Open Journal of Ophthalmology, 2013, 3, 103-117
Published Online November 2013 (http://www.scirp.org/journal/ojoph)
http://dx.doi.org/10.4236/ojoph.2013.34024
Open Access OJOph
1
Cryotherapy in Ophthalmology*
Shandiz Tehrani, Frederick W. Fraunfelder#
Casey Eye Institute, Oregon Health & Science University, Portland, USA.
Received January 7th, 2013; revised February 8th, 2013; accepted March 5th, 2013
Copyright © 2013 Shandiz Tehrani, Frederick W. Fraunfelder. This is an open access article distributed under the Creative Commons
Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is
properly cited.
ABSTRACT
Cryogens have been used to freeze living tissue for the purpose of treating benign and malignant lesions. Within the last
century, ophthalmologists have found cryotherapy to be useful in treating a variety of ocular pathologies. Here, we re-
view the history of cryotherapy, its introduction to the field of ophthalmology, its proposed mechanism of action, and its
current applications in treating surface and intraocular eye disease.
Keywords: Cryotherapy; Cryosurgery; Cryogenic Surgery; Cryoprobe; Cryospray; Liquid Nitrogen; Surface Eye
Disease
1. Introduction
Cryotherapy (also known as cryocautery, cryogenic sur-
gery, and cryosurgery) has been used to treat a variety of
ophthalmic conditions, including surface and intraocular
pathology. Cryotherapy may be preferable in treating
certain surface and intraocular diseases (including benign
and malignant lesions), as there are few post-operative
adverse events and limited long-term complications when
compared to radiation and chemotherapy. Here, we re-
view the historical and current role of cryotherapy in
ophthalmology.
2. Historical Review
The history of medical cryotherapy is a captivating one,
and has been well documented by Lubritz [1], Cooper
and Dawber [2], and Freiman and Bouganim [3], among
others. The known benefits of cryotherapy date back to
2500 B.C., when ancient Egyptians used cold to soothe
injuries [1,4]. Hippocrates used cold to relieve swelling,
bleeding, and pain [5]. The first published report on
freezing biologic tissue came from Arnott (1797-1883),
who used freezing of tissue locally in the setting of tu-
mors [6]. Using a salt and crushed ice mixture, Arnott
used cryotherapy for palliation of pain in breast cancer,
uterine cancers, and treatment of some skin cancers. He
also used his cold treatment for acne, neuralgia, and
headaches, and was able to achieve temperatures of
−24˚C.
With the advent of liquefied gases, it was realized that
a rapid freeze with a colder cryogen could effectively
treat tumors. In 1899, White became the first to use
commercially available refrigerants (liquefied gases) for
medical care. He published reports on using liquid air for
the treatment of lupus, herpes zoster, nevi, warts, chan-
croid, varicose leg ulcers, carbuncles, and epitheliomas
[7,8]. Irvine and Turnacliffe expanded the uses of liquid
air treatment to seborrheic keratosis, senile keratosis,
lichen simplex, and poison ivy dermatitis [9].
Allington was the first to use liquid nitrogen in the
treatment of skin lesions [10]. This became the preferred
gas because liquid oxygen is explosive and the two gases
have similar boiling points (oxygen = −182.9˚C, nitrogen
= −195.6˚C). Allington used a cotton swab dipped in
liquid nitrogen to treat skin tumors. Unfortunately, there
was loss of the heat sink potential with the transfer be-
tween the cotton swab and the skin, rendering this
method insufficient for effectively treating skin tumors
and malignancies.
Cooper designed a liquid nitrogen probe that achieved
a temperature of −195.6˚C [11]. He treated Parkinson’s
disease and inoperable brain tumors by freezing the
thalamus and the lesion, respectively. Torre and Zacarian
further advanced the field by developing hand held de-
*This report was supported by an unrestricted grant from Research to
Prevent Blindness to Casey Eye Institute.
The authors have no relevant financial disclosures or interests.
#Corresponding author.

Cryotherapy in Ophthalmology 104
vices, which facilitated one-handed cryospray and cryo-
probe procedures [12].
Liquid nitrogen cryotherapy spread to multiple spe-
cialties from that point forward [2]. Dermatologists ad-
vanced cryotherapy treatments of benign and malignant
tumors of the skin. Neurosurgeons were able to perform
liquid nitrogen-assisted transsphenoidal hypophysectomy.
Liquid nitrogen treatment of oral and cervical cancers, as
well as cryosurgery to the uterus, was described.
Today, liquid nitrogen is the most popular medical
cryogen. Carbon dioxide (melting point = −79˚C) is still
used worldwide because of relatively easy storage. How-
ever, because of its higher boiling point, carbon dioxide
is generally suitable for treating benign conditions only.
Similarly, nitrous oxide (boiling point = −89˚C) is fa-
vored by some gynecologists and oral surgeons, but only
for benign lesions. Freon (boiling point = −29.8˚C to
−40.8˚C) has also been used to treat benign tumors. Cur-
rently, the acceptable minimal temperature to achieve
cell death is −50˚C to −55˚C [13,14]. The standard of
care in dermatology, oral surgery, otolaryngology, neu-
rosurgery, and gynecology is liquid nitrogen cryotherapy
for malignancies [2,15,16]. Interestingly, this has yet to
translate fully to ophthalmology, where multiple cryo-
gens are used in lieu of liquid nitrogen for tumors in and
around the eye.
3. Early Advancements of Cryotherapy in
Ophthalmology
Cryotherapy of the eye was first reported by Bietti in
1933 [17]. He reported on the use of cryogenics to pro-
duce a thermal chorioretinitis to seal a retinal hole. The
technique used a metal probe, pre-cooled in a mixture of
carbon dioxide and acetone, with application of the probe
to the outer wall of the eye overlying the retinal hole.
Two years later, Deutschmann used cryosurgery in the
form of solid carbon dioxide probes applied in the same
fashion to treat retinal detachments [18]. It was not until
1961 that cryotherapy reemerged within the subspecialty
of ophthalmology. Krwawicz developed a metal probe,
which he immersed in a mixture of alcohol and solid
carbon dioxide for the use of intracapsular cataract ex-
traction [19]. Amoils improved cryoextraction techniques
by developing a liquid nitrogen probe [20]. Over the next
few years, cryoextraction of cataracts was adopted by
many ophthalmologists around the world [21].
Advances in treatment of retinal detachments and
retinal tears were also made with cryotherapy. Cryore-
tinopexy was done with various types of cryoapplica-
tors. Bellows and Kelman created retinal cryopexy in-
struments for the treatment of retinal tears and for cryo-
extraction [22,23]. Schepens, Lincoff, and others were
key figures in the advancement of cryoretinopexy surgi-
cal techniques and in using cryoretinopexy with scleral
buckling for retinal detachments [24-26]. Application of
a cryoprobe to the sclera for 5 seconds was shown to
create a white area in the underlying retina and seal reti-
nal tears and holes [23,25]. In most instances, solid car-
bon dioxide was utilized to achieve a temperature of
−50˚C to −60˚C.
After popularization of cryoretinopexy and cryoex-
traction, cryotherapy with different cryogens was used to
treat a variety of benign and malignant eye diseases. In
the 1950s and 1960s, advances in keratomileusis and
lamellar corneal grafting techniques using a cryolathe
and carbon dioxide snow, were put forth by Barraquer
and Kaufman [27,28]. In 1972, Zacarian published the
first series of cases using liquid nitrogen cryosurgery
around the eye and orbit for tumors [29]. Fraunfelder and
colleagues described cryosurgical treatment of ocular and
periocular squamous cell carcinomas in cattle [30-32]
and in humans [33,34].
4. Cryogens
Ophthalmologists who do use cryotherapy primarily use
freon (boiling point = −29.8˚C to −40.8˚C), nitrous oxide
(boiling point = −88.5˚C), or solid carbon dioxide (melt-
ing point = −79˚C) rather than liquid nitrogen (boiling
point = −195.6˚C) [16]. The boiling point of liquid ni-
trogen is by far the lowest of the available cryogens used
in medicine, making it the most effective in cell destruc-
tion. It is well established in the dermatology literature
that a rapid freeze of skin tumors with liquid nitrogen is
much more effective than a slow freeze (using alternative
cryogens) in eradicating tumor cells [35-40]. This is true
in the eye as well, where a number of case series have
shown the tumoricidal nature of liquid nitrogen [41-44].
The method of cryotherapy and types of cryogens used
in the treatment of eye disease are not standardized
within ophthalmology. In addition, the physiochemical
and biological effects of the different cryogens on the
ocular tissues have not been fully elucidated. Lastly, the
lack of familiarity with the use and storage of liquid ni-
trogen further limits the exposure of ophthalmologists-
in-training to this cryogen. Thus, the practice of oph-
thalmic cryotherapy is likely limited by the type of train-
ing the ophthalmologist received during the residency
and fellowship years.
5. Safety of Cryotherapy
Although vertebrate cells and tissue are highly suscepti-
ble to the destructive effects of cryotherapy, not all
pathogenic organisms are fully destroyed by exposure to
liquid nitrogen or other cryogens. In fact, a slow freezing
method followed by storage in liquid nitrogen allows for
excellent cryopreservation of viruses, microorganisms,
and cells. Using a cryoprobe (which is a closed system),
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Cryotherapy in Ophthalmology 105
involves no risk of contamination as there is no exposure
of vapor or sprays arising from the cryogen. However,
with an open system such as a liquid nitrogen cryospray,
precautions must be taken to prevent contamination from
the freezing agent. This is achieved by passing the liquid
nitrogen through a cryogenic filter (including the Gelman
and Millipore filters) when the liquid nitrogen tank is
being filled. In addition, cold filters (including Brymill
filters) may be used when transferring liquid nitrogen
from the storage tank to handheld cryotherapy units.
These filtration methods have consistently been shown to
prevent transfer of bacteria, fungi, and molds [24,45,46].
Most complications from ocular cryotherapy with liq-
uid nitrogen are related to surgeon inexperience and pro-
longed contact of a cryoprobe or cryospray with surface
tissue. Many times, a novice cryosurgeon is unable to
break the contact of the cryoprobe with the tissue, lead-
ing to an over-freeze. Depending on the tissue undergo-
ing cryotherapy, the most common complications from
cryotherapy include transitory uveitis, temporary chemo-
sis, subconjunctival hemorrhage, corneal endothelial da-
mage, paralysis of extraocular muscles from cryotherapy
over muscle insertion sites, and sector iris atrophy [47].
Rarely, there have been reports of scleral melting after
liquid nitrogen cryotherapy [48]. Although the above-
mentioned adverse events rarely have long-term conse-
quences, cryosurgery with liquid nitrogen is not a benign
procedure and requires practical experience. Novice
cryosurgeons will need to observe and learn when and
how to use cryotherapy to treat surface eye lesions and
intraocular diseases prior to performing the procedure
themselves.
6. Cellular Effects of Cryotherapy
The mechanism of cellular destruction during the freeze
phase of cryotherapy is multifactorial and not yet fully
elucidated. Some effects are well known, including is-
chemia through 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, cellu-
lar apoptosis after freezing injury, and the buildup of
toxic concentrations of solutes inside cells [46,49,50].
The latter mechanism is explained by cell dehydration,
which occurs when water is withdrawn to make ice crys-
tals intra- and extracellularly. As cryotherapy freezes ex-
tracellular fluid, pure water crystals form extracellularly,
thus concentrating the remaining extracellular solutes. At
the same time the extracellular water is forming ice, the
intracellular water is cooling below its freezing point but
not forming ice crystals. This is called supercooling. The
cell membrane is permeable to supercooled water but not
to ice crystals. The supercooled water will tend to flow
out of the cell and freeze externally. The net result of
this process is cellular dehydration and solute concentra-
tion intracellularly, which further destabilizes the cell
[51].
The thaw phase of cryotherapy may be just as crucial
as the freeze phase in cell destruction. A slow thaw al-
lows for longer vascular stasis and longer exposure to
toxic solute levels within the cell. The effect is enhanced
by repeat freeze-thaw cycles, usually performed 2 - 3
times. The depth of freeze is related to the contact time
(the longer the application, the deeper the freeze) [46].
Which of the aforementioned mechanism leads to cell
death during cryosurgery depends on the following fac-
tors: the cryogen employed (and thus the rate of freeze
and the final temperature achieved), the method and
length of application, the number of freeze-thaw cycles,
the type of cells being frozen, the water content and vas-
cularity of the tissue, and the rate of thaw. In regards to
the type of cells undergoing cryotherapy, it has been
shown that melanocytes are very sensitive to freezing.
Hence there is a risk of depigmentation of skin after cu-
taneous cryosurgery [46]. Collagen is the most resilient
tissue, and cartilage necrosis is extremely rare with cryo-
therapy. Thus, cryosurgery is particularly suitable in ar-
eas where maintenance of elasticity and structure are
important.
The ability of a cryogen to freeze depends not only on
its boiling point, but also upon the method by which it is
applied to biologic tissue. If a thermocouple is placed
within a living tissue at a location next to the application
of a cryoprobe, a rapid and precipitous temperature fall
will be appreciated in the beginning. This will be fol-
lowed by a slow fall in the temperature until a point is
reached where the temperature equilibrates despite con-
tinuous cryogen application. This is because the cryogen
acts as a heat sink while the surrounding tissues, reheated
by blood vessels, resupply heat. The heat sink essentially
loses efficiency with distance so that it is less effective in
removing heat from the tissues at increasing distances
from the cryoprobe application point. Eventually a point
is reached when heat is being renewed as fast as it is be-
ing extracted, a steady state condition occurs and the
final temperature remains constant [52]. We have simu-
lated the above scenario in the lab using non-living ani-
mal tissue, a liquid nitrogen cryospray, and a thermocou-
ple (Figure 1).
Research by Wilkes and Fraunfelder nicely illustrated
the salient factors in cellular and clinical ophthalmic
cryosurgery [46]. The ability of a cryogen to freeze is
dependent on its ability to remove heat, which is deter-
mined by its boiling point. The ice ball produced by a
cryoprobe becomes warmer as distance from the cryo-
probe is increased. The broad categories of in vivo cryo-
injury include intracellular and extracellular ice forma-
tion and ischemic infarction. A rapid freeze and a slow
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Cryotherapy in Ophthalmology 106
Figure 1. Tissue temperature with liquid nitrogen cryos-
pray application. Using a Brymill liquid nitrogen cryospray,
non-viable chicken skin at room temperature, and a 24 g
thermocouple (inserted superficially), liquid nitrogen was
sprayed at a distance of <1 cm. Five readings at each time
point were recorded. Error bars represent standard devia-
tions.
thaw produce the most cell death. Multiple freeze/thaw
cycles are more destructive for both normal and patho-
logic tissue than a single cycle. The pathologic hallmark
of cryotherapy is ischemic necrosis. Large blood vessels
are highly resistant to cryoinjury, while microvasculature
is susceptible. Peripheral nerves are sensitive to cryoin-
jury. Melanocytes are sensitive to cryoinjury, while the
destruction of hair follicles occurs with double freeze/
thaw cycles to −20˚C. Infection is rare after cryosurgery.
Edema occurs after cryosurgery and resolves over 1 - 2
weeks. Healing time after cryosurgery ranges from 3 - 6
weeks.
7. Cryotherapy for Surface Eye Pathology
7.1. Special Considerations
When freezing skin tumors or eyelid tumors, the tem-
perature of the underlying tissue can be monitored by
inserting a thermocouple. For cryosurgery on the surface
of the eye, this is not practical. One cannot insert a ther-
mocouple into the sclera or cornea of the eye without
putting the patient at risk of long-term scarring, infection,
or globe perforation. To overcome this obstacle, a series
of experiments were undertaken by Fraunfelder and
Wingfield [43]. These findings described a microspatula
thermocouple which was placed, through a vertical inci-
sion, into the cornea of human eye bank eyes or anesthe-
tized dog eyes. A cryoprobe was then applied adjacent to
the thermocouple. If the cryoprobe was placed on the
surface of the globe for only 2 - 3 seconds, no drop in
temperature was recorded on the microthermocouple,
suggesting that this was a safe amount of time to apply a
cold liquid nitrogen cryoprobe. In contrast, prior research
by Fraunfelder and associates revealed loss of endothelial
cells with freezing times approaching 5 seconds. A tem-
perature of −25˚C at the level of the endothelium will kill
these fragile cells, and an ice ball of 5mm or larger did
lead to endothelial cell loss. Based on the data from these
studies, a series of surface eye malignancies were treated
with liquid nitrogen cryotherapy, taking care to keep the
contact time of the cryoprobe to less than 3 seconds, and
usually 1 - 2 seconds.
7.2. Benign Pathology
7.2.1. Advancing Wavelike E pi theli opathy
The etiology of advancing wavelike epitheliopathy
(AWLE) is probably multifactorial. It has been hypothe-
sized that prior ocular surgery, contact lens wear, contact
lens solution, glaucoma drop toxicity, and underlying in-
flammatory or dermatologic disorders may all cause this
condition [53]. Confocal microscopy has shown the pre-
sence of atypical elongated cells oriented centripetally
with hyperreflective nuclei. Pathologic diagnosis is con-
sistent with unremarkable corneal epithelium when stained
with hematoxylin-eosin, with no evidence of cytologic
alterations or dysplastic change, while full-thickness con-
junctival biopsies have revealed parakeratosis of the con-
junctival epithelium with underlying focal mononuclear
cell infiltrates compressing and extending into the over-
lying epithelium [53]. Patients with AWLE present with
foreign body sensation or blurred vision. AWLE is diag-
nosed by a well-demarcated patch of coarse, irregular
epithelium which appeared in recurrent waves extending
from the limbus towards the visual axis. The waves were
most easily seen by shining a broad slit-lamp beam tan-
gentially across the surface of the cornea, or with scle-
rotic scatter revealing the distinct margins. One of the
only published treatment method to date describes the
application of 1% silver nitrate solution to the corneo-
scleral limbus with removal of the corneal epithelium
through debridement [53].
Liquid nitrogen cryotherapy for AWLE was described
in a 2006 series [54]. Using a cryospray, a double freeze-
thaw was performed on the corneoscleral limbus and
surface corneal epithelium of 5 eyes affected by AWLE.
With a median follow-up of 15 months, AWLE resolved
within 2 weeks without recurrence or the need for re-
peated cryotherapy. Four of the five eyes had a history of
glaucoma on topical medication and 2 had a history of
corneal transplantation. None of the patients in this series
wore contact lenses. Visual acuity improved only slightly
in all subjects and antecedent eye disease, such as cata-
racts, glaucoma, and irregular astigmatism, limited the
best-corrected visual acuity. There were no surgical com-
plications as a result of treatment with liquid nitrogen
cryotherapy spray.
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Cryotherapy in Ophthalmology 107
As the liquid nitrogen spray creates a superficial freeze
when applied for less than 1 second, the unwanted cor-
neal epithelium can be frozen without damage to the un-
derlying corneal stroma or endothelium. In addition, lo-
calized cryotherapy spares the non-treated corneal sur-
face and limbus, preserving the regenerative potential of
the corneal epithelium. Liquid nitrogen cryotherapy, us-
ing the spray technique described, appears to be an effec-
tive means of eradicating AWLE and may be used as an
alternative to silver nitrate 1% solution.
7.2.2. C onjunctival Amyloidosis
Conjunctival amyloidosis is rarely associated with sys-
temic disease [55,56]. The etiology of primary ocular
conjunctival amyloidosis has not been fully elucidated.
However, it likely involves production of precursor im-
munoglobulin light-chains by a population of benign,
localized B-lymphocytes, followed by deposition of amy-
loid in the conjunctiva [57]. Patients may present with
painless swellings of the conjunctiva or eyelids, pseu-
doptosis, or epiphora [58]. Clinically, the conjunctival le-
sions appear as small, pink-red or yellow-red nodules
which are well-vascularized, and involving the palpebral
and forniceal conjunctiva [58]. Histologically, conjunc-
tival amyloidosis appears as an acellular, amorphous,
eosinophilic material with the characteristic staining with
Congo-red of dichroic birefringence. The traditional treat-
ment of localized conjunctival amyloidosis has been sur-
gical debulking, with repeat debulking surgery should the
amyloidosis recur [55,57].
Liquid nitrogen cryotherapy of primary ocular con-
junctival amyloidosis was recently reported in a series of
4 patients [59]. Liquid nitrogen cryospray was applied to
the lesions, either directly or after excisional biopsy to
debulk the amyloid lesions. With a median follow-up of
24.5 months, 2 of the 4 patients had post-treatment re-
currence of conjunctival amyloidosis after the first treat-
ment, at 14 and 10 months respectively. Conjunctival
amyloidosis was eradicated in all subjects after repeat
cryotherapy. Surgical debulking prior to cryotherapy may
be beneficial in allowing the freezing to reach the deeper
blood supply of the lesions.
7.2.3. Conjun cti v al Lym phangiectasia
Conjunctival lymphangiectasia is characterized by di-
lated and prominent lymphatic channels within the con-
junctiva. The condition is usually unilateral, however bi-
lateral cases may be seen in Turner syndrome or Nonne-
Milroy-Miege disease. Symptoms include ocular irrita-
tion, dryness, epiphora, blurred vision, and pain [60]. The
terms lymphangiectasia and lymphangioma are used in-
terchangeably, and if there is bleeding into the lymph
channels, the condition is called hemorrhagic lymphan-
giectasia [61]. The etiology of lymphangiectasia remains
unknown. Simple excision or marsupialization, or both,
have been the traditional therapeutic options for this con-
dition.
The use of cryosurgery to treat hemorrhagic lym-
phangiectasia was first reported in 1975 [62]. A case
series of conjunctival lymphangiectasia treated with liq-
uid nitrogen cryotherapy was reported in 2009 [63]. Us-
ing a cryoprobe, cryotherapy was applied in a double
freeze-thaw fashion after an incisional biopsy of a por-
tion of the conjunctiva in 4 patients with conjunctival
lymphangiectasia. With a mean follow-up of 24.5 months,
2 patients remained lesion free after therapy, while the
other 2 patients had recurrence. The average time to re-
currence was 18 months after therapy. Repeat cryother-
apy led to resolution of recurrent conjunctival lymphan-
giectasia in all patients treated.
7.2.4. Conjun cti v al Sarcoi dosis
Sarcoidosis is a chronic, multisystem, granulomatous dis-
order of uncertain etiology. Organ systems involved in-
clude the lungs, skin, lymph nodes, and eyes. Ocular
symptoms are present in a significant portion of patients
with systemic sarcoidosis, with the most common of
these symptoms being uveitis and conjunctival nodules
[64]. Biopsy of conjunctival nodules is sometimes per-
formed to aid in the diagnosis of sarcoidosis. These nod-
ules are typified by the presence of non-infectious, non-
caseating granulomas. The nodules can create ocular irri-
tation and foreign body sensation. Treatment of these no-
dules include lubrication, topical cyclosporine [65], or
excision. Liquid nitrogen cryotherapy has recently been
shown to treat conjunctival sarcoidosis in a 54-year-old
woman [66]. In this case, multiple, bilateral, bi-psy-
proven conjunctival sarcoid nodules were treated with
liquid nitrogen cryospray. The patient remained free of
conjunctival sarcoidosis 6 months after cryotherapy.
7.2.5. Conjunctival Vascular Tumors
Vascular tumors of the conjunctiva include capillary he-
mangiomas, varices, and hemangiopericytomas. De-
pending on the type, management of these tumors typi-
cally includes local excision, CO2 laser, cautery, topical
corticosteroids, or oral propanolol. Given their inherent
vascular nature, these tumors may be especially suscepti-
ble to cryotherapy if easily accessible. A case report of a
liquid cryotherapy to treat a conjunctival vascular tumor
was reported in 2005 [44]. This report was a case of pre-
sumptive acquired conjunctival capillary hemangioma as
the patient declined an excisional biopsy. Using a cryos-
pray method, the lesion underwent liquid nitrogen cryo-
therapy, with significant regression of the lesion over 6
weeks. The lesion remained at its minimal size 1 year
after therapy, although it had not completely regressed. It
remains to be seen if certain vascular tumors would
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Cryotherapy in Ophthalmology 108
benefit from adjuvant cryotherapy if traditional therapies
prove to be ineffective.
7.2.6. Pterygia
Pterygia are benign, wing-shaped folds of conjunctival
and fibrovascular tissue extending over the limbus and
encroaching onto the superficial cornea. Proliferation is
thought to arise from activated limbal epithelial stem
cells. The etiology of pterygia is unknown, but epidemi-
ologic studies have implicated ultraviolet light, exposure
to the environment, and chronic irritation as causative
factors [67-69] These external factors may disrupt the
apoptotic and anti-proliferative signals of epithelial stem
cells [70,71]. The current definitive therapy for pterygia
is surgical removal. Without additional treatment of the
surgical bed after excision, pterygia excision is often
complicated by recurrence. Various post-excision, adju-
vant treatments have been described in the past, with
recurrence rates of 6% with conjunctival autograft, 13%
with beta-irradiation, and 29% with mitomycin C com-
pared to 53% with excision alone after more than 5 years
of follow-up [72].
The use of adjuvant liquid nitrogen cryotherapy of the
surgical site after de novo and recurrent pterygia excision
was recently described [73]. In this series, after excision
of the pterygia, cryotherapy with a cryoprobe was per-
formed, with the tip of the cryoprobe in contact with the
corneoscleral limbus for approximately 1 second. A dou-
ble freeze-thaw technique was used. In the de novo
pterygia group (median follow up of 24.5 months), only
1 out of 15 patients had a recurrent pterygium after exci-
sion and cryotherapy, 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 recur-
rent pterygium after excision and cryotherapy, resulting
in a recurrence rate of 29.6% per year. Thus, liquid ni-
trogen cryotherapy appears to be an appropriate adjuvant
treatment after de novo pterygia excision to minimize
recurrence (Figure 2(a) and (b)). However, recurrent ptery-
gia have not been shown to be susceptible to adjuvant
liquid nitrogen cryotherapy, with high rates of recurrence
despite cryotherapy [73].
7.2.7. Superior Limbic Keratoconjunctivitis
The etiology of superior limbic keratoconjunctivitis (SLK)
remains uncertain. One proposed mechanism is soft tis-
sue microtrauma between the superior palpebral and su-
perior bulbar conjunctival surfaces from normal repeti-
tive eye blinking in susceptible individuals [74-76]. An-
other hypothesis indicated an insufficient local tear sup-
ply [77-79]. A multitude of treatments are suggested for
SLK, including thermocautery, chemocautery, conjunc-
tival resection, punctual occlusion, topical application of
autologous serum, topical cyclosporine, topical ketotifen
(a)
(b)
Figure 2. (a) Pterygium before excision and cryotherapy; (b)
Appearance of eye 1 year after excision and cryotherapy.
fumarate, bandage contact lenses, topical lodoxamide
tromethamine, botulinum toxin, and topical vitamin A
eyedrops [77-84]. The fact that there are so many treat-
ments frequently means that no single treatment is ade-
quate, and that the disease may be a result of a combina-
tion of factors including dry eyes, mechanical trauma,
local inflammation, and the effect of Graves disease on
the eyes [85].
SLK typically presents with one or more of the fol-
lowing clinical symptoms: unilateral or bilateral ocular
burning, foreign body sensation, ocular pain, epiphora,
photophobia, blepharospasm, and decreased vision. Some
patients have mucus discharge and corneal filaments.
Examination findings include superior conjunctival in-
flammation with fine punctate staining by rose bengal of
the upper cornea, superior limbus, and adjacent conjunc-
tiva. Filaments are sometimes present at the superior lim-
bus, with some patients exhibiting pseudoptosis. There is
usually a fine papillary reaction of the upper eyelid
palpebral conjunctiva.
A case report of liquid nitrogen cryotherapy for the
treatment of SLK refractive to medical therapy was re-
ported in 2009 [86]. Four patients underwent liquid ni-
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Cryotherapy in Ophthalmology 109
trogen cryospray with a double freeze-thaw technique to
the superior limbus and inflamed conjunctiva (Figure
3(a) and (b)). Resolution of symptoms and signs oc-
curred within 2 weeks in all cases. The SLK recurred in 2
of 4 patients with a median follow-up of 10 months. Re-
currences were treated with another round of liquid ni-
trogen cryotherapy (mean time to recurrence 3.6 months),
while no eyes required a third treatment. Liquid nitrogen
cryotherapy of SLK may act by removing the redundant
superior conjunctiva by causing a scar to form between
the superior bulbar conjunctiva and the underlying Te-
non’s capsule and sclera [86]. It remains to be seen if the
effects of cryotherapy on SLK are permanent.
7.2.8. Trichiasis
Trichiasis is a misdirection of eyelashes that is acquired.
In-turning if eyelashes and their subsequent contact with
the cornea and conjunctiva leads to foreign body sensa-
tion by the patient. Treatment modalities for trichiasis
include manual epilation, electrolysis, cryotherapy, argon
(a)
(b)
Figure 3. (a) Superior limbic keratoconjunctivitis (SLK); (b)
Appearance of superior limbus 6 months after cryotherapy
for SLK.
laser, radiofrequency epilation and surgery.
Cryotherapy for trichiasis was first reported in 1997,
using a nitrous oxide cryoprobe [87]. In this series, local
treatment of eyelids using a double freeze-thaw tech-
nique and a microthermocouple achieved a low tempera-
ture of 20˚C [87]. The use of liquid nitrogen for trichiasis
cryotherapy was reported soon after, with success in
greater than 90% of patients [88]. Subsequent use of
cryotherapy to treat trichiasis in the setting of trachoma
[89] and ocular cicatricial pemphigoid [90] has been re-
ported. While highly successful, cryotherapy is not rec-
ommended for trichiasis in the setting of paralytic lids,
heavily pigmented patients, or trichiasis involving less
than one-third of the eyelid margin [88].
7.2.9. V er nal Kera to conjun ct ivitis
Vernal keratoconjunctivitis (VKC) is an immune-medi-
ated disorder affecting the ocular surface, with a combi-
nation of environmental triggers and a pro-inflammatory
state contributing to the pathogenesis. Clinical findings
include the presence of upper tarsal giant papillae, cor-
neal shield ulcers, or gelatinous limbal infiltrates (Horner-
Trantas dots). The giant papillary changes in VKC are
collections of neutrophils, eosinophils, lymphocytes, and
other leukocytes surrounding a central vascular core [91].
Patients with VKC usually present with symptoms of
ocular itching, tearing, mucus secretion, and photopho-
bia.
Cryotherapy for VKC has been reported by several
groups, with the first report appearing in 1982 [92].
Singh reported a 22% recurrence rate with short-term
follow up using a carbon dioxide cryogen [92]. Abiose
and Merz, also using a carbon dioxide cryogen, had a
50% recurrence of giant papillae at just 4 weeks post
treatment [93]. Mtanda and Sangawe studied 34 eyes
with VKC treated with a carbon dioxide cryogen with
disease recurrence in 2 eyes at 5 months [94]. Sank-
arkumar et al. studied 30 eyes of 15 patients with VKC,
who underwent treatment a carbon dioxide cryogen. Re-
ported recurrence was only 3.3% at one year [95]. Jiang
et al. combined resection, cryotherapy, and amniotic mem-
brane transplantation for the treatment of VKC [96]. In
this study of 16 eyes (follow-up ranging between 3 - 22
months), fourteen eyes (87.5%) were symptom-free 1
month after surgery with no evidence of VKC on exam.
Recurrence of VKC was observed in 2 eyes (12.5%) after
cryotherapy.
Liquid nitrogen cryotherapy (using a cryoprobe) for
VKC in 3 eyes was reported in 2008 [58]. The median
follow-up was 24 months. Although clinical symptoms
and visual acuity improved 1 month after therapy, giant
papillae recurrence was noted after 1 month. Recurrent
VKC was noted as early as 9 months after therapy. The
median time to recurrence was 12 months.
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Cryotherapy in Ophthalmology 110
Although cryotherapy may kill the central vascular
core of giant papillae early on (resulting in some positive
results after therapy), the high rate of recurrence may
make cryosurgery an ineffective therapy for VKC. In
addition, given the environmental and systemic factors
that contribute to VKC, recurrence is likely in the ab-
sence of continued anti-inflammatory and immunosup-
pressive therapy.
7.3. Pre-Malignancy and Malignancy
7.3.1. Primar y Acqui red Melanosis and Mel anoma of
the Conjunctiva
Primary acquired melanosis (PAM) of the conjunctiva is
a pre-malignant transformation of melanocytic cells.
PAM occurs in up to 35% of adult Caucasians [97],
while cases have been reported in highly pigmented indi-
viduals [98]. The presentation of PAM is usually unilat-
eral, although bilateral cases have been reported [98].
The majority of PAM conjunctival lesions is painless and
asymptomatic, and may involve the cornea. However, a
small portion of PAM lesions may give rise to conjunc-
tival melanoma. In a large series of over 300 eyes with
PAM, it was estimated that 8% of PAM cases evolved
into melanoma at 5 years, 12% at 10 years, and 21% at
15 years [98].
The mainstay of PAM management includes observa-
tion for malignant behavior (i.e. enlargement). Lesions
with high suspicion for malignant transformation may be
treated surgically, including excisional biopsy followed
by intra-operative double freeze-thaw cryotherapy. Cryo-
therapy for the treatment of PAM was first described in
the early 1980’s [99]. Excision and cryotherapy of PAM
has proven to be an effective treatment [100], although
recurrences are not unusual. In a recent report of over
100 cases of PAM treated with excision and cryotherapy,
and at least 3 years follow-up, the reported rate of PAM
recurrence was 27%, with 3% progressing to melanoma
[98].
Conjunctival melanoma can arise de novo, from a
preexisting nevus, or from PAM. By far, PAM is the
most common precursor to conjunctival melanoma, with
up to 75% of conjunctival melanomas arising in associa-
tion with PAM [101]. As in PAM, conjunctival mela-
noma is often seen in lightly pigmented individuals. Con-
junctival melanomas typically present as pigmented,
fleshy, raised lesions, and may exhibit a prominent feeder
vessel (Figure 4(a)). Malignant conjunctival melanoma
metastasize to regional lymph nodes and other organs,
including brain.
Treatment of conjunctival melanoma varies according
to the extent and location of involvement [100]. Adjuvant
cryotherapy for conjunctival melanoma was described as
early as 1980 [102,103]. Melanomas involving the bulbar
conjunctiva and cornea may be treated by alcohol epithe-
liectomy and partial scelroconjunctivectomy using the
“no-touch” technique, followed by intra-operative double
freeze-thaw cryotherapy (Figure 4(b) and (c)). In addi-
tion to the above, melanomas involving the forniceal
conjunctiva may require larger excision and mucous/
amniotic membrane grafts. Conjunctival melanotic le-
(a)
(b)
(c)
Figure 4. (a) Paralimbalconjunctival melanoma; (b) Para-
limbal bed after removal of a conjunctival melanoma. Note
the liquid nitrogen cryoprobe prior to application to the
paralimbal region; (c) Paralimbal bed in (c) immediately
after application of the liquid nitrogen cryoprobe. Note the
frozen ice ball on the surface on the eye.
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Cryotherapy in Ophthalmology 111
sions that extent into and beyond the globe may require
enucleation and exenteration. Metastatic melanomas re-
quire systemic therapy.
7.3.2. Conjunctival Intra epithelial Neopl asia and
Squamous Cell Carcinoma
Conjunctival intraepithelial neoplasia (CIN) is a local-
ized squamous cell neoplasm that is minimally aggres-
sive and confined to the surface epithelium. Classifica-
tion and grading of CIN is based on the depth of in-
volvement of dysplastic cells: mild CIN involves ~1/3 of
the epithelial depth, moderate CIN involves ~1/2 of the
epithelial depth, and severe CIN (previously called car-
cinoma in situ) involves full thickness epithelium without
invasion beyond the epithelial basement membrane. If
the basement membrane is compromised and invaded by
the abnormal cells, then the lesion has progressed to
squamous cell carcinoma.
Conjunctival intraepithelial neoplasia and squamous
cell carcinoma occur more frequently in immunocom-
promised individuals (including individuals with ac-
quired immunodeficiency syndrome). Other possible risk
factors include sun exposure and human papillomavirus
infection [104]. Clinically, CIN and squamous cell car-
cinoma may present as fleshy, elevated lesion at the lim-
bus. Adjacent corneal epithelial involvement is not un-
common. Although squamous cell carcinoma is locally
invasive, it rarely metastasizes.
Adjuvant cryotherapy for CIN and squamous cell car-
cinoma was first proposed in 1977 [34]. Early studies
using excision followed by nitrous oxide cryoprobes
showed relatively good results with a 9% recurrence rate
with at least 5 years of follow up [105]. More recently,
an optimized technique for excision and cryotherapy has
been described (similar to conjunctival PAM and mela-
noma excision and cryotherapy), which includes treat-
ment of the lesion by alcohol epitheliectomy and partial
scelroconjunctivectomy using the “no-touch” technique,
followed by intra-operative double freeze-thaw cryothe-
rapy [100]. In a study of 60 patients with CIN and con-
junctival squamous cell carcinoma treated with excision
and cryotherapy, after a mean follow up of 56 months,
the rate of recurrence was 4.5% for CIN and 5.3% for
squamous cell carcinoma [106].
7.3.3. Reactiv e Lymphoid Hyperpl as ia and
Conjunctival Lymphoma
Reactive lymphoid hyperplasia (RLH) is a benign prolif-
eration of lymphoid tissue in the ocular adnexa, which
may present unilaterally or bilaterally. Histologically,
RLH lesions appear as polymorphic proliferations of
small lymphocytes and intermixed plasma cells, immu-
noblasts, and histiocytes. Conjunctival RLH is usually
asymptomatic, with patients seeking medical attention
because of cosmetic appearance or the fear of an uncer-
tain diagnosis. The forniceal, bulbar, and palpebral con-
junctivae can be affected, with a predilection for the for-
nices. RLH lesions have a potential for malignant trans-
formation and systemic lymphoma, necessitating an ex-
cisional biopsy to rule out malignancy. Traditionally,
conjunctival RLH has been treated with excision, while
adjuvant radiation was reserved for biopsy-proven ma-
lignant lesions.
Cryotherapy for reactive lymphoid hyperplasia of the
conjunctiva was first described in 1977 [33,34]. Eichler
and Fraunfelder reported a retrospective case series of
various conjunctival lymphoid tumors (including RLH)
treated by liquid nitrogen cryospray [41]. With a mean
follow up of 75 months, 5 biopsy-proven lymphoid hy-
perplastic lesions were treated. Four out of five lesions
were locally eradicated after only 1 treatment, while the
fifth lesion was eradicated after repeat treatment. Thus, it
appears that cryotherapy is a viable option in treating
RLH.
Conjunctival lymphoma is on the same spectrum as
RLH, with the former being malignant. The great major-
ity of conjunctival lymphomas are B-cell in origin, with
T-cell lymphomas presenting in extremely rare cases
[107]. Most conjunctival lymphomas are localized and
not associated with systemic disease at presentation.
However, systemic involvement may occur over time.
Clinically, conjunctival lymphomas present in a similar
fashion to RLH and may appear as a salmon pink,
smooth, and soft lesion. Histopathologically, while RLH
demonstrates a polycolonal expansion of lymphoid cells,
malignant lymphoma is characterized by a diffuse sheet
of monotonous, small, round lymphocytes, and may ex-
hibit nuclear and mitotic features suggestive of higher
malignant potential.
Diagnosis and treatment of localized conjunctival lym-
phoma includes excisional biopsy and adjuvant therapy,
which has included external beam radiation, brachyther-
apy, cryotherapy, intralesional interferon injections, and
systemic rituximab [108]. Cryotherapy offers an advan-
tage over radiation therapy in that there is very little risk
to surrounding tissue. In addition, cryotherapy avoids
possible local and systemic side-effects of interferon and
rituximab administration, respectively.
Cryotherapy for conjunctival lymphoma was first pro-
posed in 1977 [34]. Subsequently, in a series of 37 le-
sions of biopsy-proven conjunctival lymphomas treated
with excisional biopsy and liquid nitrogen cryotherapy,
the authors reported local eradication in 65% (24/37),
92% (34/37), and 97% (36/37) of lesions after the first,
second, and third cryotherapy treatment, respectively
(average follow up time of 75 months) [41]. Most re-
cently, a rare case of isolated T-cell conjunctival lym-
phoma in a 57-year-old female was treated with local
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Cryotherapy in Ophthalmology 112
excision and triple-freeze cryotherapy, resulting in local
eradication without systemic involvement after 24 months
of follow up [107].
8. Cryotherapy for Intraocular Pathology
8.1. Retinal Tears and Detachments
Retinal tears and detachments arise for physical separa-
tion of the neurosensory retina and the underlying retinal
pigment epithelium (RPE). Retinal tears may arise from
trauma or traction from the overlying vitreous. Retinal
tears may then allow fluid influx between the neurosen-
sory retina and the RPE, causing further extension of the
separation and leading to a retinal detachment. Retinal
detachments arising from retinal tears are referred to as
rhegmatogenous retinal detachments. Retinal detachments
arising from a tractional component without a tear are
called tractional retinal detachments. Lastly, retinal de-
tachments arising from a collection of exudate between
the neurosensory retina and the RPE are called exudative
retinal detachments.
The treatment of retinal tears and detachments are
multiple and depend on the patient, the size and location
of the lesion, as well as surgeon preference. Prophylactic
treatment of retinal tears without detachment may in-
clude cryotherapy (Figure 5(a) and (b)) and/or laser
therapy just outside of the tear to wall off the break. The
goal of retinal detachment repair includes bringing the
retina and RPE into contact to allow for reattachment and
may include pneumatic retinopexy or pars plana vitrec-
tomy with scleral buckle or silicone oil. In certain set-
tings, further chorioretinal scarring, using cryotherapy or
laser therapy, is used to adhere the detached retina to
avoid repeat detachment.
The early history of cryotherapy use in retinal tear and
detachment repair is described in detail in Section III.
Briefly, cryotherapy of the eye was first reported by Bi-
etti in 1933 to seal a retinal hole [17]. Shortly after,
Deutschmann used cryosurgery to treat retinal detach-
ments [18]. Bellows and Kelman created retinal cryo-
pexy instruments for the treatment of retinal tears [22,
109]. Cryoretinopexy in conjunction with scleral buck-
ling for retinal detachments was also described [24-26].
Yanoff reported results from a series of 100 eyes
treated with transconjunctival cryotherapy to seal pe-
ripheral retinal breaks, with only 3 eyes developing reti-
nal detachments and requiring additional procedures
[110]. Wolfensberger and colleagues reported excellent
results using prophylactic 360 degree peripheral retinal
cryotherapy of fellow eyes after contralateral giant retinal
tears [111]. Although generally safe, retinal cryopexy has
been reported to cause cystoid macular edema [112],
likely secondary to transient breakdown of the blood-re-
tina barrier [113]. In addition, cases of retinal necrosis
(a)
(b)
Figure 5. (a) Multiple retinal breaks; (b) Chorioretinal
scarring after application of external cryotherapy to areas
around retinal breaks in (a).
with overtreatment using cryotherapy have been reported
[114].
The safety and efficacy profile of cryotherapy for reti-
nal tear repair is comparable to other techniques. In a
recent randomized clinical trial of patients undergoing
repair of rhegmatogenous retinal detachments with either
intraoperative cryotherapy or postoperative (1 month later)
laser retinopexy, the authors found that reattachment and
postoperative complication rates were similar in both
groups [115]. Although the study found that visual re-
covery was faster in the retinopexy group, the difference
in visual acuity after 6 months was not significant. In
addition, cryotherapy intraoperatively during scleral buckl-
ing procedure provided the advantage of one intervention
with lower costs.
8.2. Retinopathy of Prematurity
Retinopathy of prematurity (ROP, also called retrolental
fibroplasia) is an ischemic retinopathy of premature and
low birth weight infants. The incidence of ROP in the
United States is about 1300 newborn children annually,
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Cryotherapy in Ophthalmology 113
with severe visual impairment in a large percentage. The
risk of ROP is inversely proportional to birth weight,
with 37% of infants weighing less than 750 grams de-
veloping severe ROP. The diagnosis of ROP is rarely
made in infants with birth weights of greater than 2000
grams. The Preferred Practice Patterns of the American
Academy of Ophthalmology recommends screening for
newborns with less than 30 weeks of gestation and/or a
birth weight of less than 1500 grams.
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 subse-
quent iatrogenic oxygen supplementation, halts and alters
normal retinal vasculature development, leading to the
onset of ROP and abnormal neovascularization. Severe
ROP can progress to fibroglial proliferation, vitreoretinal
traction, and retinal detachment.
Hindle and Leyton reported the first use of cryother-
apy to prevent progression of ROP in 1978 [116]. This
revolutionized the treatment of ROP, as prior treatments
were limited. 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 [117].
Three month [117] and 12 month [118] data from this
trial were promising, with cryotherapy reducing unfa-
vorable outcomes by half. Five-year data from the
CRYO-ROP study supported the safety and efficacy of
cryotherapy treatment of ROP [119]. Ten-year data from
the CRYO-ROP study showed that 44.4% of treated eyes
(versus 62.1% of untreated eyes) were legally blind,
showing long-term value from cryotherapy in preserving
visual acuity in eyes with ROP [120]. More recently,
laser therapy has become the standard of care for ROP
management, while anti-vascular endothelial growth fac-
tor (anti-VEGF) therapy has shown promise as an addi-
tional modality for the treatment of ROP [121].
8.3. Retinal Capillary Hemangiomas
Retinal capillary hemangiomas (RCHs) are benign vas-
cular tumors that may occur sporadically (sometimes
referred to as von Hippel lesions) or in the setting of von
Hippel-Lindau (VHL) disease. In the setting of VHL dis-
ease, RCHs are usually detected in the second or third
decade of life, and seen in up to 60% of patients with
VHL disease [122]. In a retrospective case series of 68
patients with RCHs, it was found that 46% of patients
had VHL disease [123]. The majority of patients with
RCHs have no significant vision loss from the lesion
[124], likely due to the predominately superotemporal
and midperipheral retinal location of most RCHs [123].
Treatment of RCHs is based on size, location, associ-
ate edema, and effects of visual acuity. The majority of
RCHs may be safely observed [125]. Singh et al. re-
ported that 82% (68 total patients) of observed RCH le-
sions remained stable with a mean follow up of 84
months [125]. For RCHs requiring treatment, laser pho-
tocoagulation and cryotherapy have been shown to be
equally effective in controlling the growth of the lesion,
as well as the associated retinal edema. In the same study
by Singh and colleagues, 74% of treated RCHs remained
controlled with one session of laser photocoagulation or
cryotherapy [125].
9. Summary and 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 oph-
thalmology has helped advance maturing fields (such as
cataract extraction), while in other instances revolution-
ized patient care (including retinopathy of prematurity
and ocular surface malignancies). Further applications of
cryotherapy in eye disease continue to emerge.
10. Acknowledgements
We’d like to thank Dr. Robert Watzke for his contribu-
tion of photos documenting the use of cryotherapy for
retinal tear repair.
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