Introduction

The popularity of dermal filling agents for soft tissue augmentation and restoration of volume in the face has increased significantly over the last few decades. Augmentation with biodegradable or non-biodegradable soft tissue fillers is particularly beneficial in the brow, mid-face, and perioral regions to restore volume and revive the appearance of youth. Although more serious complications are rare, they can occur immediately following treatment or can be delayed by months or even years, particularly with the use of permanent filling agents. Strategies for reversal of augmentation depend on the complication and the filling agent used. Unlike biodegradable agents, particularly hyaluronic acids (HAs), permanent fillers require more invasive techniques and can be more difficult to correct in the event of misplacement or serious adverse reactions.

Filler complications

Adverse effects following soft tissue augmentation are generally classified as early (up to 1 year) or delayed (appearing over 1 year after treatment) complications (Box 28.1). Delayed-onset reactions are almost always associated with non-biodegradable filling agents.

The most common complications result from inappropriate or too-superficial placement of the filling agent, leading to palpable or visible implants, nodule formation, beading, textural changes, bluish discoloration secondary to the Tyndall effect, and hypertrophic scarring of the treated folds. Intramuscular injection of synthetic fillers, particularly in areas of expression or excessive movement, invariably leads to lumpiness and migration of the filler. Hypersensitivity is rare but can occur with all fillers composed of foreign-body material. These reactions range from persistent itching, burning, and edema to granulomatous foreign-body reactions. A rare but serious complication is vascular compromise by compression, injury, and / or obstruction of the vessel(s), which can lead to necrosis in the glabella or nasolabial folds. Retinal embolism after intravascular injection has been reported.

Late-onset reactions to biodegradable agents usually emerge 5–6 months after treatment but can be quiescent for over a year with more permanent fillers. Indeed, late- and delayed-onset reactions have been reported to occur up to three decades after augmentation with non-biodegradable products. Late adverse effects include excess fullness or persistent nodules, granulomatous or inflammatory reactions, chronic infection, and filler migration. These complications are often the most difficult to treat, and some adverse events, such as excessive fullness or inflammatory reactions in the lips after injection with permanent fillers, cannot be adequately reversed.

It is important to note that many of the treatments aimed at resolving unwanted effects from facial augmentation are associated with their own complications and risks. In a follow-up study within the Injectable Filler Safety (IFS) study, Sperling and colleagues found that 51% of participants experienced adverse reactions to reversal procedures.

Hyaluronidase

The US Food and Drug Administration (FDA) has approved hyaluronidase – a soluble protein enzyme that acts at the site of local injection to break down and hydrolyze HA – for three therapeutic indications: as an adjunct to increase the absorption and dispersion of other injected drugs, particularly retrobulbar anesthetic block in ophthalmologic surgery; for the subcutaneous infusion of fluids (hypodermoclysis), used mostly in the elderly population for mild-to-moderate dehydration and in young infants or children in whom intravenous administration is not possible; and as an adjunct for subcutaneous urography, improving the resorption of radiopaque agents.

Because hylauronidase causes more rapid spreading of subcutaneous injected agents, it has been used extensively with intravenous anesthesia and pain medicine. The addition of hyaluronidase to local anesthesia has been controversial, with some reports citing insufficient evidence or lack of efficacy, while others claim it reduces the anesthetic volume required, increases the area affected, and speeds the onset of aesthetic action. With the enzyme’s ability to reduce traumatic tissue swelling and chronic inflammation, clinicians have begun to investigate its role in the management of chronic pain. Therapeutic off-label applications in dermatology have yielded variable success for the treatment of diabetic scleredema, scleroderma, and pretibial myxedema, along with lymphedema and keloids.

Hyaluronidase in cosmetic dermatology

In 2004, different reports by Soparkar and colleagues and Lambros detailed the use of hyaluronidase to dissolve unwanted side effects after augmentation with HA in the periocular region up to 5 years after initial HA injection. Since then, hyaluronidase has gained enormous popularity among cosmetic practitioners as an off-label ‘eraser’ for HA filling agents, with a reported ability to reverse bluish Tyndall discoloration, lumps and nodules due to overfilling or improper placement, foreign-body reactions, and injection necrosis (Box 28.2).

Box 28.2

Cosmetic indications for the use of hyaluronidase

Overfilling / excessive HA

Product misplacement

Non-inflammatory nodules

Bluish discoloration

Lumps and contour irregularities

Vascular compromise

Several reports have documented the use of hyaluronidase to resolve the slightly bluish effect secondary to the Tyndall effect, caused by too-superficial injections of HA. Brody treated a 64-year-old woman who presented with visible, slightly blue masses beneath each eye 6 weeks after superficial HA injections in the periorbital area. Most of the material disappeared within 24 hours after 75 U of intradermal hyaluronidase; reinjection of the remaining small nodules dissolved the rest of the material within 5 days. In 2006, Hirsch and colleagues reported the case of a woman who developed a large blue ‘egg’ in the subdermal space at the right nasojugal fold 4 days after HA injection. Two injections of 75 U of hyaluronidase a few days apart led to complete resolution. Similar results were reported a year later by Hirsch and colleagues in a 48-year-old woman who received an overabundance of HA for the bilateral treatment of nasojugal folds and subsequently presented with two large, blue-tinted bulbous nodules under each eye. Hyaluronidase dissolved most of the material within 72 hours (Fig. 28.1)

Figure 28.1 (A) Presentation with blue discoloration after hyaluronic acid injections into the tear troughs. (B) Full resolution 24 hours after treatment with hyaluronidase.

Pearl 2

Hyaluronidase can be used after injection of hyaluronic acid fillers to correct asymmetry, overcorrection, the Tyndall effect, and vascular occlusion.

Brody describes a 68-year-old woman who presented with multiple warm, red, indurated nodules after augmentation with HA. Punch biopsy revealed dermal fibrosis and chronic inflammation with focal granulomatous features. Traditional management with intralesional triamcinolone acetonide, antibiotic courses of cephalexin and trimethoprim-sulfisoxazole, and multiple courses of prednisone had little sustaining effect. At 5 months, the one persistent nodule was treated with 15 U of hyaluronidase and disappeared without recurrence within 24 hours.

Hirsch and colleagues arrested tissue necrosis in a 44-year-old woman with multiple deep dermal injections of HA into the nasolabial folds whose nose began to ‘turn purple’ 6 hours later. Close examination revealed impending necrosis near the labial artery. After aspirin, topical nitroglycerin paste, and hot compresses for 8 hours failed to provide relief, 30 U hyaluronidase was injected to dissolve a suspected thrombus, with improvement noted at 8 hours and full resolution at 2 weeks (Fig. 28.2). A similar case was reported by Hirsch and colleagues in a 43-year-old woman who had undergone multiple rejuvenation sessions with collagen and HA in the past but experienced impending necrosis 48 hours after injection with HA for the augmentation of the nasolabial folds. Hyaluronidase brought immediate resolution of pain and a return to normal by day 13. Early intervention with the enzyme is recommended in cases of vascular compromise; Kim and colleagues demonstrated no benefit when used >24 hours after HA injection in rabbit ears.

Figure 28.2 (A) Impending necrosis after hyaluronic acid treatment of the nasolabial fold. (B) Improvement 15 minutes after 60 U hyaluronidase injection, warm compress, and massage. (C) Full resolution at 2 months.

Other enzymatic reversers

In February 2010, the FDA approval of collagenase Clostridium histolyticum (Xiaflex^®) for the treatment of patients with Dupuytren’s contracture (a genetic disorder of pathological collagen production) has led to some debate about the enzyme’s ability to reverse the effect of collagen-based fillers. However, collagenase is associated with serious potential side effects, including tendon rupture and ligament damage, complex regional pain syndrome, sensory abnormality, injection-site hemorrhage, and severe allergic reactions after subsequent treatment sessions, and has not been studied for collagen reversal in the face.

Similarly, alginase enzymes have been found in various species of organisms in soil and marine environments and may theoretically reverse misplacement of soft tissue augmentation should alginate filling agents return to the market.

Conservative ‘reversers’

In some cases, non-intervention – ’watchful waiting’ – or conservative management is the most appropriate course of action, particularly with the use of short-term biodegradable filling agents (Table 28.1). Non-inflammatory and non-painful lumps or nodules seen after treatment are usually due to improper injection techniques or misplacement / overcorrection of the filler material (Fig. 28.3). These cases will often resolve after a period of 1–2 weeks and can be combined with massage and possibly saline injection to help disperse the filling agent. Superficial injection of particulate fillers (calcium hydroxylapatite [CaHA] or polymethylmethacrylate [PMMA]) can produce ‘white bumps’ of visible material; these may be treated with saline injections and vigorous massage to ‘break up’ the deposits. In an animal study, Voigts and colleagues demonstrated that early intervention with fluid (sterile water or saline) combined with massage corrected any observed palpable accumulation of CaHA (nodules or irregular contours).

Table 28.1 Conservative versus semi-invasive and invasive ‘reversers’

Figure 28.3 (A) Overcorrection of the tear trough with a hyaluronic acid filler. (B) After injection of hyaluronidase were injected into each side.

In cases of suspected vascular compromise, firm massage, and warm compress should be applied immediately to increase vasodilation. The use of 2% nitroglycerin paste has also been reported to increase vasodilation but remains controversial as it may exacerbate intravascular occlusion caused by particulate fillers including CaHA and PMMA. Finally hyaluronidase should be used when vascular occlusion is caused by HA filler. If caught early, tissue necrosis may be avoided.

Antibiotics, corticosteroids, and 5-fluorouracil

Red, painful nodules appearing from 2 weeks up to 1 year after treatment indicate infection and require immediate treatment with systemic antibiotics, incision and drainage, and hyaluronidase (Fig. 28.4). Clarithromycin 500 mg or minocycline 100 mg twice a day for 6 weeks will cover most early infections, although the length of treatment depends on the degree of infection and the duration of the implant.

Figure 28.4 (A) Non-inflammatory nodules after injection of calcium hydroxylapatite in the lip. (B) Non-inflammatory nodules after poly-L-lactic acid injection into the temples.

More severe infections require intravenous antibiotics followed by a course of oral antibiotics and judicial use of intralesional corticosteroids to assist in eliminating persistent inflammatory nodules. Because steroids can worsen inflammation and activate a biofilm, they should only be injected with concomitant use of antibiotics and should only be used in late-onset infections after erythema, tenderness, and edema have subsided. Intralesional steroid-related adverse effects are primarily limited to skin and subcutaneous atrophy. Systemic steroid side effects would not be expected if conservative frequency and dosing were used. If the nodule does not respond to antibiotics or corticosteroids, intralesional 5-fluorouracil (5-FU) mixed with triamcinolone has been shown to improve some granulomatous reactions.

Invasive reversal techniques

Injection of particulate fillers may result in the late appearance of visible nodules or bumps that are painless and non-inflammatory (Fig. 28.5). These may require ‘unroofing’ and evacuation with a needle tip or removal via superficial dermabrasion.

Figure 28.5 (A) Inflammatory nodule arising 1 month after hyaluronic acid filler was injected into the nasolabial fold. (B) Immediately following surgical drainage and after injection of hyaluronidase. (C) Five months after.

Late-onset infectious nodules appearing more than 1 year after treatment are sometimes attributed to the formation of a biofilm, which can be confirmed by biopsy and culture; infection will recur if the biofilm is not removed. Biofilms are usually associated with non-biodegradable fillers. Combination gels, such as PMMA or polyalkylimide, are most susceptible to complications from biofilms. Removal of the implant may sometimes be accomplished by expression through a small, sterile incision made over the site of augmentation (Fig. 28.6). Other cases require local anesthetic over the infected nodule, and extraction of the filling agent with an empty syringe and 16-gauge needle. However, needle aspiration of partially or completely non-resorbable polymers is rarely successful, particularly in cases of delayed presentation. Surgery is generally considered the last option after failure of more conservative approaches and should only be performed by experienced physicians. Fifty-two percent of patients in the IFS study experienced adverse effects such as scarring and asymmetry from surgical reversal.

Figure 28.6 (A) Fluctuant nodule arising 6 months after an ‘unknown’ permanent filler was injected. (B) After aspiration of nodule contents (filler and inflammatory cells) with an 18-gauge needle under sterile technique.

Lasers may provide a less invasive alternative for removal of infectious or granulomatous lesions after antibiotic and corticosteroid failure. Cassuto and colleagues describe the use of two different types of laser-assisted treatments in 20 patients to heat and penetrate skin and mucosa, allowing melting and evacuation of organic any synthetic components of granulomatous filler reactions with lower morbidity and better cosmetic results than surgical excision. Goldan describes an irrigation system whereby a 14- to 16-gauge cannula was inserted under ultrasound guidance and fixed in place with sutures, followed by frequent irrigation by injecting and aspirating solutions up to eight times a day. Though it was not always possible to remove all of the material, irrigation provides an alternative to surgery and may be particularly helpful in cases in which repeated attempts at surgical aspiration have failed.

Conclusion

The rise in popularity of soft tissue augmentation for restoration of volume in the face necessitates a greater understanding of and treatment options for the management of related adverse effects. All filling agents can lead to complications, some of which can be treated by non-invasive approaches. Biodegradable fillers are less likely to cause more severe reactions; complications generally appear within 6 months and are easily managed conservatively. The availability of hyaluronidase to ‘erase’ unwanted effects makes the use of HA filling agents that much more appealing. Adverse events from the placement of permanent fillers can appear years after initial treatment and often require invasive reversal techniques. Optimal management of these complications can be difficult and requires a thorough knowledge of available interventions and their likely outcomes.