A quick literature review on PubMed using the words in the title of this article gives 12 results ranging from “cryosurgical ablation of a conjunctival adenocarcinoma in an ostrich” to “the cryodestruction of multiple apocrine hidrocystomas in a cat”. Such a survey would suggest that cryotherapy has little part to play in treatment of eye disease regularly seen in dogs and cats but is that really the case? Putting the same words into Google Scholar gave 1,780 results in 0.07 seconds though it will take a little longer to scroll through them all and see which have any relevance to what I’m about to tell you.
Interestingly, even on the first page of that latter search there was a fascinating paper from the human literature in the Journal of Dermatologic Surgery and Oncology which I must admit isn’t on my regular reading list. Back in 1977, Frederick Fraunfelder, Harold Farris and Thomas Wallace published a paper on “the cryosurgical management of 1,200 ocular and periocular squamous‐cell carcinomas in cattle and 270 benign and malignant ocular and periocular lesions in humans”. We like to think that One Health is a new and ground-breaking idea, don’t we, but here were two medics and a vet getting together to show the same technique working for cows and people back when I was still at secondary school.
Look at the numbers they were talking about. We are all into evidence-based veterinary medicine, aren’t we? And the key feature of EBVM is meta-analysis of copious data from the relevant papers. But looking at more recent papers we have ones involving 16 eyes of nine dogs, taking a paper on cryosurgery for pigmentary keratitis in pugs as an example. Or 46 palpebral masses from 31 dogs. The authors of that paper suggested that mixed adenoma/papilloma cases were more likely to recur after resection and cryotherapy than adenoma. But that was based on 17 adenomas and 6 adenoma-papillomas so whether one can really say that is unclear. What we need are the sort of numbers that 1977 paper involved – hundreds and thousands! And yet that paper has been buried and forgotten, it seems, but for the fantastic opportunity that Google Scholar gives us.
Changing cryosurgery to cryotherapy in PubMed did come up with four more papers with slightly higher numbers of cases so maybe it was my literature searching skills that were at fault. I should, for instance, have remembered Heidi Featherstone and colleagues’ paper back in 2009 detailing “14 dogs with unilateral canine limbal melanoma which were managed surgically by partial lamellar resection, cryotherapy (1,1,1,2-tetrafluoroethane)”. Tetrafluoroethane is the agent better known as Freon, a refrigerant coolant now being phased out because of its climate change implications. To be fair, Heidi was writing about its use 10 years ago before climate change was so
high on our agendas.
What coolants are available these days?
Cryogens include liquid nitrogen, an extremely cold agent which liquifies at -196°C, so acts very rapidly but is not easily stored or used without an expensive delivery system. Nitrous oxide is not as cold at -89°C while a carbon dioxide spray cools to -78°C. How cold do we need to get? The technique of cryodestruction is used for eyelid neoplasms, for the hair follicles of distichial lashes (Figures 1 to 5) or in a more specialised manner for the ciliary body in cyclocryotherapy for glaucoma. We’ll leave that latter use to one side as it is only relevant in specialist referral centres. Tumour cells, or the follicles of distichial lashes, die during freezing by the build-up of ice within the cell which then bursts the cell as it expands during melting. Each cell within a tumour or hair follicle thus needs to be kept at below -25°C for at least a minute before thawing. The problem is that tissue at -5°C looks just like it does at -25°C. How do we know what the temperature is? Early papers on cryosurgery in veterinary ophthalmology back in the 1980s recommended using thermocouples embedded in the tissue to determine the temperature of the tissue. These days infrared cameras are much more readily available which demonstrate the surface temperature of any lesion subject to cryosurgery. It is not quite what an embedded cryoprobe would show, but thermal cameras do allow evaluation of the temperatures one is achieving at the surface of a lesion for a very reasonable price.
As it is the thawing that really does the damage it doesn’t matter how quickly the tissue is frozen. What is important is that the thaw is slow. In a richly vascularised tissue like the eyelid any frozen area is rapidly thawed through blood flow. The answer is to use a clamp to prevent blood flow to the area while the lesion is being frozen. Generally, we use two freeze–thaw cycles for distichial lashes, though in some larger benign palpebral tumours three may be employed. Where though is the evidence that cryotherapy works in distichiasis? Others have suggested electroepilation or sharp knife resection of the hair follicles but those studies were back in the 1960s by Geoff Startup or the 1970s by Donald Lawson and involved small case reports. Publication of Chambers and Slatter’s paper in the Journal of Small Animal Practice in 1984 would not be allowed today from an ethics and welfare perspective. They took four “random source” dogs – from the pound, I guess, as they were writing from California – and froze their normal eyelids to -89°C. The non-steroidal anti-inflammatory flunixin was given intravenously but no anaesthetic as far as I can see. The dogs were then euthanised and their eyelids examined histopathologically at various times post-operatively. They found fibrin and inflammatory cells and karyorrhexis of epithelial cells immediately after surgery but the normal lid architecture had regenerated by 30 days. Eight clinical canine patients in the same paper were successfully treated with cryotherapy for distichiasis with depigmentation as the only side effect seen and no regrowth seen with follow-up for six months.
Human patients with distichiasis treated with cryotherapy are generally managed by surgically separating the anterior and posterior lamellae of the eyelids and then freezing the posterior portion which includes the Meibomian glands from which the distichia arise (O’Donnell and Collin, 1993). Success rates were variable from those reports: only two patients of the 24 in O’Donnell and Collin’s study needed an additional cryotherapeutic surgery while nearly half of the 13 patients in another report required a second intervention (Anderson and Harvey, 1981). We have one case report of this split lid cryotherapy in the veterinary literature, that from Pip Boydell who sadly died of a brain tumour last year and so is no longer with us to continue his work using this technique on dogs (Enache et al., 2015).
So, where does all of this leave us today? Recently, I’m pleased to say, an easily used cryosurgical appliance has been marketed to vets in the UK: a handheld device which readily allows a fine spray of nitrous oxide to be directed towards an eyelid lesion, be it a tumour or a distichial follicle in the Meibomian gland. Currently we have no published evidence of the efficacy of this device in veterinary patients and the relevant website gives only anecdotal reports. Having said that, use of cryotherapy in human cervical cancer patients has given a cure rate in cases with early detection of over 90 percent (Dolan et al., 2014) so one might expect a good response rate in benign periocular tumours. The success rate in distichiasis is more difficult to evaluate as quite often these hairs regrow in cases where electroepilation has been used without surgical resection.
Its handleability and ease of use are superb and I look forward to using it for distichia and lid masses in the future. With any luck, in another year or two I’ll be able to put a more qualitative account in the peer-reviewed literature and demonstrate that my first impressions have been confirmed.