Cryotherapy in Ophthalmology

CRYOTHERAPY
Moderator- Dr. Rekha B.K.
Presenter- Devanshu Arora
SEMINAR
September 09, 2015 Department of Ophthalmology, JNMC, Belagavi 1

INTRODUCTION
• CRYOTHERAPY
(also known as – Cryosurgery, cryoabalation, cryocautery
& cryogenic surgery)
• Is a technique that uses an extreme cold produced by an
instrument to freeze and destroy abnormal tissue.
• The term "cryotherapy" comes from the Greek
Cryo- meaning cold, and therapy- meaning cure.

BRIEF HISTORY
• With the advent of liquefied gases, it was
realized that a rapid freeze with a colder cryogen
could effectively treat tumors and skin
conditions.
1899
• White, was the first to use Cryogens in the form
of liquefied gases for medical care.
• Allington was the first to use liquid nitrogen in the
treatment of skin lesions.
He used a cotton swab dipped in liquid nitrogen
to treat skin tumors

1960s
• Cooper designed a liquid nitrogen probe that
achieved a temperature of −195.6 ̊C and used it
for inoperable brain tumors
• From this point on, Liquid nitrogen cryotherapy
spread to multiple specialties
Today
• Liquid nitrogen is the most popular medical
cryogen.
• Carbon dioxide is still used worldwide because
of relatively easy storage.
Other Cryogens are- Nitrous Oxide & Freon

INTRODUCTION OF CRYOTHERAPY IN
OPHTHALMOLOGY
1933
• Cryotherapy of the eye was first reported by Bietti
(to seal a retinal hole by a probe, pre-cooled in a
mixture of carbon dioxide and acetone)
1961
• Cryoprobe first used for intra-capsular cataract
extraction
(widely used thereafter in 1970s)
1964
• Advances in treatment of retinal tears &
detachments with cryotherapy were made.
• Schepens & Lincoff
• Cryotherapy also used for treatment of variety of
benign & malignant eye tumors

CELLULAR EFFECTS OF
CRYOTHERAPY
Effects of cryotherapy include:
• Ischemia caused by
vascular stasis and
the destruction of small caliber blood vessels
• Ice crystal formation inside cells leading to cell wall
rupture
• Denaturing of lipid- protein complexes
• Osmotic stress
• Tissue necrosis
• Cellular apoptosis after freezing injury by the buildup of
toxic concentrations of solutes inside cells

As Cryotherapy freezes extracellular fluid, pure water
crystals form extracellularly
Thus,
concentrating
the remaining
extracellular
solutes
The intracellular water is cooling below
its freezing point but not forming ice
crystals
Known as
Supercooling
Cell membrane is
permeable to
supercooled water
So the supercooled water will tend to
flow out of the cell and freeze externally
The net result is-
• Cellular dehydration
• Solute concentration intracellularly

THAW PHASE
• For adequate cellular destruction, the thaw phase of
cryotherapy is just as crucial.
• A slow thaw allows for longer vascular stasis and longer
exposure to toxic solute levels within the cell
• The effect is enhanced by repeated freeze-thaw cycles,
usually performed 2-3 times
known as “DOUBLE FREEZE THAW TECHNIQUE”

SALIENT PRINCIPLES OF CRYO-APPLICATION IN
CELLULAR & CLINICAL OPHTHALMOLOGY
• The ability of a cryogen to freeze is dependent on its
ability to remove heat, which is determined by its boiling
point.
• The ice ball produced by a cryoprobe becomes warmer as
distance from the cryoprobe is increased.
• A rapid freeze and a slow thaw produce the most cell
death.
• The pathologic hallmark of cryotherapy is ischemic
necrosis.
• Large blood vessels are highly resistant to cryoinjury,
while microvasculature is susceptible.

VARIOUS CRYOGENS
For Ophthalmological uses the cryogens primarily used for
cryotherapy are:
• Freon (boiling point = −29.8 ̊C to −40.8 ̊C)
• Nitrous oxide (boiling point = −88.5 ̊C)
• Solid carbon dioxide (melting point = −79 ̊C)
• Liquid nitrogen (boiling point = −195.6 ̊C)
Boiling point of liquid nitrogen is by far the lowest, making it
the most effective in cell destruction.

EQUIPMENTS FOR CRYOTHERAPY
• Cryoconsole
• Appropriately sized
cryoprobe for the
procedure
• Source of electricity
to run the
cryoconsole
The cryoprobe connects to the cryoconsole with insulated
tubing that is part of the probe itself

• Tank of gas
(containing the cryogen as liquid form under pressure)
It is attached through valves and tubing to the
cryoconsole
• In all retinal cases, an indirect ophthalmoscope and
condensing lens

CRYOPROBE
• A cryoprobe is a closed system where the cryogen is
circulated within a metal probe and the cold probe is
applied to the tissue.
• Specifically, the probe is supplied with a cryogen from a
pressurized source.
• For example if the cryogen is liquid nitrogen-
It converts to gaseous nitrogen when released & allowed
to pass within the probe, cooling the probe to extremely
low temperatures.

• Probes with varying tip sizes and angulations have been
developed for different applications
4x10 mm Collins
Trichiasis Probe
1.5 mm Curved
Cataract Probe
3.0 mm
Glaucoma Probe

Cryoprobes for Retina
2.5 mm Standard
Retinal Probe
2.5 mm
Mid-Reach
Retinal Probe
2.5 mm Extended
Retinal Probe

Patient Preparation
• For Retinal Cryopexy:
Either topical anesthesia or subconjunctival injection
of local anesthetic (lignocaine) in the same quadrant
as the lesion to be treated.
• For conjunctival neoplasms, lid neoplams & trichiasis:
Local infiltration of anesthesia is done.
• For Peripheral Cryoabalation of the retina or choroid and
Cyclocryotherapy for glaucoma:
Peribulbar Block should be given.

TECHNIQUE
• Before beginning, make sure that there is adequate gas in
the tank &
that connections have been correctly made and tightened.
• Proper cooling of the tip should be checked by depressing
the foot switch.
• After appropriate anesthesia has been instituted, the
cryoprobe is applied while still warm to the tissue
undergoing treatment.

• The footswitch is then depressed to allow coolant to flow
to the tip.
• An ice ball should form at the tissue at the tip.
• Once tissue has started adhering to the tip, the probe
should not be moved, because of the risk of tearing or
breaking the tissue.
• The freeze application is limited to the time specified
depending on the lesion & then it is allowed to thaw.

COMPLICATIONS OF CRYOTHERAPY
• Most complications from ocular cryotherapy are related to
surgeon inexperience
&
Prolonged contact of a cryoprobe or cryospray with
surface tissue, leading to an over-freeze.

Depending on the tissue undergoing cryotherapy, the most
common complications from cryotherapy include:
• Transitory uveitis
• Temporary chemosis
• Subconjunctival hemorrhage
• Corneal endothelial damage
• Paralysis of extra ocular muscles from cryotherapy over
muscle insertion sites
• Sector iris atrophy

• Although these adverse effects rarely have long-term
consequences,
Cryosurgery specially with liquid nitrogen should be
performed carefully and only after adequate practical
experience.

APPLICATIONS OF
CRYOTHERAPY FOR SPECIFIC
OCULAR PATHOLOGIES
1. CRYOTHERAPY FOR SURFACE EYE
DISEASES:

SPECIAL CONSIDERATIONS
• As per various studies it was seen that,
If the cryoprobe was placed on the surface of the globe
for only 2 - 3 seconds, it was a safe amount of time to
apply a cold liquid nitrogen cryoprobe without causing
undue damage.
• A temperature of −25 ̊C at the level of the endothelium will
kill these fragile cells, and
An ice ball of 5mm or larger will lead to endothelial cell
loss.
This would happen if freeze time is kept 5 seconds
or more

TRICHIASIS
• Cryotherapy may be used as a treatment option for
chronic trichiasis.
• Cryotherapy is preferred when there are more than one
trichiatic lashes together in an area of the eyelid.
• Freon or Nitrous oxide is used to destroy the follicles by
freezing them.

• Cryotherapy for trichiasis was first reported in 1997, using
a nitrous oxide cryoprobe
Local treatment of eyelids using a double freeze-thaw
technique was used with low temperatures reaching -20 ̊C
• Success rate is high of more than 90% but complications
are common-
 Eyelid notching & scarring
 Pigmentary skin changes
 Destruction of normal eyelashes

BASAL CELL CARCINOMAOF THE EYELIDS
• It is a malignant tumor derived from cells of the basal
layer of the epidermis.
• Up to 50-60% of BCC affect the lower eyelid
• Medial Canthus is involved 25-30% of times (C/I for cryo)
• Upper eyelid – 15%
• Treatment Modalities include:
Surgery
Radiotherapy
Cryotherapy

Cryotherapy may be used in:
• Small superficial type of Basal Cell Carcinoma
• Pigmented variety of Basal Cell Carcinoma
• Eyelid notching
Cryotherapy is contraindicated in:
• Medial canthal lesions
• Recurrent Basal Cell Carcinoma
Radiotherapy & Cryotherapy are both contraindicated in:
• Lesions greater than 1cm in diameter
• Morphea or Sclerosing type of Basal Cell Carcinoma

TECHNIQUE FOR BASAL CELL CARCINOMA
Double freeze-thaw cycles are used –
• With 45 seconds of freeze for tumors ≤ 5mm in size
&
• 60 seconds of freeze for tumors >5mm in size followed by
slow thaw.
• Nitrous oxide probe is used with high flow rate and tip-
size 4 x 10 mm of ‘collin’ type.
• Similar technique was used in a study
(published in- British Journal of Ophthalmology, 2011
“Nitrous oxide cryotherapy for Primary Periocular Basal
Cell Carcinoma” – a 5 year follow up)

VERNAL KERATOCONJUNCTIVITIS
• The giant papillary changes in VKC are collections of
neutrophils, eosinophils, lymphocytes, and other
leukocytes surrounding a central vascular core
• Cryotherapy aims at killing the central vascular core of
giant papillae

VARIOUS STUDIES FOR CRYOTHERAPY FOR VKC
• Sankarkumar et al. studied 30 eyes of 15 patients with
VKC, in 1992 who underwent treatment with carbon
dioxide cryogen. Reported recurrence was 3.3% at one
year
• Jiang et al.(2006) combined resection, cryotherapy, and
amniotic membrane transplantation for the treatment of
VKC. It was concluded that resection and cryotherapy
combined with AMT is an effective & safe treatment for
VKC.

• Liquid nitrogen cryotherapy (using a cryoprobe) for VKC
in 3 eyes was reported in 2008.
(F.W. Fraunfelder, “Transactions of American
ophthalmological Society”, Vol 106, 2008.)
• Giant papillae recurrence was noted after 1 month.
• Recurrent VKC was noted with a median time of
development as 12 months.
• Cryotherapy may kill the central vascular core of giant
papillae early on (resulting in some positive results after
therapy),
But the high rate of recurrence may make cryosurgery an
ineffective therapy for Vernal kerato-conjunctivitis.

ADJUVANT CRYOTHERAPY WITH
PTERYGIUM EXCISSION
• Various post-excision, adjuvant treatments have been
described in the past, with different recurrence rates:
 6% with Conjunctival autograft
 13% with Beta-irradiation
 29% with Mitomycin-C
 53% with excision alone

• The use of adjuvant liquid nitrogen cryotherapy of the
surgical site was studied in both de novo and recurrent
pterygia excision
by F.W. Fraunfelder (published – “Cryotherapy for
Pterygia”, ophthalmology Vol 115, No. 12, 2008)
• In this series, after excision of the pterygia, Cryotherapy
with a 2mm cryoprobe was performed, with the tip of the
cryoprobe in contact with the corneoscleral limbus for
approximately 1 second.
• A double freeze-thaw technique was used.
• After cryotherapy, the conjunctiva was closed up to the
limbus with 6-0 plain gut sutures.

• In the de novo pterygia group (median follow up of 24.5
months), only 1 out of 15 patients had a recurrent
pterygium
Resulting in a recurrence rate of 3.3% per year.
• In the recurrent pterygia group (median follow up of 27
months), 4 out of 6 patients had a recurrent pterygium
after treatment,
Resulting in a recurrence rate of 29.6% per year.

• Thus, liquid nitrogen cryotherapy appears to be an
appropriate adjuvant treatment after de-novo pterygia
excision to minimize recurrence.
• However, recurrent pterygia have NOT been shown to be
susceptible to adjuvant liquid nitrogen cryotherapy, with
high rates of recurrence despite cryotherapy.

Conjunctival Intraepithelial Neoplasia and
Squamous Cell Carcinoma
• Conjunctival intraepithelial neoplasia (CIN) is a localized
squamous cell neoplasm that is minimally aggressive
and confined to the surface epithelium.
• If the basement membrane is compromised and invaded
by the abnormal cells, then the lesion has progressed to
Squamous Cell Carcinoma.

• Clinically, CIN and squamous cell carcinoma may present
as fleshy, elevated lesion at the limbus.
• Adjacent corneal epithelium may also be involved.
• Early studies using excision followed by nitrous oxide
cryoprobes showed relatively good results with a 9%
recurrence rate (with 5 years of follow up).
• More recently, an optimized technique for excision with
‘No Touch’ technique and combined cryotherapy with
liquid nitrogen has been described.

• It includes treatment of the lesion by alcohol
epitheliectomy and partial scelroconjunctivectomy using
the “no-touch” technique,
followed by intra-operative double freeze-thaw
cryotherapy applied to the edges of the remaining bulbar
conjunctiva & the scleral base if there was episcleral
adhesion of the tumor.

• In a study of 60 patients with CIN and conjunctival
squamous cell carcinoma treated with excision and
cryotherapy with the same technique, (by M. Tunc, et al.)
• After a mean follow up of 56 months, the rate of
recurrence was 4.5% for CIN and 5.3% for squamous cell
carcinoma

PrimaryAcquired Melanosis and
Melanoma of the Conjunctiva
• Primary acquired melanosis (PAM) of the conjunctiva is a
pre-malignant transformation of melanocytic cells in the
conjunctiva.
• It usually manifests in the middle age, as a unilateral,
superficial, solitary patch or diffuse pigmentation of the
bulbar, forniceal and palpebral conjunctiva.
MANAGEMENT –
• Conjunctival PAM is usually managed by simple
observation if it is limited in extent and not rapidly
progressive.

• Prominent or progressive PAM lesions are usually
Excised (if small) or Biopsied (if too large to be excised)
On basis of Histopathological studies
PAM without Atypia
OBSERVATION
PAM with Atypia
<3 clock
hours:
Cryotherapy
alone
>3 clock hours:
Surgical
Excision with
Excision Edge
Cryotherapy

• Double freeze-thaw cycles of cryotherapy are applied.
• Excision & Cryotherapy of Primary Acquired Melanoma
has proven to be an effective treatment but recurrences
can occur.
• In a recent report of over 100 cases of PAM treated with
excision and cryotherapy after a 3 year follow-up, the
reported rate of PAM recurrence was 27%, with 3%
progressing to Melanoma.
(J.A. Shields, et al. published- “Transactions of the American
Ophthalmology society”, Vol105, 2007)

CONJUNCTIVAL MELANOMA
• It can arise:
 De novo
 From a preexisting nevus or
 From Primary Acquired Melanoma (75% cases)
• Conjunctival melanoma appears as a pigmented, fleshy,
mass located in the bulbar, forniceal or palpebral
conjunctiva
• and may exhibit a prominent feeder vessel

• Treatment of Conjunctival Melanomas varies according to
the extent and location of involvement:
Melanomas involving the bulbar conjunctiva & cornea –
Alcohol epitheliectomy and partial
scleroconjunctivectomy by “No Touch” technique
If extent of involvement
was < 3 clock hours
Intra-operative double freeze-
thaw cryotherapy to the
excision edge and excision
base
If extent of involvement
was > 3 clock hours
Post-operative
plaque
Brachytherapy

2. CRYOTHERAPY FOR INTRAOCULAR
PATHOLOGY:
1) Cryoextraction of Cataract
2) Cyclocryotherapy
3) Cryotherapy for intra-ocular tumors
4) Retinal Breaks & Detachment
5) Retinopathy of Prematurity

CRYOEXTRACTION OF CATARACT
• Cryotherapy was widely used for cataract extraction in the
1970s when Intra-capsular cataract extraction was the
treatment of choice for senile cataracts.
• Since now Intracapsular cataract extraction is not
performed, cryotherapy for lens extraction is no more
required

• TECHNIQUE:
A 12-14 mm incision used to be given, the surface of the
lens was dried and cryoprobe tip was applied to the lens
capsule.
• The cryogen was then released to pass into the tip
causing the tip to cool rapidly and adhere to the lens
capsule
• Once adhesion is complete, the lens can be removed by
pulling gently on the cryoprobe

CYCLOCRYOTHERAPY
• Cyclocryotherapy is a cyclodestructive procedure which
aims at destroying the secretory epithelium of the ciliary
body.
Indications:
 Refractory glaucoma with poor vision or poor visual
potential
 Pain relief due to elevated IOP in a painful blind eye
 Neovascular Glaucoma
 If conventional glaucoma surgery fail to control IOP

Surgical technique of Cyclocryotherapy:
• Performed usually under peribulbar anesthesia
• A circular and convex retinal cryoprobe (3mm or 4mm tip)
is applied directly on the intact conjunctival surface.
• The edge of the tip is placed 1-1.5mm from the limbus for
1 minute, thus bringing the center of tip directly over
cilliary body
• The ice-ball is allowed to thaw slowly, rather than using
irrigation, to allow maximal effect.
Cycloabalation can be achieved by
Cyclocryotherapy Cyclophotocoagulation with laser

• Complications include:
Reduced visual acuity, uveitis, hemorrhage& phthisis bulbi
• To reduce the complication rate (particularly phthisis
bulbi), the treatment is usually limited to one application at
each clock hour (six in total) over 180°
• All the complications are less common with Trans-scleral
Cyclophotocoagulation(TCP) Laser therapy which is a
better alternative to cyclocryotherapy.

Post-op regimen:
• Atropine eye drops and an antibiotic-steroid combination
are prescribed.
• All glaucoma medications are continued post-operatively
• The full effect of treatment may take 2-4 weeks to become
manifest, so a second treatment is not considered until 1
month has passed.
• If required, the same area may be retreated, or another
quadrant may be included.

INTRA-OCULAR TUMORS
• The advantage of cryotherapy to treat intraocular tumors
is the ability to treat trans-sclerally.
The damage to the sclera is minimal and negligible while
the intraocular tumor is destroyed.
Indications:
 Retinoblastoma
 Retinal Capillary Hemangiomas
 Vasoproliferative tumors

RETINOBLASTOMA
• Very small tumors, not more than 3mm in diameter and
2mm thickness can be treated by cryotherapy alone.
• Vitreous seeds are usually not treatable with cryotherapy
unless they are lying in the immediate vicinity of the
tumor.
• Cryotherapy, however in Retinoblastoma is usually used
for consolidation of the tumor after chemotherapy.
• Tumor recurrences when small can also be treated with
cryotherapy.

PROCEDURE FOR INTRA-OCULAR TUMORS
• Intra-ocular tumors are treated using a 2.5 mm tip retinal
cryoprobe.
• Lesions located anteriorly are easily treated with cryo
since conjunctiva need not be opened.
• For tumors located posteriorly, limited conjunctival
opening is made to make the probe reach posteriorly.

• With the indirect ophthalmoscope view, indentation
caused by the probe tip is positioned under the center of
the lesion and freezing is commenced.

• Freezing is done till the ice ball totally encloses the tumor
mass.
• The probe is allowed to defreeze completely before
freezing again.
• The cycle is repeated thrice
• Topical steroids are given for a few days.
Complications:
• Retinal edema occurs frequently
• Less frequently – Secondary Retinal Detachment
Retinal Hemorrhages

RETINAL CRYOPEXY
• It is a procedure employing cryotherapy to induce a
chorioretinal scar.
• It is used for the treatment of retinal tears & detachments.
• Retinal tears may arise from trauma or traction from the
overlying vitreous.
• Retinal tears may then allow fluid influx between the
neurosensory retina and the RPE, causing further
extension of the separation and leading to a retinal
detachment.

PROPHYLACTIC MANAGEMENT OF RETINAL
BREAKS
• 3 Modalities:
 Cryotherapy
 Laser photocoagulation
 Scleral Buckling
Retinal tears that should be treated include:
 Symptomatic tear
 High Myopes
 Any break with subretinal fluid more than 1DD
 History of RD in fellow eye
 Horse-shoe shaped tears

• Cryotherapy is preferred over laser photocoagulation in:
 Hazy ocular media
 Peripherally located tears near the ora-serrata
 Small pupils

• Cryotherapy may also be used intraoperatively when
scleral buckling is done for the treatment of retinal
detachment.
• In a recent RCT, published 2010 (by RP Lira at al.)
patients undergoing scleral buckling for rhegmatogenous
retinal detachments along with either intra-op cryotherapy
or post-op laser retinopexy (1 month later)
• The reattachment and post-operative complication rates
were similar in both groups

RETINOPATHY OF PREMATURITY
• ROP is an ischemic retinopathy of premature and low
birth weight infants.
• The development of retinal vasculature begins during
week 16 of gestation and can progress to the final weeks
of gestation.
• Premature birth, in conjunction with subsequent iatrogenic
oxygen supplementation, halts and alters normal retinal
vasculature development, leading to the onset of ROP
and abnormal neovascularization.

• First use of cryotherapy to prevent progression of ROP
was reported in 1978.
• This revolutionized the treatment of ROP
• In this technique, trans-scleral cryotherapy is used to
ablate areas of avascular retina and thereby prevent
further neovascularization.
• In 1988, the first multicenter randomized trial of
cryotherapy for treatment of ROP (the CRYO-ROP study)
was reported.
• 9751 less than 1251gm babies were studied across 23
centers & one eye was randomized for cryotherapy.

• Five-year data from the CRYO-ROP study supported the
safety and efficacy of cryotherapy treatment of ROP.
• Ten-year data from the CRYO-ROP study showed long-
term value from cryotherapy in preserving visual acuity in
eyes with ROP.
• Cryotherapy has been shown to be an effective treatment
for ROP stage 3+
• Cryotherapy has been employed to achieve peripheral
retinal ablation for ROP since the 1970s but now has
largely been replaced by laser photocoagulation.

CONCLUSION
• Cryotherapy in ophthalmology has a rich history and
continues to be an important supplement in the treatment
of ophthalmic pathology.
• The use of cryotherapy in ophthalmology has helped
advance maturing fields, while in other instances
revolutionized patient care
(including ocular surface malignancies).
• Further applications of cryotherapy in eye disease
continue to emerge.

REFERENCES
• Ophthalmology 4th edition- Yanoff & Duker
• Clinical Ophthalmology–A Systematic Approach 7th edition (by
Jack J Kanski)
• American Academy of Ophthalmology(AAO)
BSCS section 12
• Indian Journal of Ophthalmology Vol.63, Issue-3
• Open Journal of Ophthalmology, 2013, 3, 103-117
• Internet – http://www.medscape.com
http://www.keelerusa.com
February 18, 2015 Department of Ophthalmology, JNMC, Belagavi 72

VKC
• Jiang et al.(2006) combined resection, cryotherapy, and
amniotic membrane transplantation for the treatment of
VKC.
• In this study of 16 eyes, fourteen eyes (87.5%) were
symptom-free 1 month after surgery with no evidence of
VKC on examination.
Recurrence of VKC was observed in 2 eyes (12.5%) after
cryotherapy.
• It was concluded that resection and cryotherapy
combined with AMT is an effective & safe treatment for
VKC.

Cryotherapy in Ophthalmology

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