment. In this method, low
energy microwaves are used for less than 1 anterior corneal surface. Bowman membrane
second along with mitomycin and UV rays as
accelerated C3R. Collagen shrinkage occurs transplantation is a new add on in the
at 150 µm in the stroma, as the temperature
rises to 650C and this effect is then locked management of KC.
with the help of C3R.48
CONFLICT OF INTEREST : Nil
CONCLUSION
FINANCIAL SUPPORT: Nil
Corneal tomography is a bench mark in early
diagnosis and management of keratoconus. Correspondence Address
Mini sclera or scleral lenses are especially
useful even in cases of irregular astigmatism Dr Anuradha Raj
and VKC. Collagen cross-linking has been Associate Professor,
Department of Ophthalmology,
All India Institute of Medical Sciences, Bathinda,
Punjab.
E-mail:[email protected]

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sensor in patients with keratoconus. 31. Hafezi F, Mrochen M, Iseli HP, Seiler

Ophthalmology. 2002;109:1996– T. Collagen crosslinking with

2003. ultraviolet-A and hypoosmolar

22. Sibug ME, Datiles 3rd MB, Kashima K, riboflavin solution in thin corneas. J

McCain L, Kracher G. Specular Cataract Refract Surg. 2009;35:621–

microscopy studies on the corneal 624.

endothelium after cessation of contact 32. Kymionis GD, Diakonis VF,

lens wear. Cornea. 1991;10:395–401. Coskunseven E, et al. Customized

23. Ramos I, et al. Keratoconus pachymetric guided epithelial

associated with corneal guttata. Int J debridement for corneal collagen

Kerat Ect Cor Dis.2012;1:173–8. cross linking. BMC Ophthalmol.

24. Hollingsworth JG, Efron N, Tullo AB. 2009;9:10. Vinciguerra P, Randleman

In vivo corneal confocal microscopy in JB, Romano V, et al. Transepithelial

keratoconus. Ophthalmic Physiol Opt. iontophoresis corneal collagen cross-

2005;25:254–260. linking for progressive keratoconus:

25. Li Y, Meisler DM, Tang M, et al. initial clinical outcomes. J Refract

Keratoconus diagnosis with optical Surg. 2014;30(11):746–53.

coherence tomography pachymetry 33. Torricelli AA, Ford MR, Singh V, et al.

mapping. Ophthalmology. BAC-EDTA transepithelial riboflavin-

2008;115(12):2159–2166. UVA crosslinking has greater

26. Reinstein DZ, Archer TJ, Gobbe M. biomechanical stiffening effect than

Corneal epithelial thickness profi le in standard epithelium-off in rabbit

the diagnosis of keratoconus. J corneas. Exp Eye Res. 2014;125:114–

Refract Surg. 2009;25:604–610. 117.

27. Rathi VM, Mandathara PS, Dumpati S. 34. Schumacher S, Oeftiger L, Mrochen

Contact lens in keratoconus. Indian J M. Equivalence of biomechanical

Ophthalmol 2013;61:410-415. changes induced by rapid and

28. Kohlhaas M, Spoerl E, Schilde T, et al. standard corneal cross-linking, using

Biomechanical evidence of the riboflavin and ultraviolet radiation.

distribution of cross-links in corneas Invest Ophthalmol Vis Sci.

treated with riboflavin and ultraviolet 2011;52:9048–9052.

A light. J Cataract & Refractive 35. Hammer A, Richoz O, Arba Mosquera

Surgery. 2006;32(2):279–283. S, et al. Corneal biomechanical

29. Wollensak G, Spoerl E, Seiler T. properties at different corneal cross-

Stress-strain measurements of human linking (CXL) irradiances. Invest

and porcine corneas after riboflavin- Ophthalmol Vis Sci. 2014;55:2881–

ultraviolet-A-induced cross-linking. J 2884.

Cataract Refract Surg. 36. Wernli J, Schumacher S, Spoerl E, et

2003;29(9):1780–1785. al. The efficacy of corneal cross-

30. Wollensak G, Spoerl E, Seiler T. linking shows a sudden decrease with
Riboflavin/ultraviolet-a-induced
very high intensity UV light and short

collagen crosslinking for the

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treatment time. Invest Ophthalmol Keratoplasty for Keratoconus

Vis Sci. 2013;54:1176–1180. [published online ahead of print, 2019

37. Mazzotta C, Traversi C, Paradiso AL, Nov 13]. Exp Clin Transplant.

Latronico ME, Rechichi M. Pulsed light 2019;10.6002/ect.2019.0123.

accelerated crosslinking versus doi:10.6002/ect.2019.0123

continuous light accelerated 43. Salouti R, Zamani M, Ghoreyshi M,

crosslinking: one-year results. J Dapena I, Melles GRJ, Nowroozzadeh

Ophthalmol. 2014;2014:604731. MH. Comparison between manual

38. Kanellopoulos AJ. Long term results of trephination versus femtosecond

a prospective randomized bilateral laser-assisted deep anterior lamellar

eye comparison trial of higher fluence, keratoplasty for keratoconus. Br J

shorter duration ultraviolet A Ophthalmol. 2019;103(12):1716-

radiation, and riboflavin collagen 1723. doi:10.1136/bjophthalmol-

cross-linking for progressive 2018-313365

keratoconus. Clin Ophthalmol. 44. Emerah SH, Sabry MM, Saad HA,

2012;6:97–101. Ghobashy WA. Visual and refractive

39. Kymionis GD, Grentzelos MA, outcomes of posterior chamber phakic

Kankariya VP, Pallikaris IG. Combined IOL in stable keratoconus. Int J

transepithelial phototherapeutic Ophthalmol. 2019;12(5):840-843.

keratectomy and corneal collagen Published 2019 May 18.

crosslinking for ectatic disorders: doi:10.18240/ijo.2019.05.22

cretan protocol. J Cataract Refract 45. Goggin M. Crosslinking and toric

Surg. 2013;39(12):1939. phakic IOL in keratoconus. J Cataract

40. Kymionis GD, Grentzelos MA, Refract Surg. 2012;38(8):1514-1515.

Kankariya VP, et al. Long-term results 46. Ferreira TB, Güell JL, Manero F.

of combined transepithelial Combined intracorneal ring segments

phototherapeutic keratectomy and and iris-fixated phakic intraocular lens

corneal collagen crosslinking for keratoconus refractive and visual

for keratoconus: Cretan protocol. J improvement. J Refract Surg.

Cataract Refract Surg. 2014;30(5):336-341.

2014;40(9):1439-1445. 47. Tong CM, van Dijk K, Melles GRJ.

doi:10.1016/j.jcrs.2014.01.040 Update on Bowman layer

41. Henein C, Nanavaty MA. Systematic transplantation. Curr Opin

review comparing penetrating Ophthalmol. 2019;30(4):249-255.

keratoplasty and deep anterior 48. Vega-Estrada A, Alió JL, Plaza Puche

lamellar keratoplasty for management AB, Marshall J. Outcomes of a new

of keratoconus. Cont Lens Anterior microwave procedure followed by

Eye. 2017;40(1):3-14. accelerated cross-linking for the

doi:10.1016/j.clae.2016.10.001 treatment of keratoconus: a pilot

42. Song Y, Zhang J, Pan Z. Systematic study. J Refract Surg 2012; 28:787-

Review and Meta-Analysis of Clinical 793.

Outcomes of Penetrating Keratoplasty

Versus Deep Anterior Lamellar

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 29

Review Article

OCULAR ADVERSE EFFECTS CAUSED BY SYSTEMIC DRUG THERAPY –
A REVIEW

Dr Gauri Mittal, Dr Sucharita Das, Dr Manisha Bisht

INTRODUCTION PATHOPHYSIOLOGY

A variety of systemic drugs are known to Drug molecules in systemic circulation can
have toxic effects on the ocular tissue. The gain entry into the ocular structures by way
adverse effects include keratopathy, uveitis, of the uveal or retinal vasculature.3
cataract, retinopathy, optic neuropathy and
visual field defects.1 Due to the long-term The various ocular barriers which
use of systemic medications, some serious prevent systemic drugs from entering
side effects are coming to light, hence the eye can be classified as follows:
practitioners have to be made aware of them
as they seriously impair vision and are 1. Anatomical barriers
irreversible.2
a) Cornea
Certain elements increase the likelihood of It is the initial barrier to the
ocular side effects such as rich blood supply, absorption of topically administered
the relatively small total mass of the eye, drugs. It is resistant to both
long duration of use of medication, altered hydrophilic and lipophilic drugs. The
metabolism, and excretion of the drug owing corneal epithelium has tight
to decreased function of kidney and liver intercellular junctions which result in
subsequent to patient’s age or due to pre- restricted passage of hydrophilic
existing conditions affecting the concerned drugs through transcellular pathways
organ.3 and small molecules through the
paracellular pathway. The hydrated
This article reviews commonly used drugs stroma acts as a barrier to
causing ocular adverse effects to emphasize penetration of only highly lipophilic
that it can be averted, monitored, and even drugs and consists of collagen fibrils
reversed if the clinician and patient are in a lamellar arrangement which
sensitized about it. restricts diffusion of larger
molecules.4,5

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 30

transclerally to reach the choroid.

b) Conjunctiva Also, drugs from systemic circulation
The conjunctival epithelium has tight
intercellular junctions, which restrict easily penetrate to choroidal
paracellular drug transport, although
conjunctiva is relatively more extravascular space. Although,
permeable to hydrophilic molecules
and macromolecules compared to the choroid receives only a fraction of
cornea and presents 20 times greater
surface area.6,7 Some studies suggest total blood flow and drug permeation
that conjunctival circulation plays a
more vital role in drug clearance as from choroid to retina is limited by
compared to choroidal circulation.8,9
retinal pigment epithelium (RPE)(7).
c) Sclera
Sclera comprises of collagen fibres Bruch's membrane is permeable to
and proteoglycans in an extracellular
matrix. Advantages of the transscleral hydrophilic molecules, it binds to
route are as follows (i) large surface
area for absorption (ii) hydrated lipophilic molecules, resisting their
stroma, facilitating the diffusion of
hydrophilic molecules (iii) absence of permeation. Aging decreases
metabolic activity, suitability for the
administration of enzyme labile drugs permeability of Bruch's membrane to
(iv) relatively high permeability to
macromolecules (v) Ease of solutes and an inverse relation is
administration of controlled release
dosage forms.10 observed between the molecular

d) Choroid radius and permeability of the drug
The choroid is a very vascular tissue
and exhibits leaky vasculature. Drugs across bovine RPE- choroid.10,11
that escape conjunctival and
episcleral circulation can pass e) Retina
Retina has wide intercellular spaces
without tight junctions due to which
small hydrophilic/ lipophilic drugs can
permeate the retina, although large
and cationic molecules face resistance
to permeation in the retina.12

2. Blood ocular barriers

a) The blood-aqueous barrier
Comprises of the endothelium of iris
or ciliary blood vessels and non-
pigmented ciliary epithelium. It
demonstrates tight junctional
complexes, limiting the entry of

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 31

solutes into an intra-ocular Drugs having adverse effects on ocular
environment e.g. aqueous humour.4 structures
The barrier also limits the influx of
hydrophilic drugs from plasma into a) Eyelid
the aqueous humour. It is
compromised in the presence of Erythema multiforme which can
inflammation, which increases drug
permeation.7 present as a macule, papule or bullae,

b) The blood-retinal barrier is an acute self-limiting dermatosis. It
Prevents the influx of plasma
components, water, and toxic may involve skin only, or in its severe
substances into the retina. It
comprises of an outer blood-retinal form starts with high fever and
barrier (retinal pigment epithelium)
and an inner blood-retinal barrier prostration, mainly as a bullous
(tight junction endothelium of retinal
blood vessels).13 eruption of the skin and mucous
Paracellular transport through retinal
capillaries is restricted by the tight membrane.
junctions, however, certain larger-
size molecules can transcellularly The list of drugs causing erythema
permeate by passive diffusion and/or
active transport (e.g., ganciclovir or multiforme consists of paracetamol
dexamethasone).14,15
The outer blood-retinal barrier is (acetaminophen), amiodarone,
composed of tight gap and adherent
junctions that can be removed by allopurinol, ampicillin, captopril,
molecules via passive diffusion, it
exhibits significant resistance to cefazolin, clindamycin, doxycycline,
hydrophilic molecules and limited
permeability to macromolecules.16 isoniazid, phenobarbital, penicillin,

sulfadiazine, sulfonamides, and

vancomycin.18

b) Cornea

Drugs administered by systemic route

may reach the cornea via different

routes, like the tear film, aqueous

humour, and limbal vasculature,

which may potentially lead to toxicity.

Vortex keratopathy (cornea

verticillate), is a grayish or golden-

brown deposit in the corneal

epithelium in bilateral corneal

subepithelial whorl-like fashion.

i. Tamoxifen (estrogen receptor

antagonist), used in the

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 32

treatment of breast cancer causes vi. Rifabutin indicated for the
treatment of Mycobacterium
corneal verticillata. Avium Complex (MAC) infections
causes fine, diffuse, white,
ii. Amiodarone(anti-arrhythmic stellate corneal endothelial
deposits.19
drug)indicated in the treatment

and prevention of certain types of

serious, life-threatening

ventricular arrhythmias, is

reported to cause diffuse and fine c) Sclera
i. Fosamax, a bisphosphonate that
deposits resembling keratic is prescribed for postmenopausal
women to prevent calcium loss in
precipitation in the central portion bone, can cause scleritis.2
ii. Minocycline, a broad-spectrum
of the endothelium and vortex tetracycline antibiotic used to
treat chronic acne vulgaris causes
keratopathy within 1–4 months of blue pigmentary changes to the
sclera.20
the initiation of therapy.

iii. Cytarabine (antimetabolite)

indicated in the treatment of

acute myeloid leukaemia (AML)

may cause corneal epithelial

toxicity, punctuate keratopathy,

and fine refractile corneal d) Uvea

epithelial microcysts. i. Tamsulosin (α1-Adrenergic

iv. Chlorpromazine (psychotropic receptor antagonists) inhibits the

agent) can induce abnormal sympathetic autonomic nervous

pigmentation of the cornea, system, which results in

corneal edema, deposition of relaxation of the smooth muscles

numerous white granules in the in the neck of the bladder and

subepithelial corneal stroma at prostatic urethra as well as in the

high doses of the drug. iris. This leads to intraoperative

v. Clofazimine recommended for the floppy iris syndrome in patients

treatment of leprosy, psoriasis, undergoing cataract surgery.

pyoderma gangrenosum, and There is a propensity for the

discoid lupus has been reported floppy iris stroma to prolapse

to cause discoloration (reddish- toward the surgical incision

brown) of the cornea. despite proper wound

construction and pupil constriction

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 33

even with standard preoperative f) Anterior chamber angle

pharmacological measures.18 i. Certain drugs (β- blockers and
cardiac glycosides like digoxin)
ii. Rifabutin has been associated reduce IOP by decreasing the
aqueous production.
with anterior uveitis, intermediate
ii. Antihistaminic and antipsychotic
uveitis, and panuveitis.21 agents (phenothiazines and
Tricyclic anti-depressants) due to
iii. Cidofovir used for their anticholinergic effect
produce pupillary dilatation and
cytomegalovirus retinitis can lead produce narrow angle glaucoma.

to non-granulomatous anterior iii. Corticosteroids: There are steroid
specific receptors on the
uveitis.1 trabecular meshwork (TM), these
TM cells get activated by steroids
e) Pupil and cause accumulation of
amorphous material in the
i. Sympathetic innervation supplies extracellular matrix, thickening of
trabecular beams and juxta
the dilator pupillae and canalicular tissue and thereby
decrease the out-flow space for
parasympathetic innervation aqueous humour. On tapering or
discontinuation of steroids, the
supply the sphincter pupillae IOP usually returns to normal
levels within 2-4 weeks but in
muscles of the iris. Drugs some cases, the IOP remains high
for a long time.22
affecting the autonomic pathway
g) Lens
can hence affect the size and
i. There is accumulation of water
activity of the pupil. within the lens fibres and
agglutination of lens proteins due
ii. Mydriasis is caused by anti- to inhibition of the sodium-

cholinergic agents (atropine), and

other agents having an

anticholinergic activity like

tricyclic antidepressants,

antipsychotics (chlorpromazine

and fluphenazine), antihistaminic.

iii. Miosis is caused by Codeine,

Morphine, and Anticholinesterases

(neostigmine).22

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 34

potassium pump in the lens v. Busulfan an alkylating agent used
epithelium. in the palliative treatment of
ii. Corticosteroids: Another school of chronic granulocytic leukaemia
thought is that there is an and other blood dyscrasias causes
elevation of glucose in the plasma a scattered punctate cortical
and aqueous humor which leads opacity leading to posterior
to an increase in cation subcapsular lens opacity.18
permeability, inhibition of
glucose-6-phosphate h) Vitreous
dehydrogenase, inhibition of
ribonucleic acid synthesis, and Rivaroxaban (New oral anticoagulants) used
loss of lens ATP. Therefore, there for atrial fibrillation and deep vein
is formation of posterior thrombosis, acts by binding and neutralizing
subcapsular cataract in patients clotting factors or components of the
treated with corticosteroids.2 coagulation cascade leading to dense
iii. The lens opacities may progress vitreous haemorrhage.23
or remain stationary but rarely
regress upon withdrawal of the i) Optic nerve
corticosteroids.18
iv. Phenothiazines (Chlorpromazine i. Ethambutol chelates copper in the
and thioridazine) are a group of
psychotropic medications used to retinal ganglion cells and their
treat depressive, involutional,
senile, or organic psychoses and axons in the optic nerve.
various forms of schizophrenia.
These medications lead to the Reduction in copper level affects
accumulation of fine, white to
yellowish-brown granules in the cytochrome c oxidase activity in
anterior cortex just beneath the
capsule in the area of the the mitochondria, compromising
pupillary aperture, which arranges
in a stellate pattern and develops the energy supply required for
into true anterior polar cataract.18
axonal transport, which leads to

optic neuropathy. Clinical findings

are loss of visual acuity, colour

vision loss and visual field defect

(central scotoma).18

ii. Linezolid (oxazolidinone

derivative), is an antibacterial

agent used for the treatment of

severe infections of gram-positive

bacteria [streptococci,

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 35

vancomycin-resistant enterococci j) Retina
(VRE), and methicillin-resistant
staphylococcus aureus (MRSA)] i. Systemically administered drugs
that are resistant to other
antimicrobial therapies. The are restricted by the blood-retinal
mechanism of linezolid-induced
optic neuropathy may be due to barrier to enter into the retina.
the impairment of mitochondrial
protein synthesis. It causes a Although, drug molecules
symmetric painless decrease in
vision, colour vision, bilateral permeate into the retina via the
visual field defect, swollen or pale
optic disc, bilateral central circulatory system. A wide variety
scotomas, and peripheral
neuropathy.19 of systemically administered
iii. Amiodarone is an antiarrhythmic
medication, used for ventricular drugs can cause retinal toxicity
arrhythmias and atrial fibrillation.
It is a cationic amphophilic but a toxicity-induced loss of
moiety, has a long half-life and
high interaction with polar lipids, visual function is minimal or
which leads to subsequent
accumulation of amiodarone and reversible following
its metabolites as lysosomal
inclusion bodies in multiple discontinuation of therapy.19
tissues, including the optic nerve.
Amiodarone optic neuropathy is ii. There is degeneration, edema,
characterized by gradual onset,
slow progression, bilateral vision alterations in the pigment,
loss with prolonged disc
swelling.19 detachment, inflammation,

haemorrhages, and crystalline

deposits in drug-induced

retinopathy.

Vigabatrin, an antiepileptic drug

causes visual degradation,

haziness, and loss in the field of

vision. Retinopathy is irreversible.

Interferon (INF) therapy is given

in chronic hepatitis B & C, genital

warts, leukaemia, AIDS-related

Kaposi’s sarcoma, and malignant

melanoma. There is retinal

vascular endothelial dysfunction

due to an increase in retinal blood

flow and retinal wall shear rate.

On discontinuation of INF

therapy, this condition is

reversible. Ocular presentations

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 36

include bilateral cotton wool spot, reversible upon discontinuation of

retinal haemorrhage and edema, therapy.

retinal microaneurysms, central iv. Topiramate is prescribed as an

retinal vein occlusion, and loss of anticonvulsant drug to treat

visual acuity. epilepsy. Topiramate induced

Tamoxifen, indicated for the maculopathy is irreversible even

treatment of breast cancer upon discontinuation. On

increases cell membrane fluidity examination, the patient has

and protein kinase c activity bilateral paracentral scotomas.

which influences the rod outer The fundus examination reveals

segment binding and ingestion by bilateral maculopathy. A large

retinal pigment epithelial cells, accumulation of gamma-

suggesting membrane-mediated aminobutyric acid in the inner

pathways. It can cause severe retina may explain the retinal

bilateral pigmentary and toxicity of systemic topiramate.

crystalline retinopathy and visual v. Chloroquine and

field loss. hydroxychloroquine are used in

iii. Long-term therapy of systemic the treatment of malaria,

corticosteroids causes severe, extraintestinal amoebiasis,

chronic, and recurrent central rheumatoid arthritis, and lupus

serous chorioretinopathy. Serous erythematosus. It causes bull's

or exudative retinal detachment eye maculopathy, which results in

may occur due to the build-up of loss of the foveal reflex,

serous or haemorrhage fluid in parafoveal retinal pigment

the subretinal space because of epithelium irregularities, and light

hydrostatic pressure or parafoveal hypochromic lesions. It

inflammation. is usually reversible only in its

Sunitinib is used to treat earliest phases, thus early

metastatic renal cell carcinoma. It detection of toxic reaction is

causes bilateral neurosensory essential.19

retinal detachment, and diffuse vi. Thioridazine, a phenothiazine, is

oedema which is due to changes an antipsychotic drug that gets

in choroidal vascular permeability concentrated in retinal pigment

and perfusion. Although it is epithelium by binding to melanin

UJO 2020 Volume 14, Issue 1 | November 2020 | Page 37

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UJO 2020 Volume 14, Issue 1 | November 2020 | Page 39

Review Article

TOXIC OPTIC NEUROPATHY: A DIAGNOSTIC DILEMMA.

Dr Nidhi Paharia, Dr Anuradha Raj, Dr Nikhil Agrawal

ABSTRACT the incidence is relatively less in the
economically developed country yet in a
Toxic optic neuropathy (TON)/ Nutritional developing country, we come across a high
optic neuropathy (NON) is a disease that is volume of such patients, because of greater
frequently underdiagnosed/misdiagnosed. exposure of the people to toxic substances in
They present with a similar clinical picture of environment, food, and co-existing
symmetric progressive bilateral vision loss, malnutrition. No racial, gender and age-
decreased colour vision, central scotoma on dependent predisposition have been
visual field testing, and no Relative Afferent observed. Toxic and nutritional optic
Pupillary Defects because of the symmetric neuropathies present clinically with similar
nature of optic nerve involvement. TON is clinical pictures, so the final diagnosis is
caused by damage to optic nerve through often confusing and becomes a challenge to
different toxins, drugs, metals, and solvents, differentiate them from hereditary
whereas NON is due to deficiency of B mitochondrial optic neuropathy. This article
vitamins, folic acid, and amino acids. They provides an insight into the common causes,
are often diagnosed at a stage when the clinical features, and management along with
damage is done, and visual recovery is not detailed discussion of known toxic drugs.
possible.
ETIOLOGY
Keywords: Toxic optic neuropathy,
In a case of TON, the optic nerve suffers
Nutritional optic neuropathy, Colour vision, damage from various drugs, including toxins,
Visual fields methanol, tobacco, metals, and organic
solvents. The most common etiological
INTRODUCTION

In our day-to-day life, we come across a agents in a developing country like India
crossroads, where our clinical acumen is include methanol (wood alcohol), disulfiram
judged, such as to differentiate a diagnosis treatment for chronic alcoholics, ethanol,
of Toxic optic neuropathy (TON) vs. toxicity, and drugs (antitubercular, antibiotic,
Nutritional optic neuropathy (NON). Although antimalarial), tobacco and others. (Table 1)

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COMMON CAUSES OF TOXIC OPTIC NEUROPATHY

Alcohols: Methanol, Ethanol

Antitubercular drugs: Isoniazid, Ethambutol, Streptomycin

Antibiotics: linezolid, ciprofloxacin, cimetidine, chloramphenicol

Antiarrhythmic agents: Amiodarone, Digitalis

Anti-inflammatory drugs: infliximab, etarnacept, adalimumab

Antiepileptic drugs: Vigabatrin

Anticancer drug: Vincristine, Methotrexate, cisplatin, carboplatin

Anti-malarial drugs: Chloroquine, Quinine

Heavy metals: lead, mercury, thallium

Phosphodiesterase inhibitors: Viagra, sildenafil, tadalafil,
vardenafil

Others: tobacco, smoking

PATHOPHYSIOLOGY or more neurotoxic drugs act synergistically
to cause pronounced nerve injury. Patients
Optic neuropathy occurs following exposure with specific genotypes are more susceptible
to neuro-poisonous substances present in the to damage by toxins.1-2 In rare instances,
environment, intake of certain toxins TON is associated with an immune-mediated
containing food, and drug intake. TON is both component.3 The symptoms observed with
dose as well as duration dependent. Pre TON are either reversible/stabilizes most of
diagnosed patients with neuropathy are at the time when the offending drug is
risk of neurotoxic damage by the use of discontinued early. However, the prognosis
certain drugs. It has also been seen that two depends on the nature of substance involved,
degree of exposure before cessation, and

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visual acuity at diagnosis, which is again is involved with nicotinic cascade. The toxic
complicated by the level of damage effects of alcohol and tobacco are seen
irreversibly. In many patients, despite metabolically. A deficiency of Vitamin B12 or
discontinuation of the drug, damage done folate is observed following chronic exposure.
could not be restored, and no treatment has With time, these deficiencies of vitamins
been proved effective.4-5 aggravate, and there is an accumulation of
formic acid. The formic acid and cyanide
In patients of TON, the damage is not only produced to inhibit the mitochondrial function
limited to the optic nerve but also seen in (inhibiting the electron transport chain),
retina, chiasma, and optic tracts. The exact leading to disruption of ATP production,
mechanism of TON is still not well elucidated. ultimately impairs the ATP dependent axonal
The various toxins act differently on the optic transport system.
nerve. Most of the toxins cause damage to
mitochondrial oxidative phosphorylation Ethambutol also possesses the chelating
pathway. Thus, the final common pathogenic property. It is hypothesized that it
event is considered to be a mitochondrial contributes to its neurotoxicity. It leads to a
injury and an imbalance of extracellular & calcium influx into the mitochondria, and
intracellular homeostasis of free radicals.6 thus excitotoxicity is observed.9,10
This explains the similarity of TON with LHON
(Leber’s Hereditary Optic Neuropathy). TON EXAMINATIONS
is argued to be acquired mitochondrial optic
neuropathies which also have a similar History:
clinical picture.6
A complete detailed medical history and
Patients who frequently abuse alcohol & careful eye, physical, and neurologic
tobacco are generally malnourished7-8 and examination are prerequisites to diagnosing
considered more susceptible to develop both TON. An extensive history is required to
TON & NON. Nutritional optic neuropathy is uncover circumstances and situations that
more commonly caused by the deficiency of might have caused exposure to toxins.
B-complex vitamins, particularly vitamin B1 Further testing is guided by medical/physical
(thiamine), vitamin B 12 (cyanocobalamin). examination.
The other B complex vitamins like B3
(niacin), B6 (pyridoxine), and folic acid also Laboratory testing is also a valuable tool in
seem to have a role in pathogenesis. concluding the final diagnosis. Patients with
Tobacco produces metabolic deficiencies as it suspected TON samples should be sent to the
laboratory for total and differential leucocyte

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count, complete hemogram, and urinalysis. peripheral optic neuropathy.11
The blood and urine samples also need to be
screened for specific toxins, especially if At times the diagnosis of TON is challenging
exposure to a particular one is not identified because of the presence of comorbidities.
in history. If history is present or suspected, The various neurotoxic drugs are which are
identification of specific toxins (methanol, administered as a treatment for systemic
heavy metal) or its metabolites should be conditions are themselves associated with
screened in blood and urine. In order to peripheral neuropathy. It is essential to
exclude nutritional optic neuropathy, realize that the neurotoxins producing
pernicious anemia (serum B-12) and general damage in the periphery can themselves lead
nutritional status (red cell folate level) need to greater injury to the Central Nervous
to be analyzed. The other tests include System or other organs. In these cases, the
vitamin assays, serum protein concentration, peripheral neuropathy will be overshadowed
and anti-oxidant levels. Liver enzymes may by other symptoms. This becomes apparent
indicate alcoholism.11,12 gradually when the patient will recover.13

The ingestion of systemic drugs/medications, Ophthalmologic evaluation:
exposure of toxins in the workplace, social
habits & history of alcohol (quantity & A patient suspected/diagnosed with TON may
quality), diet, gastrointestinal disease, present with symmetric, progressive,
surgery, anemia needs evaluation. Systemic bilateral (acute/chronic), painless loss of
history also needs to be ruled out, including visual acuity with variable optic nerve head
the presence/absence of diabetes mellitus, pallor, impaired color vision (mainly red),
renal failure, thyroid dysfunction, as these and contrast perception, a central blur while
lead to the accumulation of toxin because of reading (relative scotoma), which is
impaired metabolism and excretion.11-13 continuous and slowly progressing.14,15 The
visual acuity may vary from mild reduction to
Complete family history is also essential to no severe visual loss. Therefore, a complete
rule out hereditary optic neuropathies. In evaluation of color vision and visual fields is
cases where alcohol/drug abuse is suspected, a must to investigate in a patient diagnosed
family history might help to come to a with TON.9,12
conclusion. The symptoms to observe should
include sensory disturbance in the Relative afferent pupillary defect (RAPD) is
extremities and gait problems, indicating the usually not observed because optic
involvement of the cerebellum; thus, toxic neuropathy is virtually always symmetric and
bilateral. The pupil often reacts bilaterally

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with an adequate constriction to a strong Visual field
stimulus of light, but they normally respond
to near stimulation. Clinically, there is no Visual field evaluation is essential in the
apparent difference observed from the diagnosis of patients suspected with TON.
normal population.9,11 The occurrence of central/centrocaecal
scotomas with the preservation of peripheral
Dyschromatopsia is a typical feature, which fields is characteristics of these patients.
can be tested with colour vision tests or Rarely, other visual field defects may also be
Ishihara plates. However, we should rule out seen. In the case of ethambutol toxicity, the
patients with congenital colour vision defects. most common visual field defects are central
The occurrence of dyschromatopsia is the scotoma; however, bi-temporal defects and
earliest sign of toxicity seen in patients with peripheral constriction of fields have also
Ethambutol, and blue-yellow colour changes been reported.16,17 The field defects are
are most commonly observed.9,12 relatively symmetrical, with soft margins.
They are easier to plot for coloured defects,
The fundus examination of patients with TON such as for red than white stimuli.12,18
is normal in the early stages. Although in a
few cases, bilateral disc edema and Neuroimaging in toxic/nutritional optic
hyperemia may be seen in cases of Isoniazid, neuropathy
Amiodarone toxicity. Disc hemorrhages may
also be present. Most of the patients diagnosed with TON,
who undergo imaging test Magnetic
In some case of drug toxicity, vision loss is resonance imaging (MRI) yield normal
caused by interruption of mitochondrial results. However, this is one of the crucial
function in the optic nerve, leading to tests done mainly to rule out compressive
hyperemia, edema, and optic nerve atrophy. lesions, demyelinating disease, other
Pupillary response to light is diminished and pathologies, and to confirm the diagnosis
subsequently worsens, leading to no further. The most appropriate is MRI of optic
response. With time, papillomacular bundle nerve and chiasma with/without Gadolinium
loss and the temporal pallor of optic disc enhancement.11,12
develops, which ultimately leads to visual
field defects and retinal nerve fibre layer Electrophysiological tests
loss.9 (Figure 1,2)
Electrophysiological tests, including Visual
evoked response (VEP) and pattern
electroretinography (PERG), have also been

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used in patients suspected of TON. VEP is exposure to toxic substances. Usually, vision
useful in patients with early/subclinical optic improves to normal over several days or
neuropathy. It also helps to differentiate weeks after discontinuation of therapy.
from the demyelinating disease. VEP (P100)
wave amplitude is markedly reduced with Toxic neuropathy due to drugs
normal to near-normal latency in patients of
tobacco alcohol amblyopia.19 The damage caused in a case of TON is dose
and duration dependent. In these patients,
To detect subclinical toxicity is difficult in when drugs are used for longer periods or
cases of TON. Regular visual field and with a higher dosage, patients should be
electrophysiological testing might have a role priorly informed about possible toxicity and
to play. For the detection of early optic educated to report immediately if any visual
damage, contrast sensitivity (CS) problem occur.20,21
measurement is helpful.
Ethambutol
ERG, (CS) measurements and retinal nerve
fibre layer thickness by OCT are suggested to Ethambutol is a bacteriostatic antimicrobial
detect early subclinical toxicity of drugs such agent used in the treatment of Tuberculosis
as antituberculosis medicine, antibiotics, against Mycobacterium avium infection. Optic
antimalarial, and others.16 nerve toxicity is the most serious adverse
effect observed with ethambutol use.16 The
TON is a diagnosis of exclusion. Hence, the exact pathologic mechanism by which
diagnosis is based on identifying specific Ethambutol acts is largely unknown, but it
toxic factors and excluding other pathologies has been hypothesized that it acts as a
giving similar clinical pictures. It is, for this chelating agent that disrupts metal-
reason, the procedures necessary for the containing enzyme system in the nucleic acid
diagnostic approach are not easily specified. structure of mycobacteria, which ultimately
leads to accumulation of free radicals and
Treatment includes removal of toxic initiating an apoptotic cascade.19 It has been
substances from the body every 4-6 weeks suggested it not only damages optic nerve
and includes an examination of visual acuity, but other retinal elements based on mfERG
colour vision, visual field, and pupillary findings.22
reaction. The prognosis of the patient
depends on the dosage and duration of

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AB

C Figure 2 – Optical coherence tomography of the same
patient showing retinal nerve fibre layer loss.
Figure 1 (A,B) Bilateral disc pallor in a 40 year old male
presenting with diminution of vision with history of
ethambutol intake for Pott’s spine for more than 6 months.
His Visual acuity for OD- 3/60 and OS – 4/60. The colour
vision on Ishihara chart was defective. (C) Visual field
defect showing centro-caecal defect of the same patient

It is seen in 6% of patients taking the drug. peripheral constriction, altitudinal field
The clinical picture is similar to other TON
observed with early occurrence of defects, and bitemporal field defects. The
dyschromatopsia. The visual symptoms begin
2-8 months after ethambutol drug intake. routine for monitoring patients on
Dyschromatopsia, along with blue-yellow
colour changes, are the most frequently Ethambutol includes visual acuity
observed and earliest sign of toxicity. Less
commonly common field defects include assessment, visual fields, fundus evaluation,

colour vision, contrast sensitivity

measurement, Optical Coherence

Tomography (OCT), and VEP.

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OCT, now a commonly used method to 25-100mg/day helps in stabilizing or
measure retinal nerve fiber layer (RNFL) reversing isoniazid induced toxicity, but its
thickness in patients with glaucoma, can be role is considered controversial, as
used to quantify changes in ethambutol improvement may be because of stopping
toxicity.23 It quantifies the loss of RNFL in the drug.
ethambutol patients of as a sign of early
toxicity before the fundus changes become As both Ethambutol and isoniazid are first-
apparent. Therefore, OCT is an additional line drugs in the treatment of tuberculosis,
objective test to monitor patients on both produce TON, practicing physicians
Ethambutol, especially when used in should remember that if stopping one does
conjunction with visual fields. not improve patient visual acuity, the other
drug should also be stopped.14
The risk of TON was higher when the drug
dosage of 25mg/kg/day or more. In such a Methanol
scenario, the dosage should be reduced to
15mg/kg/day, which is both safe and Methanol toxicity due to accidental/suicidal
effective. However, cases have been ingestion remains a common problem in
reported even with dosage lower than this23. many parts of the developing world.
The observed ocular toxicity is both dose and Methanol is responsible for toxicity with its
duration dependent; thus early recognition metabolite formic acid.26 In industrial setup,
and prompt cessation of therapy is of utmost this is formed as a result of metabolic
importance in preventing further loss of acidosis and intrinsic toxicity of formate
visual acuity. anion itself. Severe poisoning may result in
nausea, vomiting, and abdominal pain,
Isoniazid affecting the central nervous system, similar
to ethanol.27
It is also an antitubercular drug, which can
lead to TON. It is frequently associated with The formic acid is accumulated within the
bilateral optic disc swelling with concurrent optic nerve and causes classic visual
bitemporal hemianopic scotomas.24,25 Vision symptoms of flashes of light, which
improved on cessation of administration of subsequently progresses to scotomas &
the drug. The literature reviewed suggests a scintillations. Vision loss is due to the optic
somewhat favourable outcome in comparison nerve's involvement and leads to hyperemia,
to Ethambutol. Patients having prior liver/ edema, and optic nerve atrophy. Pupillary
renal failure are at higher risk. Pyridoxine light responses are diminished.

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To confirm a patient's diagnosis with availability/high cost.
methanol toxicity requires an increase in
serum methanol level with gas Intravenous Pulse steroids have also been
chromatography (>20mg/dl). Peak levels are tried in a few patients to salvage the vision,
achieved 60-90 mins after ingestion, but and the result was encouraging. The benefit
they do not correlate with toxicity level and is mainly due to the anti-inflammatory and
cannot be used as an index for prognosis. immunosuppressant effects of steroids.28,29
Arterial pH correlates with the formate level.
(<7.2 is a severe intoxication).12 Tobacco–alcohol amblyopia

The supportive therapy includes initiating Tobacco- alcohol amblyopia is characterized
airway management, correcting the by damage to papillomacular bundle, central
electrolyte imbalances, and ensuring or cecocentral scotoma, and reduction of
adequate hydration. If patients present colour vision in a patient who frequently
within 2hours of ingestion of alcohol, then abuses tobacco and alcohol.30,31 It is
gastric lavage can be considered. Treatment insidious in onset, the gradual course which
involves using buffer (sodium bicarbonate) to happens after many years of
correct metabolic acidosis and an antidote to smoking/alcohol abuse. The fundus
inhibit the metabolism of methanol to its examination involves the normal appearance
toxic metabolite, formic acid. If essential, of the optic disc with often peripapillary
hemodialysis is done to correct the acidosis dilated vessels and hemorrhages. Although
further, and remove both methanol and the syndrome is classified as optic
formate. neuropathy, the primary lesion has not been
localized to the optic nerve. The lesion may
Antidote therapy is primarily directed possibly originate in retina, chiasma, optic
towards delaying the metabolism until it is tracts.30 The loss of vision may precede the
eliminated from the system either naturally optic disc changes as detected by OCT in
or via dialysis. This is achieved with the use these patients.32
of either ethanol/fomepizole. ADH
metabolises ethanol, and the enzyme has a Most of these patients also suffer from
higher affinity for ethanol compared with
methanol. The same enzyme also severe nutritional depletion and
metabolises fomepizole, with the advantage
that it does not cause CNS depression. improvement in vision is seems to be related
However, its usage is limited because of its
to improving nutrition. It needs to be

emphasized that patients that stop or at

least reduce their smoking/consumption of

alcohol along with improved diet (green leafy

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vegetables and fruits), vitamin with acute lymphoblastic leukemia.
supplementation is critical for their recovery.
It includes administration of thiamine 100mg JAMA 2015;313(8):815–823
orally twice daily, folate 1mg once a day, and
multivitamin supplementation.12 2. Johnson DC, Corthals SL, Walker

CONCLUSION BA, et al. Genetic factors underly-

Eye care practitioners and specialist should ing the risk of thalidomide-related
consider toxic optic neuropathies, whose
diagnosis is mainly clinical and need neuropathy in patients with multiple
exclusion of other pathologies, to prevent
severe and irreversible damage to vision, as myeloma. J Clin Oncol
a result of misdiagnosis and management 2011;29(7):797–804

mistakes. Thus, early diagnosis and
treatment are mandatory and a good 3. Mauermann ML, Blumenreich MS,
prognostic indicator. Hence, we emphasize
the importance of a thorough history. Also, in Dispenzieri A, Staff NP. A case of
cases of chronic drug intake, a baseline
investigation must be undertaken before the peripheral nerve microvasculitis
starting of therapies and a sequential follow
up is essential to avoid the deterioration of associated with multiple myelo- ma
the changes.
and bortezomib treatment. Muscle
Correspondence Address Nerve 2012;46(6): 970–977


Dr Anuradha Raj 4. Verstappen CC, Koeppen S,
Associate Professor,
Department of Ophthalmology, Heimans JJ, et al. Dose-related
All India Institute of Medical Sciences, Bathinda,
PUNJAB. vincris- tine-induced peripheral
E-mail:[email protected]
neuropathy with unexpected off-
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