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Clinical Update: External Disease
Liquid Nitrogen Cryotherapy for Ocular Surface Disease
By Marianne Doran, Contributing Writer
Interviewing Frederick W. Fraunfelder, MD, and Matthew Giegengack, MD
 
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Liquid nitrogen cryotherapy is a mainstay in dermatology practices for treating warts and keratoses but is seldom used in ophthalmology. Yet this coldest of the most common medical cryogens appears to be gaining attention because of its ease of use and potential application to a wide range of eye diseases.

Frederick W. Fraunfelder, MD, director of the cornea and external disease/ refractive surgery division at the Casey Eye Institute at Oregon Health & Science University in Portland, uses liquid nitrogen cryotherapy to treat benign ocular surface conditions as well as malignancies. “We can treat a multitude of eye diseases with liquid nitrogen cryotherapy,” Dr. Fraunfelder said. “Some of these are benign, such as pterygium. You can take a pterygium off and then freeze the area where it was removed so that the pterygium doesn’t recur. You can also treat conditions like conjunctival amyloidosis or conjunctival lymphangiectasia. Superior limbic keratoconjunctivitis also responds well.”

Dr. Fraunfelder noted that his father, Frederick T. Fraunfelder, MD, began research on liquid nitrogen in the late 1960s in Little Rock, Ark., when local farmers asked him to treat “cancer eye” in their cows. The elder Dr. Fraunfelder successfully treated the bovine ocular surface malignancy with cryotherapy. He subsequently took these results and applied them to humans.

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Why Liquid Nitrogen?

Liquid nitrogen has the lowest boiling point (–195.6°C) among the commonly used cryogens, making it the coldest and the most rapid to freeze other surfaces. The rapid-freeze characteristic offers advantages in many ocular conditions. “We know that a rapid freeze of tissue kills cancers most effectively, and it can treat many benign conditions by destroying the small blood vessels,” Dr. Fraunfelder said. “A rapid freeze and a slow thaw kills the microvasculature and seems to prevent these conditions from recurring in many patients.”

In addition to inducing ischemia in small blood vessels, liquid nitrogen cryotherapy may:

  • rupture cell walls through the formation of ice crystals,
     
  • generate osmotic stress,
     
  • cause denaturing of lipid-protein complexes,
     
  • create vascular stasis with resulting loss of cellular blood supply,
     
  • cause tissue necrosis, and
     
  • build up toxic concentrations of solutes inside cells.

Moreover, liquid nitrogen cryotherapy offers ophthalmologists another therapeutic alternative for managing a range of eye and ocular surface disorders, including hemangiomas and capillary hemangiomas, eyelid tumors, actinic keratoses and even trichiasis.

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Potential Applications

Depending on the condition being treated, liquid nitrogen can be applied as a cryospray or through direct contact using a cryoprobe. Several uses may be attractive to the comprehensive ophthalmologist.

Superior limbic keratoconjunctivitis. In an interventional case series, Dr. Fraunfelder used cryotherapy to treat four patients (seven eyes) with superior limbic keratoconjunctivitis (SLK) that had not responded to artificial tears, topical ocular corticosteroids or ocular lodoxamide.1 The liquid nitrogen was applied with a Brymill E tip spray (0.013-inch aperture) from a CRY-AC-3 unit.

The treatment was performed on an outpatient basis as a double freeze-thaw technique, with one drop of topical proparacaine providing local anesthesia. The patients’ signs and symptoms resolved within two weeks, and no adverse ocular events were reported. Although two patients (three eyes) experienced a recurrence, repeat cryotherapy performed three months after the initial treatments eradicated the condition. Dr. Fraunfelder noted that SLK responds well to cryotherapy in general and, in this instance, to the extreme cold of liquid nitrogen in particular.

Conjunctival lymphangiectasia. In patients with conjunctival lymphangiectasia, prominent and dilated lymphatic channels within the conjunctiva can cause ocular irritation, dryness, epiphora, blurred vision and pain. In the first reported case series evaluating liquid nitrogen cryotherapy for the condition, Dr. Fraunfelder treated four patients (five eyes).

Each patient underwent an incisional biopsy of the involved conjunctiva to confirm conjunctival lymphangiectasia.2 Dr. Fraunfelder used a 1.5-mm Teflon-coated cryoprobe to perform the double freeze-thaw technique. During the freeze time, the cryoprobe tip was in contact with the conjunctiva for one to two seconds, at which point the inflamed conjunctiva reached a chalk-white appearance; thawing time was five or 10 seconds.

Signs and symptoms of conjunctival lymphangiectasia resolved within two weeks in the four patients. Two patients experienced recurrences—one at one year and again at three years; the second patient had a recurrence at six months (average time to recurrence, 18 months). Repeat liquid nitrogen cryotherapy resolved these recurrences, with an average length of follow-up of 24.5 months.

Conjunctival amyloidosis. Liquid nitrogen cryotherapy also has shown promise in treating this rare disorder, and it may prove to be a viable alternative to radiation and cytotoxic therapies. In a study reported in Archives of Ophthalmology,3 Dr. Fraunfelder treated four patients with primary localized conjunctival amyloidosis and no antecedent ocular disease.

Upon initial examination, the patients had a painless swelling of the conjunctiva or eyelids, often accompanied by epiphora and less often by pseudoptosis. Conjunctival lesions appeared as small pink-red or yellow-red well-vascularized nodules. Primary involvement was in the palpebral and forniceal conjunctivae. Three of the patients underwent a surgical incisional biopsy to debulk their lesion before cryotherapy. Local anesthesia for the cryotherapy procedure consisted of one drop of topical proparacaine and a subconjunctival or intratarsal injection of 0.5 to 1.0 ml of lidocaine, 1 percent, with epinephrine.

The cryotherapy was applied with a double freeze-thaw technique using a Brymill D tip (0.04064-cm aperture) until the lesions turned chalk-white; thawing occurred within five to 10 seconds. During a median follow-up of 24.5 months, two patients experienced a recurrence—one at 10 months and the other at 14 months. Repeat cryotherapy, however, controlled their conditions.

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Safety and Barriers to Wider Acceptance

In terms of safety, leaving the cryoprobe on the eye too long is the major concern. “The usual application time is one second or less,” Dr. Fraunfelder said. “If you leave it on there for five seconds or more, you can get too deep of a freeze, with the potential for a scleral or corneal melt, or you could freeze the intraocular structures and damage the iris, the corneal endothelium or even the retina. But if your application is one second or less, our research shows that liquid nitrogen cryotherapy is safe.”

Lack of familiarity, not safety, is probably the reason so few physicians take advantage of this therapy. “The main reason ophthalmologists don’t use liquid nitrogen is that they were not exposed to it in their medical training,” Dr. Fraunfelder noted. “They don’t know how to store it, how to apply it, what instrumentation to use or even where to purchase it.”

He emphasized that both specialists and general ophthalmologists can take advantage of cryotherapy in their practices. “Liquid nitrogen is easy to store and requires an investment of only about $500 to $1,000, and the cryotherapy unit may last for an entire career,” Dr. Fraunfelder said. “You have to buy a storage tank and have it refilled once a month by companies that routinely refill liquid nitrogen tanks at hospitals.”

A good tool waiting to be used. Matthew Giegengack, MD, an assistant professor of ophthalmology at Wake Forest University in Winston-Salem, N.C., agreed that ophthalmologists’ hesitancy to embrace liquid nitrogen cryotherapy is primarily due to lack of exposure to the cryogen during medical training. He believes liquid nitrogen is easier to use and at least as effective as other cryogens. “The method of application is quicker and more ergonomic because you don’t have to hold it on there as long,” Dr. Giegengack said. “From a practical point of view, the quick freeze is easier to apply, and that allows you to be more controlled in where you place it.”

In terms of safety, he does not believe that liquid nitrogen poses any greater risk to the patient than any of the other cryogens and may actually be less likely to cause problems because of its ease of use. “As people realize that liquid nitrogen is easier to use and, in my opinion, at least as effective as other cryogens, it will take off. It just needs to reach a critical mass.”
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Dr. Fraunfelder is a consultant for Brymill Cryogenic Systems. Dr. Giegengack reports no financial interests.
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1 Fraunfelder, F. W. Am J Ophthalmol 2009;147(2):234–238.
2 Fraunfelder, F. W. Trans Am Ophthalmol Soc 2009;107:229–232.
3 Fraunfelder, F. W. Arch Ophthalmol 2009;127(5):645–648.

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