Introduction

Hyaluronic acid is a substance seen in mammals. It took its name after the ancient Greek word “glass” due to its appearance resembling to glass. In 1934, Karl Meyer and John Palmer isolated a chemical compound from the vitreous body of bovine eye, hyaluronic acid. It is seen in almost all microorganisms. It is a polysaccharide that belongs to a group of compounds with the same formula, whether isolated from simple bacteria or from humans. Its application in medicine covers a wide range of fields. It can also be isolated in many human tissues, e.g., in the skin, in eye vitreous body, in joints and muscles where its works as a lubricant. Intercellular fluids of the joints also contain hyaluronic acid. In the umbilical cord, it stabilizes the contact between mother and foetus. This substance has no antigenicity, therefore frequency of adverse reactions is reduced. This is an encouraging piece of information compared with other skin implants. This advantage grants to the substance a leading position in implant market.

Fig. 1: Biochemical formula of hyaluronic acid molecules.

It should be noted that although it is considered a harmless product, an allergic granulomatous reaction has been reported after the third implantation in the nasolabial folds of a patient, therefore all patients should be informed in advance about this possible side effect [1, 2] (Fig. 1).

Case description

Fig. 2: Before implantation of hyaluronic acid. Treatment of fine forehead wrinkles.

In May 2009, a 45 year old woman (Fig. 2) decided to undergo subcutaneous injections with hyaluronic acid implant (Viscofill, IBSA, 12mg/ml cross-linked hyaluronic acid, which consisted of molecules subjected to cross-linking 4 times more than other similar products while it maintained the characteristics of single-phase gel). Prior to injections a personal history was taken free of contraindications. Then, in the context of an implantation display training seminar, the woman lied down on the medical bed, any sign of make-up or other cosmetics was removed from her skin and an antiseptic solution (Octenisept) was applied. Noted and pointed were forehead wrinkles in which small amounts of thin cross-linked Viscofill, 12 mg / ml (2 – 4 ml dose) were injected. Injected in the nasolabial folds of the woman was 1 ml Viscofill (27 mg / ml) bilaterally. Injections were performed in the skin according to the rules and instructions applied during usage of hyaluronic acid implants. After injections, an ice-bag was applied which via vasoconstriction reduced pain and oedema. As the patient was living in a distant area, treating doctor kept telephone contact with her.

Fig. 3: Severe eyelid oedema. infiltrated, erythematous, painful nodules after 10 days of the injections.

In the mid June, the woman reported to the doctor that she was swollen but she did not mention the anatomic area. An intramuscular injection of corticosteroid and receipt of antihistamines was recommended. Due to worsening of symptoms, the patient visited a private dermatologist who recommended Augmentin (625 mg) 1 x 3 / day. Symptoms instead of resolving, aggravated. After two days it was reported to the doctor that “swelling” had worsened and as a result her transportation to “Evaggelismos Hospital” was requested where she was hospitalized in the Department of Dermatology (Fig. 3). Upon clinical examination, seen were infiltrated, red nodules in the sites of injections on the forehead. Patient’s eyelid were severely swollen to the point that she was unable to open them, resulting in a temporary disability to see. On the contrary there were no sings of pathology in nasolabial folds.

When she was admitted to the department, she was administered IV Voncon 1 gr (Vancomycin) 1 x 2, solu-medrol 500 IV / 12h, Ultra-Levure 1 x 3 per os. On the next day, instead of intravenous solu-medrol 500, she was administered Medrol (32 mg) tablets 1 x 1 / day for 5 days followed by dose tapering. On the third day after the beginning of treatment, patient started to half open her eyelids and stopped complaining about weight, pain and tension on the forehead. During laboratory testing taken were cultures from incision of nodules which were all negative. No microorganism was isolated in a culture. Immunology testing showed a small increase in IgG immunoglobulin fraction (1832 mg / dL) (normal range: 879 – 1700 mg / dL). No other abnormal parameter was seen in the other laboratory-haematology-biochemical testing. Receipt of a tissue segment was avoided to keep the infection from spreading and for ethical reasons.

Fig. 4: In the end of treatment with antibiotics and corticosteroids. Nodules have reduced in size. First application of hyaluronidase in the lesions.

After recession of the symptoms the patient was discharged continuing on Augmentin antibiotic (625 mg) 1 x 3 / day, for one further week while she continued on per os corticosteroid regimen. Every 2 weeks, after treatment completion, she was administered intralesional hyaluronidase (30 U) per site (2 sites per nodule: a total of 5, that is 150 U). Before administration of hyaluronidase, a subcutaneous test was performed waiting for a possible reaction (Fig. 4). After six months, scars were formed on the implantation sites.

Discussion

Implants with hyaluronic acid is a simple and rapid restoration of dips and wrinkles of the skin mostly on aged areas of the face [3, 4]. Synthetic molecules of hyaluronic acid are used in the treatment of thin wrinkles on the forehead, glabella and periorbital area. In addition, small tensile atrophic acme scars are significantly improved after hyaluronic acid injection [5, 6].

These injections with molecules of synthetic hyaluronic acid are considered more safe that implant molecules of a different structure (such as silicone, bovine collagen or acrylic molecules). Yet these molecules cause redness, bruises, ecchymoses or foreign-body reactions in a small percentage of patients. These allergic reactions disappear within 10 days at the latest. As no severe allergic reactions or foreign body reactions are seen with hyaluronic acid, subcutaneous test is not considered necessary prior to implantation. It is also possible that reactions might occur even after a negative test [7, 8].

Fig. 5: After the third implantation of hyaluronidase nodules have decreased in size.

Several studies report occurrence of granulomatous reactions. In our case, the woman presented red, infiltrated nodules on her forehead after implantation of small amounts of thin hyaluronic acid. Nodules were painful and contained purulence with was absorbed with a syringe. Subsequent cultures were negative. It was obvious that the nodules had been transformed to sterile abscesses. A small increase in serum IgG immunoglobulin incriminated a previous infection. Most probably, formation of sterile allergic abscesses was fired by protein traces remaining in the implantation material. This reinforces our view, as even though in the nasolabial folds of the volunteer highly viscous amounts were injected, no adverse reactions were seen. Obviously, the different biotechnology applied in the manufacture of molecules played a role to the appearance of complications. Injection of hyaluronidase has facilitated degradation of remaining molecules of hyaluronic acid in the skin [9, 10].