Introduction
Ozone an inactivated, trivalent (O3) form of oxygen (O2) was named by German scientist Christian Frederick Schonbein in the mid-nineteenth century (1). The therapeutic concentrations of ozone were used primarily to disinfect operating rooms in 1856 and subsequently for water treatment in 1860 (Foundation for alternative science & Technology). Since then, several authors began to focus on the use of ozone in medical therapy. However it was not until 1992 when Gierek-Łapińska and Antoszewski reported the efficacy of ozone in the treatment of different ophthalmologic diseases namely infectious conjunctivitis and keratitis, corneal degeneration and diseases of the posterior segment of the eye (2, 3). To date, several methods for the application of medical O3 have been introduced, to be precise direct intra-arterial and intravenous application, rectal insufflations, intramuscular injections, major and minor autohemotherapy, ozonated water, intra-articular injection, ozone bagging, ozonated oil and inhalation of ozone (4–9).
A critical appraisal of relevant literature when it comes to ozone use in ophthalmologic diseases revealed sporadic clinical reports, from a few centers mainly Cuba. A double blind controlled clinical trail by Moreno et al. (10) comprising of 123 patients with retinitis pigmentosa, reported efficacy of ozonated blood in 62 patients assigned to the treatment, although its action was temporary. Another clinical evaluation by Mapolon et al. (11) reported remission of photophobia and photopsia in all 50 patients with retinitis pigmentosa treated with ozone. Diaz et al. (12) in a clinical study of 180 patients suffering from different ophthalmologic diseases like retinitis pigmentosa, myopia, chronic open angle glaucoma, optic atrophy and diabetic retinopathy who were treated with daily rectal ozone therapy, demonstrated improvement ranging from 23–63% at follow-up over one year. Satiesteban et al. (13) in a cross sectional study involving 60 patients suffering from optic nerve dysfunction (OND) of different etiologies and time of evolution treated with mixture of ozone/oxygen endovenously by autohemotherapy, during 15 sessions demonstrated 86% and 83% improvement in Pelli Robson Contrast Sensitivity Test (PRCST) and visual field (VF) by Goldmann Perimetry.
We report two cases of viral blepharitis in children treated with O3. For the first time we have decided to apply ozone thera­py directly to the skin in a close distance, using Ozony Tron X (probe-tube used in dermatology) with good clinical outcome. The purpose of this paper is, firstly, to objectively evaluate clinical application of O3, secondly to assess the validity of ozone therapy in children with viral blepharitis.

Case report
An 11-years old boy developed accumulation of small vesicles involving the both lid margins and periocular skin. The disease was preceded by a week long period of itching and inflammation followed by a vesicular eruption. Out of concern for eye involvement ophthalmological consultation was obtained. On referral to ophthalmologist on the skin of the upper and lower eyelid small bullous eruptions of the size of several millimeter were present, which demonstrated the tendency to group themselves (Fig. 1.). These lesions had inflamed, erythematous base. The patient reported having suffered HSV infection 2 years earlier due to excessive exposure to sunlight. During the recent infection the conjunctiva was cultured and it was found not to be infected and the cornea was clear. The diagnosis of recurrent HSV infection was confirmed by Tzanck smear.
The second patient, a 10-years old child complained of similar symptoms for two days. Disturbing swelling and redness of the eyelids were the reason for referral to ophthalmologist. On the swollen skin of both eyelids small vesicular eruptions with the tendency to group appeared (Fig. 2.).
Ozone was administered. The patients started their ozone treatment at the beginning of an eruption. It should be noted that ozone therapy applied on inflammatory changes of the skin of eyelids was isolated and treated without additional conventional (pharmacological) treatment. Method applied by us is based on active oxygen produced by the generator of the ozone from the device Ozony Tron X (Mymed). The method of applying the ozone with the glass-probe on the skin surfaces is shown on the Figure 3.
Treatments were performed once daily using ozone on inflamed skin of both eyelids and were limited to 2 sessions in the first child and to 3 in the second child. The time of application of the ozone ranged between 20 to 60 seconds on 1 cm2 of skin surface. In our method we used the probe very precisely in order not to exceed the cutaneous-conjunctival border. The treatment with daily insufflations of medical ozone was completed when patients did not complain of any discomfort and local changes have completely resolved.
In both cases rapid improvement right after the first application was noted – subjective discomfort (itching, burning) disappeared. Ophthalmological examination of the affected eyes revealed disappearance of the redness and appearance of a little crusts where the bullous eruptions were placed. Ophthalmoscopy did not reveal any pathological signs. The patient had no more signs of herpes after the 3rd session, with this treatment was completed (Fig. 4.). Similar outcome was established in the other case after 2nd course of our management. The recurrence tendency was not observed after two years following treatment.

Discussion
Modern ozone therapy is considered as an alternative approach for a wide variety of health problems, utilized as an additional supporting treatment or where no other effective management exists. For the first time we have decided to apply ozone therapy directly to the skin in a close distance, using OzonyTron X (probe-tube used in dermatology) in pediatric patients with viral blephatitis with good clinical outcome. It has been previously reported, that ozone effectively inactivates viruses (14, 15). Elimination of viruses using ozone is carried out in two stages: the first stage-extracellular, where a selective reaction of ozone with unsaturated fatty acids of cell membrane takes place, and which leads to infiltration of oxygenated metabolic products to the cell inside. The second stage-intracellular, consisting in a direct intervention of peroxides in autoreproduction of a virus.
In spite of this excellent antiviral and antibacterial effect, ozone has not been widely utilized in medicine because of the widespread belief that it is toxic to human (14). Apart from this, Marchetti & Monaca (16) reported case of death due to air embolism during ozone use in the psoriasis treatment. Daschner (17) reported Hepatitis C and HIV infections following ozone autohaemotherapy. Furthermore Faustini et al. (18) in cross sectional study demonstrated that transmission of HCV infection due to cross contamination occurred amongst 6 out of 31 patients who were exposed to autohaemotherapy or intramuscular injection in an outpatient clinic of a hospital in Italy. Lo Giudice et al. (19) presented case report of a 45-year-old woman with acute bilateral vitreo-retinal hemorrhages following oxygen–ozone therapy for lumbar disk herniation. Corea et al. (20) also reported case of vertebrobasilar stroke after treatement with ozone-oxygen for lumbar disc herniation. It is interesting to notice that in our case there was absence of side effects in patients receiving ozone therapy. Eukary­otic cells protect the skin from the ozone caused damage, due to resistance to the attack of atoms of oxygen. Additional protection is provided by the anatomic structure of the skin (cells arranged in layers). Therefore, we used safely ozone to the eyelids skin.
The application of ozone by OzonyTron X probe is painless which is important, especially in case of children. The diameter of the used probe was too big in comparison with the location and the range of skin lesions on the eyelids, thus required considerable technical skills. We recommend to try another way of application of ozone on the eyelid that it: “to blow ozone” – a non-contact method. Our suggestion of the appliance is that a probe of a smaller diameter should be developed for ophthalmological use.
We observed a “cut-off” of the course of disease and also clear shortening of the disease course, if therapy starts early. In our observations, we noticed that superficial changes more quickly resolved (2–3 applications) and did not require additional pharmacological treatment. From our experience we find that if the inflammation involved the deeper skin layers, or indicate mixed infection (viral, bacterial) the duration of ozone therapy definitely lengthened.
It was important to perform treatments daily, to continue therapy till healing was complete and not to stop treatment prematurely because immediate recurrence of the disease is likely. It can be possible also that ozone obtains a complete healing of herpes simplex blepharitis without recurrence after therapy but it is necessary to have a longer follow-up time. There is a need for a long term follow-up or a cohort study to determine whether these findings are on short term or long term basis.

Conclusions: 
1. Regional oxygenation in the treatment of patients with blephatritis is fast and efficient.
2. Superficial, intermittent ozone therapy in the treatment of viral blepharitis is painless and does not give any complications.
3. Ozone therapy should be considered as a supportive treatment in the therapy of blepharitis with complex etiology (bacterial, viral, fungal).
4. Ozone can be effectively used as a monotherapy in the superficial inflammation, especially viral.

 

References:
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3. Gierek-Łapińska A, Antoszewski Z, Myga B, et al.: Preliminary report on using general ozone therapy in diseases of the posterior segment of the eye. Klin Oczna 1992, 94, 139-140.
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10. Moreno N, Peláez O, Alemán T, et al.: Controlled clinical trial on the use of ozonated blood as a treatment for retinitis pigmentosa. Abstract from 2nd International Symposium on Ozone Applications, Cuba 1997.
11. Mapolon Y, Palmal M, Resio E et al.: Effects of ozone in patietns with retinitis pigmentosa. Abstract from 2nd International Symposium on Ozone Applications, Cuba 1997.
12. Díaz EC, Borrego L, Menéndez S, et al.: Ozone therapy in different ophthalmologic diseases. Abstract from 2 nd International Symposium on Ozone Applications, Cuba 1997.
13. Santiesteban R, Menéndez S, Francisco M, Luis S: Ozone therapy in patients suffering from optic nerve dysfunction. Abstract from 2nd International Symposium on Ozone Applications, Cuba 1997.
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19. Lo Giudice G, Valdi F, Gismondi M, et al.: Acute bilateral vitreoretinal hemorrhages following oxygen-ozone therapy for lumbar disk herniation. Am J Ophthalmol 2004, 138(1), 175-177.
20. Corea F, Amici S, Murgia N, et al.: A case of vertebrobasilar stroke during oxygenozone therapy. J Stroke Cerebrovasc Dis 2004, 13(6), 259-261.

Adres do korespondencji/ Reprint requests to:
dr hab. n. med. Lidia Puchalska-Niedbał (e-mail: lidianiedbal@tlen.pl)
Katedra i Klinika Okulistyki PUM
al. Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland

Fig. 1. First case – condition before treatment. Redness, a small bullous eruptions of both eyelids of the right eye.
Ryc. 1. Przypadek pierwszy – stan przed wdrożeniem leczenia. Zaczerwienienie, małe pęcherzowe wykwity na obu powiekach oka prawego.



Fig. 2. Second case – prior eye treatment. Skin with small vesicular eruptions.
Ryc. 2. Drugi przypadek – stan przed leczeniem oczu. Skóra z małymi pęcherzykowatymi wykwitami.



Fig. 3. The method of applying ozone with the glass-probe on the skin surface.
Ryc. 3. Metoda przykładania szklanej sondy z ozonem na skórę powiek.



Fig. 4. First case – condition after three sessions with ozone therapy. No inflammatory lesions.
Ryc. 4. Przypadek pierwszy – stan po trzech aplikacjach terapii ozonowej. Brak zmian zapalnych.