Delayed migration of soft tissue fillers in the periocular area masquerading as eyelid and orbital pathology

Abstract

Soft tissue fillers used for facial rejuvenation can cause complications. We present two cases of late migration of injected fillers mimicking other pathology in the periocular area. Case 1 is a 52-year-old woman referred with chronic bilateral upper lid swelling, mimicking blepharochalasis syndrome, 5¹/₂ years after undergoing injection of hyaluronic acid filler in both brows. Extensive blood investigations were normal. Bilateral, sequential upper lid biopsy revealed migrated hyaluronic acid filler, which was successfully treated with hyaluronidase. Case 2 is a 62-year-old woman who presented with a right lower lid mass 8 years after undergoing injection of polyalkylimide gel into both cheeks. CT scanning confirmed an intermediate density soft tissue mass overlying the inferior orbital rim. Histology from surgical excision reported chronic granulomatous inflammation due to migrated polyalkylimide gel. An awareness of late migration of fillers causing eyelid swelling and masses in the periocular area will prevent unnecessary investigations and facilitate prompt management.

Background

With increasing demand for cosmetic surgery, soft tissue fillers are gaining in popularity worldwide.¹ This is mainly due to their ease of administration, affordability and the minimally invasive nature of the procedure.² The current pandemic has driven the wearing of face masks to an unprecedented level, leaving only the upper face exposed. We anticipate this will translate to more aesthetic procedures in the periocular region. Although complications of soft tissue fillers are generally mild and mostly short-lived, serious complications occur and are being increasingly reported in the medical literature.³ One such complication is delayed migration of the soft tissue filler, which may present as chronic eyelid swelling and periocular masses remote to the injection site many years after administration of the filler.^4–14

We describe the management of two female patients with late migration of soft tissue fillers mimicking other pathology in the periocular area. Both cases are supported by histological evidence and illustrate the importance of considering the migration of soft tissue filler in the differential diagnosis of diffuse eyelid swelling or a localised periocular mass, regardless of the injection site or the temporal relationship to the aesthetic treatment. Awareness of this complication can save unnecessary investigation and facilitate prompt management. Furthermore, the possibility of late migration should be discussed with patients considering injection of soft tissue fillers in the face.

Case presentation

Case 1

A 52-year-old woman (patient 1) was referred with a 5-year history of bilateral upper lid swelling, more severe on the left side, fluctuating and worse in the morning. She admitted to dry eyes, dry mouth, backache, nasal congestion and a history of previous nasal septoplasty, but she was otherwise healthy, a non-smoker and on no systemic medication. Five and a half years earlier, she had 0.275 mL of Juvederm Ultra (Allergan, Irvine, California, USA), a hyaluronic acid filler, injected into the lateral aspect of both eyebrows to effect a brow lift. However, because of the length of time that had elapsed since her brow injection, and her denial of any injection into the upper eyelids, this was not thought to be relevant to her presenting problem. Examination revealed diffuse bilateral upper lid oedema and mild mechanical ptosis, worse on the left side (figure 1A). Apart from tear film insufficiency, ocular examination was otherwise unremarkable.

Figure 1.

(A) Diffuse bilateral upper lid oedema in patient 1 (worse on left side) 5¹/₂ years after hyaluronic acid injection in both lateral brows. (B) One year after left upper lid debulking, note bilateral upper lid oedema (worse on right side) and blepharoptosis. (C) Six months after right upper lid debulking, note improvement in right upper lid swelling and ptosis. (D) Seven weeks after hyaluronidase injection into both upper lids, note resolution of bilateral upper eyelid swelling but mild left ptosis and dermatochalasis persists.

Case 2

A 62-year-old woman (patient 2) was referred with a right lower lid lump and discomfort 8 years after receiving an injection of polyalkylimide gel filler (Bio-Alcamid; Polymekon, Brindisi, Italy) in both cheeks. She was otherwise healthy. Examination revealed a rubbery, non-tender 2 cm subcutaneous mass in the lateral aspect of the right lower lid without cutaneous inflammation, closely related to the inferior orbital rim (figure 2A). Ocular examination was otherwise unremarkable.

Figure 2.

(A) Well-circumscribed subcutaneous mass in right lower lid of patient 2 without overlying cutaneous inflammation (black arrow). (B) Intermediate density mass (white arrow) on axial CT scan overlying right inferior orbital rim and extending over the zygoma. (C) Intraoperative appearance of lobulated right lower lid mass containing polyalkylimide gel, of note are the focal excrescences (black arrows) due to weakness in the capsule. (D) Macroscopic appearance of excised right lower lid mass. (E) Excellent postoperative appearance.

Differential diagnosis

Patient 1

Although the history of periocular filler was known, due to the long time lag between the brow injection and the onset of eyelid swelling, plus the fact that the swelling was not localised to the lateral brow, other diagnostic possibilities were considered, such as blepharochalasis syndrome, angioneurotic oedema, thyroid eye disease, connective tissue disease and other causes of orbital inflammation. In the absence of any positive blood investigations and due to the fluctuating nature of her upper lid swelling, blepharochalasis syndrome was thought to be the most likely diagnosis.

Patient 2

The absence of proptosis, globe restriction or other orbital signs made an orbital inflammatory mass unlikely. Similarly, there were no signs to suggest a neoplastic process, such as a lymphoma or sarcoma, and migration of the polyalkylimide filler was suspected as the cause of the right lower lid mass.

Investigations

Patient 1 underwent thorough blood investigations, including full blood count, urea and electrolytes, inflammatory markers, antinuclear antibodies, antineutrophil cytoplasmic antibodies, thyroid function tests, C1 esterase inhibitor and rheumatoid factor, to exclude a systemic cause for her eyelid swelling. All investigations were normal.

Patient 2 was suspected to have migrated soft tissue filler, so a CT scan of her orbits was requested to better define the mass and exclude orbital involvement. This revealed an intermediate density soft tissue mass overlying the right inferior orbital rim and extending over the zygoma without intraorbital involvement (figure 2B).

Treatment

Patient 1 underwent left upper lid blepharoplasty and skin biopsy with a good cosmetic outcome. Microscopy revealed mild hyperkeratosis, acanthosis, spongiosis and lymphocytic exocytosis with a mild lymphocytic infiltrate, oedema and dilated lymphatic channels in the underlying dermis (figure 3A). The histological features were thought to be consistent with blepharochalasis syndrome and conservative management was advised until the inflammatory phase of the disease abated. Over the course of the following year, her right upper lid swelling progressed and there was also some recurrence of the oedema on the left side (figure 1B). The patient was keen for further intervention, so she underwent right upper lid blepharoplasty and biopsy (figure 1C). Microscopy now revealed extensive basophilic infiltration of the subepithelial compartment and orbicularis muscle with patchy lymphocytic infiltration (figure 3B). The basophilic material was stained with Alcian blue (figure 3C) and was dissolved with hyaluronidase (figure 3D), confirming hyaluronic acid filler as the cause of the lid swelling. Furthermore, there was no convincing depletion of elastic fibres on Verhoeff’s Van Gieson stain and immunohistochemistry revealed no discernible selective deposition of IgA on elastin fibres or other cutaneous structures to suggest blepharochalasis syndrome. On histological review, the original left upper lid biopsy was also consistent with hyaluronic acid filler rather than blepharochalasis syndrome (figure 3E, F). Patient 1 was subsequently treated with hyaluronidase injections (Hyalase; Wockhardt, UK), 300 units (2 mL) into each upper lid with resolution of the bilateral upper lid swelling (figure 1D).

Figure 3.

Histopathology of case 1. (A) Oedema, dilated lymphatic channels in the underlying dermis and mild lymphocytic infiltrate on low power of left upper lid biopsy (H&E ×2.5). (B) Basophilic material within orbicularis muscle of right upper lid (H&E ×10). (C) Hyaluronic acid filler in right upper lid (Alcian blue ×10). (D) Hyaluronic acid filler in right upper lid dissolved after pretreatment with hyaluronidase (Alcian blue ×10). (E) Review of left upper lid biopsy revealed hyaluronic acid filler present (Alcian blue ×10). (F) Hyaluronic acid filler in left upper lid biopsy dissolved after pretreatment with hyaluronidase (Alcian blue ×10).

Patient 2 underwent surgical exploration of the right lower lid through a subciliary approach and excision of a well-circumscribed, pale lobulated mass containing a turbid gel (figure 2C, D). Histological examination of the mass confirmed chronic granulomatous inflammation with fibrosis surrounding an amorphous, basophilic material, confirming late migration of the polyalkylimide filler into the lower lid (figure 4).

Figure 4.

Histopathology of case 2. (A) Copious basophilic material (polyalkylimide gel) interlaced by narrow bands of fibrous tissue, abutting skeletal muscle on low power view of right lower lid mass (H&E ×1.6). (B) Granulomatous reaction to basophilic material (polyalkylimide gel), with multinucleated foreign-body type giant cells within fibrous septae on higher magnification (H&E ×10).

Outcome and follow-up

Patient 1 reported complete resolution of her lid swelling within days of her hyaluronidase injection, and the swelling has not recurred in the subsequent 4¹/₂ years. However, there has been slight progression of her left ptosis and mild left upper lid dermatochalasis (figure 5).

Figure 5.

Slight progression of left ptosis and dermatochalasis, but no recurrent oedema, 3 years after hyaluronidase injection in patient 1.

Patient 2 had a good cosmetic result (figure 2E) and has been discharged with no recurrence of her right lower lid mass 8 years postoperatively.

Discussion

Soft tissue fillers have been used in the cosmetic industry for over two decades to reduce wrinkles, enhance volume and improve the contour of facial features. Injection of fillers is relatively painless, simple, minimally invasive and relatively cheap with rapid recovery.² Therefore, there is increasing demand worldwide, with hyaluronic acid accounting for approximately 75% of the market.¹ The widespread wearing of face masks during the COVID-19 pandemic is likely to continue for some time and, in that setting, reading facial expression is mostly limited to the eyes and upper face. Therefore, we anticipate a shift in aesthetic practice to focus on the upper face, with less emphasis on other areas, such as lip enhancement. Although serious complications of soft tissue fillers are rare, the frequency is increasing with the greater demand, and more late complications are manifesting with the passage of time.³ The situation is not helped by the lack of regulation in the cosmetics industry.

Hyaluronic acid, a polysaccharide which occurs naturally in the body, is well tolerated and adverse effects of subcutaneous injection, including discomfort, itching, erythema, oedema, blue discolouration (Tyndall effect), bruising or haematoma formation, are generally minor, short-lived and tend to occur soon after injection.^{3 4} However, more serious complications have been reported, including chronic eyelid or periocular swelling,^5–8 late-onset granulomatous inflammation,^{15 16} encapsulation without inflammation^{9 17} and delayed migration, even into the orbit.2 10–12 18 In rare instances, inadvertent intra-arterial embolisation can occur, leading to blindness, motor nerve palsy and skin necrosis.^19–21

Although hyaluronic acid fillers are marketed as temporary and usually resorb within 6–18 months,³ in the case of patient 1, the injected hyaluronic acid persisted in the tissue for at least 7 years after the injection, remained after surgical debulking, and only resolved after it was dissolved with hyaluronidase. Tissue mobility, anatomical location (including skin thickness), particle size, concentration and cross-linking are all factors that affect the durability of injected hyaluronic acid fillers.^{3 22} Cross-linking creates a more effective physical and chemical barrier to endogenous hyaluronidase.²³ Cross-linked fillers are classified as monophasic or biphasic. Monophasic fillers consist of a homogeneous mixture of high-molecular-weight and low-molecular-weight hyaluronic acid. Biphasic fillers are heterogenous and consist of cross-linked particles of hyaluronic acid dispersed in a non-cross-linked hyaluronic acid vehicle. Monophasic fillers are further categorised as monodensified when cross-linking occurs after homogeneous mixing, or polydensified when cross-linking occurs separately before the mixture is produced.²² Juvederm Ultra, which our patient received, is an injectable monophasic monodensified hyaluronic acid preparation, which is cross-linked to resist hydrolysis. It has a higher degree of cross-linking compared with other popular hyaluronic acid dermal fillers, thereby increasing its longevity.²³ There is evidence that biphasic and monophasic monodensified fillers are more durable than monophasic polydensified fillers.²² In our view, our patient’s chronic bilateral upper lid swelling was due to a combination of the hydrophilic nature of hyaluronic acid, impaired lymphatic drainage in the periorbital fat by direct pressure of the filler on the lymphatics and mild chronic inflammation. Dilated lymphatic channels and a lymphocytic infiltrate were evident on histology and this is also borne out in previous medical literature.³ It is worth noting that some surgeons advocate hyaluronidase injection as a diagnostic tool when retained hyaluronic acid filler is suspected, but not confirmed, without resorting to biopsy.^{7 8}

Polyalkylimide (Bio-Alcamid) is a hydrophilic, non-biodegradable gel consisting of 96% water and 4% synthetic polymer. It is injected in the subdermal or preperiosteal layer and becomes encapsulated by a collagenous capsule, theoretically forming an endoprosthesis. When it was first introduced at the turn of the 21^st century, it was thought to resist migration.²⁴ However, it is now known to be prone to migration and other late complications, such as infection, abscess formation, recurrent swelling, inflammatory masses, and it is notably difficult to remove.4 10 13 14 25 26

Several factors may play a role in migration of soft tissue fillers away from the site of injection, including poor injection technique, high volume of filler, injecting filler under pressure, overzealous massage, recurrent movement of muscles of facial expression, gravity, pressure-induced displacement of an earlier filler by another one and intravascular injection.² One can only speculate on the possible reasons for migration of the hyaluronic acid filler in patient 1 because of her delayed presentation. However, it is worth noting that late migration of polyalkylimide in patient 2 was antigravity, resulting in a chronic inflammatory mass in the right lower lid 8 years after being injected in the cheek. In their series of 16 patients with migration of polyalkylimide filler to the periocular area, AlHarbi et al reported 10 patients with lower lid involvement, all from cheek injection. Migration into the lower lid occurred 3–8 years after injection and all 10 cases had a trial of removal of the filler from the original site by needling before the filler migrated.¹³ That suggests that disruption of the capsule may have played a role in causing the migration. Although there was no such history in our patient, there were dehiscences in the wall of the inflammatory mass noted preoperatively with gel filler extruding, suggesting that spontaneous rupture of the capsule may have preceded the migration of polyalkylimide (figure 2C). Massage did not appear to be a factor in either of our patients.

Polyalkylimide is not approved by the US Food and Drug Administration and it has also fallen out of favour in most of Europe. However, because of its tendency to late migration, patients may still present to our clinics with complications of this filler in the periocular region many years after being injected at remote sites, such as the glabella, cheeks or the temple. Although hyaluronic acid, the most commonly used filler, is temporary, it may also persist for many years and migrate in the periocular region resulting in chronic eyelid swelling or periocular masses, which may masquerade as other pathology.

Despite a history of previous soft tissue filler injection being elicited in both of our patients, there was enough diagnostic doubt in patient 1 to prompt extensive investigations and eyelid biopsy, resulting in a delay in diagnosis and management. A reliable history of previous soft tissue fillers is not always forthcoming, and practitioners should remain alert to the possibility of late migration of fillers in the periocular area to prevent unnecessary investigations and facilitate prompt treatment. Furthermore, patients should be made aware of this possible complication when considering injection of soft tissue fillers in the face.

Patient’s perspective.

Patient 1

I chose to have the filler mainly because of peer pressure. All my friends were having it done and, foolishly, I followed suit. I was led to believe by the clinic that it was temporary, that is, 6–9 months maximum, and then it would disappear.

The filler was injected just below the outer aspect of my eyebrows and was meant to give my eyebrows a lift and give the impression of a smooth upper eyelid. I noticed after a few days that there was a bump under my brow and after a few months my upper eyelids became very swollen. I started to feel extremely self-conscious and grew my fringe long to cover my eyes, but told myself it would soon disappear. It never did.

I spent years going around opticians, eye specialists and various consultants to no avail. At the time, I did not realise that the eyelid swelling was due to the filler and attributed it to an extreme allergy to cosmetics or some other unknown reason. I had all but given up when a consultant ophthalmologist at my local hospital referred me to another consultant ophthalmologist at a tertiary centre. He asked me lots of questions that really made me think and it was then that I remembered and told him about the filler that had been injected into my brows at a cosmetic clinic.

The consultant did lots of tests and after the biopsy confirmed that the filler was responsible for my eyelid swelling, he suggested having a hyaluronidase injection to see if that would work. At that point, I was in despair and willing to try anything. Most importantly, I trusted him. After the hyaluronidase was injected into my upper eyelids, I went home and could see my eyelids gradually returning completely to normal. I was ecstatic and, at the same time, extremely grateful to the consultant. To this day, my eyes have remained without swelling and are completely normal. I learnt my lesson the hard way. My advice to other patients in general is to avoid fillers at all cost, but if you make the same mistake that I did and have a filler injected that causes the same adverse reaction as mine, there is hope and a solution.

Patient 2

I had been ill and lost a lot of weight that I never regained in my face over time. I had a lot of premature lines/wrinkles, which I believed the filler would correct. I was assured the product was natural and therefore, there would be no side effects. Despite this, I paid for a small amount to be injected into my groin to satisfy myself that was the case before I proceeded. At no time was I told there was a risk of the product breaking/migrating.

I was disappointed with the result as it did not have the visual effect I was expecting, or indeed solve my issue. I would not advise anyone to have fillers for purely cosmetic purposes.

Learning points.

• Migration of filler in the periocular region may masquerade as other pathology.

• Eliciting a history of periocular filler can save unnecessary investigation in patients presenting with diffuse eyelid swelling or subcutaneous eyelid masses.

• Temporary fillers may be much longer lasting than the manufacturers suggest.

• Fillers can migrate at any time and in any direction, even antigravity.

• Determining the type of filler is important as permanent fillers may not be easily removed.