REVIEW

CURRENT
OPINION Periocular hyaluronic acid fillers: applications,
implications, complications
Rachna Murthy a,b, Jonathan C.P. Roos a,b, and Robert A. Goldberg c

Purpose of review
The use of dermal filler in the periocular area is increasing – both for functional and aesthetic indications.
Hyaluronic acid fillers dominate the market; these treatments offer an alternative to some surgical
procedures with the advantage of instant results, minimal healing time and low complication rates.
However, success depends on judicious selection of patients, products and procedures to achieve
favourable outcomes. This article reviews current understanding of the principal complications in the
periocular area and their management.
Recent findings
Hyaluronic acid is a ubiquitous, biodegradable, nonspecies-specific molecular substrate with limited
potential for immunogenic reactions. However, in the periocular area, such products can migrate and last
significantly longer than the expected filler lifespan. Contamination or subsequent immune stimulation can
trigger delayed-onset inflammatory reactions. Though minor vascular occlusions are not uncommon, cases
of blindness secondary to facial filler injections are thought to be rare. Timely enzymatic degradation with
injectable hyaluronidase can be effective in the treatment of some such complications. But recent studies
demonstrate lack of penetration through arterial walls and optic nerve sheath, casting doubt on the role of
retrobulbar hyaluronidase in the management of vision loss because of embolism with hyaluronic acid filler.
Summary
Hyaluronic acid fillers represent an emerging and important addition to the armamentarium of the
oculofacial plastic surgeon with their use in the aesthetic field also expected continue to rise. The
oculoplastic facial surgeon, armed with a thorough knowledge of facial anatomy, safe injection planes and
the means of minimizing and treating complications is in the best position to lead clinically in the use of
this well tolerated and effective treatment modality.
Keywords
complications, dermal filler, hyaluronic acid, nonsurgical restoration, periocular, vision loss

INTRODUCTION early as the 1890s but by the 1980s, injectable

The dermal filler market is already a multibillion
dollar industry and growing. Hyaluronic acid fillers
currently enjoy a near monopoly of the market with
estimated revenue from injectable treatments pro-
jected to be over $11 billion annually by 2020 [1].
Globally, the number of filler treatments in 2014
exceeded 5.5 million, and in 2016, the American
Society for Aesthetic Plastic Surgeons reported more
than 2.5 million procedures being performed in the
United States alone [2]. Over the last half decade,
there has been an over 40% increase in the number
of injectable procedures [2], and this high rate of
growth is expected to continue.
However, the use of dermal fillers for facial
rejuvenation is not new. Paraffin wax was first used
in the early 1800s but associated with significant
complications. Fat injections were introduced as
collagen had become the market leader in semiper-
manent fillers. It offered significant improvements
in safety compared with the earlier substrates but
was associated with a high incidence of allergy and
inflammation [3].
a
Department of Clinical Neurosciences, University of Cambridge, Cam-
bridge, bDepartment of Ophthalmology, Ipswich Hospital, Ipswich, UK
and cJules Stein Eye Institute, Division of Orbital and Oculoplastic
Surgery, University of California, Los Angeles, California, USA
Correspondence to Rachna Murthy, BSc, FRCOphth, Cambridge Uni-
versity Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2
2QQ, UK. Tel: +44 7774247167;
e-mail: rachna.murthy@addenbrookes.nhs.uk; rm943@cam.ac.uk
Curr Opin Ophthalmol 2019, 30:395–400
DOI:10.1097/ICU.0000000000000595

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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Oculoplastic and orbital surgery
KEY POINTS
 Hyaluronic acid filler will take on an increasing role in
oculoplastic practice and replace some
surgical procedures.
 Hyaluronic acid fillers are generally effective and
well tolerated.
 It is important to be conscious of the potential for body
dysmorphic disorder to avoid causing harm to patients.
 Complications can generally be managed to ensure a
good outcome.
 Visual loss must be treated urgently, but retrobulbar
hyaluronidase may not be well tolerated or effective.
The market is now dominated by hyaluronic
acid fillers, which were first FDA-approved in
1996 [4]. Hyaluronic acid is a naturally occurring
linear polymeric dimer of N-acetyl glucosamine
and glucuronic acid and a component of all connec-
tive tissue, it being the building blocks of mucopo-
lysaccharides. These molecules are evolutionarily
highly conserved and – not being species-specific
– confer only a limited potential for immunological
rejection. Naturally occurring hyaluronic acid has
little role in functional and aesthetic treatment
because of its rapid turnover and degradation in
tissues. Synthetic hyaluronic acid fillers are, there-
fore, stabilized after synthesis by cross-linking. In
most market-leading products, this is achieved using
1,4-butanediol diglycidyl ether (BDDE) [5]. This
alters half-life and viscosity and means that com-
mercial products vary in uniformity and size of
particles and in their concentration. Though hya-
luronic acid fillers remain biodegradable, they can
have a moderate-to-long duration (6–24 months)
depending on their individual characteristics and
constituents as well as patient factors, such as deg-
radative enzyme expression.
APPLICATIONS
Although mostly known for aesthetic rejuvenation,
hyaluronic acid fillers have been used to good effect
in the management of functional disorders when
nonsurgical treatment is preferred, or as a temporiz-
ing measure prior to surgical rehabilitation [6].
As hyaluronic acid augments tissue volume in
the periocular area, it has been used for anterior
lamellar expansion, treatment of upper and lower
eyelid retraction as well as expansion of the anoph-
thalmic socket [7–9]. Myomodulation – the alter-
ation of muscle function using hyaluronic acid – has
also been described. For this application, filler is
396 www.co-ophthalmology.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
placed in tissue planes so as to alter the fulcrum
of a muscle, and thus augmenting or reducing its
strength. This has recently been demonstrated for
instance in the rehabilitation post facial nerve pare-
&&
sis [10 ]. Although theoretically temporary, the
duration of effect can be much longer than the
expected filler lifespan [11]. For example, hyalur-
onic acid in the tear trough area has been demon-
strated to last for over 7 years [12]. Correspondingly,
complications may arise long after the filler lifespan
when patients may no longer recall or volunteer a
history of such treatments.
In the aesthetic field, there has been a transition
from the superficial treatment of lines and wrinkles
in the face to volumization and ‘lifting’ with fillers.
With age, there are many changes in the periocular
area; these include malar fat pad descent and atro-
phy, thinning of the orbital septum, orbital fat
prolapse into the eyelid and exposure of the orbi-
cularis retaining ligament [13]. Aesthetic injectable
treatments in the periocular area can help to dis-
guise the resultant contour changes [14].
IMPLICATIONS
Hyaluronic acid treatments offer an alternative to
some surgery, with rapid results, minimal or no
downtime and are office-based procedures that
can be repeated. There are potential significant
financial advantages for both the patient and doc-
tor. However, patient factors, product selection and
choice of procedure are critical to optimizing out-
comes.
A 10-point plan for avoiding hyaluronic acid
filler-related complications during facial aesthetic
&&
treatments has recently been described [15 ]. Suc-
cess is predicated on obtaining a thorough medical
and aesthetic history to include previous aesthetic
procedures, operations and motivation. Body dys-
morphic disorder is increasingly being recognized in
&&
patients [16 ] seeking aesthetic treatments (and
perhaps also in their treating clinicians!). Practi-
tioners must be alert to this during patient assess-
ment, differentiating between patient’s wants and
needs and offering referral for psychological sup-
port, if necessary. Informed consent should include
financial consent as part of the treatment plan, as
well as management of expectations.
Selection of the correct product for the desired
effect is also important. Hyaluronic acid concentra-
tions vary in the different products available and can
result in varied amounts of tissue swelling. Higher
degree of cross-linking confers higher viscosity and
can determine the optimal depth of placement and
longevity of the product. This also allows for differ-
ent hyaluronic acid products to be layered over each
Volume 30  Number 5  September 2019

other. Such layering over late or minimally biode-
gradable fillers may aggravate stable material and
cause a reaction resulting in late, long-lasting com-
plications [17].
A stringent aseptic technique is essential, using
skin preparation with 2% chlorhexidine gluconate
in 70% isopropyl alcohol or 10% povidone iodine
[18]. Sodium hypochlorous has been demonstrated
to have the advantage of having antimicrobial prop-
erties without the risks of resistance or ocular irrita-
tion. It is garnering increasing interest in medical
&
practices for skin preparation [19 ].
COMPLICATIONS
Complications can similarly be divided into patient-
related, product-related and procedure-related
causes but as they are often multifactorial are dis-
cussed here by type of event [20].
Haematoma
Happily, most adverse reactions are transient and
mild; over 90% of adverse events are injection site-
related redness, swelling or bruising. In the perioc-
ular area, bruising is usually immediate, secondary
to direct puncture of vessels, or delayed because of
external stretch by swelling because of the hygro-
scopic nature of hyaluronic acid [21]. The risk of
haematoma formation can be minimized by avoid-
ing antithrombotic agents prior to treatments for
variable lengths of time. Prescription medication,
such as nonsteroidal anti-inflammatory medication
as well as certain supplements including gingko
biloba, garlic tablets, arnica and evening primrose
oil can also increase the risk of bruising [22]. It is
debated whether a needle or cannula is preferable to
minimize bruising. Perhaps counterintuitively, a
larger gauge cannula, such as 25G may reduce the
risk of puncturing vessel walls compared with
smaller diameter cannulas or needles.
Early-onset nodules
Early onset nodules usually relate to accumulation
of filler in one area, particularly noticeable in
regions of thin skin coverage over bone. Manage-
ment is with firm massage or dispersal with hyal-
uronidase [23].
Blue-grey dyschromia or Tyndall effect
A common complication in the periocular area
results from the Tyndall effect, named after a promi-
nent 19th century Irish physicist. Blue light is scat-
tered to a greater extent than longer wave-lengths
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Periocular hyaluronic acid fillers Murthy et al.
when passing through small particles (incidentally
this, is why the sky appears blue). Light passing
through a colloid, therefore, has a bluish tinge and
too superficial placement of hyaluronic acid filler
with too great a volume, or too viscous a product,
results the appearance of blue-grey appearing lumps.
This theory has been disputed by Rootman et al. [24]
who posit that the bluish tinge results from displace-
ment of veins, which become visible through the
thin periocular skin. Regardless of mechanism, this
blue-grey color change, particularly prone to form in
the tear trough, can be seen early (weeks) or late
(months or years) after periorbital HAG injections.
Management is with cover makeup, skin treatments
to thicken the dermis, or dispersal using hyaluroni-
dase.
Malar oedema
Malar oedema has been reported in over 11% of tear
&&
trough treatments with filler [25 ]. Anatomically,
the malar septum divides the superficial orbicularis
oculi fat (SOOF) into superficial and deep compart-
ments. The superficial compartment has compro-
mised lymphatic drainage, whereas the deep
compartment’s lymphatic drainage is contiguous
with the cheek. Excessive volume or viscous product
placed too superficially can, therefore, compress the
lymphatics, compromising drainage and resulting
in oedema. The swelling may present years after the
treatment because of impairment of the orbicularis
muscle pump or filler degradation: as the hyaluronic
acid breaks down, because of its hydrophilic nature,
it can attract more water. Bernardini’s group have
demonstrated that conservative management with
hyaluronidase and repeat hyaluronic acid filler after
15 days can result in satisfactory results without
requirement for surgical blepharoplasty [26].
Delayed-onset nodules
Delayed-onset nodules have been reported with all
hyaluronic acid products; the incidence has been
reported as 0.5% of all hyaluronic acid treatments
[26]. Such nodules can appear years after treatment
in the periocular area because of the longevity of
products in this anatomical location. The history
will often be notable for a preceding systemic or
local infectious or immune trigger, such as local
trauma [26]. A seasonal variation is observed, with
increased incidence during the winter months coin-
ciding with respiratory tract infections [27]. High
molecular weight hyaluronic acid is anti-inflamma-
tory but the low molecular weight hyaluronic acid
may be pro-inflammatory, resulting in a shift over
time. During hyaluronic acid fillers degradation,
www.co-ophthalmology.com 397
Oculoplastic and orbital surgery
low molecular weight fragments are presented to
the immune system and may account for delayed
inflammation [28]. Introduction of skin commen-
sal flora with further aesthetic treatments may trig-
ger formation of inflammatory nodules; in-vitro
addition of Proprionibacterium acnes to hyaluronic
acid stimulates T-cell activation and not seen with
hyaluronic acid alone [29]. Hyaluronic acid is also
manufactured using a bacterial fermentation, and
batches could contain antigenic impurities [30].
Some microbes form biofilms, which when sur-
rounded by or covered by filler can prove refractory
to treatment. The hyaluronic acid ‘shield’ is
thought to provide tolerance to the immune
system and prevent diffusion of antibiotics [31].
However, in practice, culture of such nodules is
usually negative. Treatment is empirical with
antibiotics; macrolides and tetracyclines have
additional anti-inflammatory properties, and can
therefore, be particularly advantageous in this
situation. Hyaluronidase can be used to disperse
the hyaluronic acid if symptoms persist. A short
course of systemic steroid, intra-lesional steroid
or 5-Fluorouracil may be useful in addition, recog-
nizing that subsequent focal atrophy can compli-
cate cutaneous steroid injections.
Filler migration is a separate and recognized
entity in the periocular area. Patients may present
months to years after treatments with noninflam-
matory masses because of hyaluronic acid from
distant injected sites [32].
Vascular occlusion and vision loss
The incidence of ischaemic complications from fill-
ers is estimated to be up to 3 in 1000 injections [33].
The periocular area, despite its rich network of vas-
cular anastomoses is susceptible to cutaneous vas-
cular compromise; injections to the glabella for the
treatment of frown lines and the dorsum of the nose
during nonsurgical rhinoplasty appear particularly
prone to cause occlusions. The clinical presentation
is characterized by severe prolonged pain and
blanching followed by livedo reticularis because of
swelling of venules from obstruction of capillaries.
Late signs include a marked delineation of the
necrotic area and formation of small white pustules
[34,35].
Intracranial emboli resulting in vision loss
or cerebrovascular infarction can be devastating.
Between 1906 and 2019, there have been over 190
cases of blindness because of aesthetic injectable
treatments reported in the literature [36]. Most of
these have been because of autologous fat injection
&&
[37,38 ], and retrograde embolus into the ophthal-
mic and central retinal arteries. Hyaluronic acid has
398 www.co-ophthalmology.com
Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
smaller particulate size than fat and is more likely
to obstruct the distal branches of the ophthalmic
artery, including the retinal and choroidal branches
[39,40]. Filler material injected into an artery
might be expected to flow downstream with
the direction of blood flow. However, Poiseuille’s
law shows that this is not so. Resistance increases
exponentially with branching and reduced vessel
diameter, so filler injected quickly and under pres-
sure may find less resistance with retrograde passage
to more proximal vessels [29]. The periorbital area
is particularly risky: most of the arterial supply to
the face is from the external carotid artery except
the supply to the eye, upper nose and central fore-
head, which arise from branches of the internal
carotid. The ophthalmic artery has multiple
branches that project outside the ocular area onto
the nose and forehead, the dorsal nasal, angular
artery, supratrochlear and supraorbital arteries.
These branches anastomose with many other arter-
ies in the face explaining why intravascular injec-
tion at sites distant from the eye can result in
visual loss.
Hyaluronidase can reverse skin ischaemia by
flooding the tissue with high-dose hyaluronidase
until reperfusion is obtained [41]. It has been dem-
onstrated to be able to diffuse across some vessel
walls [42]. But its role in cases of vision loss remains
controversial because of a paucity of evidence in the
medical literature. A report has suggested that 450
units of retrobulbar hyaluronidase can reverse
&
vision loss [43 ]. Unfortunately, in the reported
case, there was no objective assessment of vision
or ocular examination to confirm mechanism or
reduction of vision, casting doubt on the effective-
ness of the treatment. Although hyaluronidase may
be able to cross some vessel walls, in-vitro studies of
fresh human postenucleation optic nerve specimens
have confirmed that hyaluronidase cannot pene-
trate the optic nerve to reach the central retinal
&&
artery [44 ]. A rabbit model has also been used to
evaluate the role of retrobulbar hyaluronidase in
central retinal artery occlusion with hyaluronic
acid. Retinal perfusion was assessed with angiogra-
phy, and retinal function with ERG. Hyaluronidase
had no effect on perfusion or function in six
completely occluded arteries. In two partially
occluded arteries, only one improved retinal perfu-
sion but not function [45]. Similarly in a case of
ischaemic oculomotor palsy and vision loss because
of injection of hyaluronic acid into the nasal dor-
sum, retrobulbar and subcutaneous hyaluronidse
was able to resolve the orbital ischaemia but not
reverse the vision loss [46]. However, complete
visual recovery was reported after subcutaneous
hyaluronidase administration in a patient with
Volume 30  Number 5  September 2019

hyaluronic acid-induced ischaemic optic neuropa-
thy with ophthalmoplegia and an altitudinal field
defect [47]. Another series of six cases of vision loss,
showed improved visual acuity or complete reversal
in four of the cases [48]. The authors postulate that
early supratrochlear/supraorbital hyaluronidase,
ocular massage and rebreathing into a plastic bag
can be well tolerated, uncomplicated and effective
methods to enable restoration of the retinal circula-
tion and reverse vision loss.
A consensus guidance for the treatment of hya-
luronic acid aesthetic interventional induced visual
loss (AIIVL) highlights medical and mechanical
treatments for the management of vision loss
&&
[49 ]. The current evidence suggests that complete
obstruction of the central retinal artery in the optic
nerve is not amenable to treatment with retrobulbar
hyaluronidase and that the risks associated with
attempted administration in inexperienced hands
poses additional further risk to patients.
CONCLUSION
Hyaluronic acid fillers are an important addition to
the armamentarium of the oculofacial surgeon, the
results are typically excellent, and their use in the
aesthetic field will continue to rise. Although com-
plications will occur in the best hands and cannot be
avoided completely, physicians are best prepared for
maximal safety by having knowledge of facial anat-
omy, safe injection planes and means of minimizing
and treating complications.
Acknowledgements
None.
Contributions statement: All authors have contributed to
the writing of this publication.
Ethics statement: R.M. received solicited information on
request for the purposes of this publication from Allergan
PLC (Irvine, USA).
License: The corresponding author has the right to grant
on behalf of all authors and does grant on behalf of all
authors, an exclusive licence on a worldwide basis to
permit this article to be published.
Guarantor: R.M. serves as guarantor of this work.
Financial support and sponsorship
None.
Conflicts of interest
The authors use fillers in their professional practice.
J.C.P.R. and R.M. have attended educational seminars
hosted by Allergan and R.M. has received honoraria for
hosting such events.
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
Periocular hyaluronic acid fillers Murthy et al.
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42. Chiang C, Zhou S, Chen C, et al. Intravenous hyaluronidase with urokinase as
treatment for rabbit retinal artery hyaluronic acid embolism. Plast Reconstr
Surg 2015; 136(5 suppl):196S–203S.
43. Chestnut C. Restoration of visual loss with retrobulbar hyaluronidase injection
& after hyaluronic acid filler. Dermatol Surg 2018; 44:435–437.
Case report showing success with retrobulbar hyaluronidase but with the limita-
tions alluded to in this article.
44. Adulkar N, Cheng C, Lee L, et al. In vitro evaluation of hyaluronidase
&& penetrating of the optic nerve sheath. Ophthalmic Plast Reconstr Surg
2019. [Epub ahead of print]
Bench research showing that retrobulbar hyaluronidase is unlikely to be
helpful as it fails to dissolve intravascular hyaloruonidase inside the optic nerve
sheath.
45. Hwang CJ, Mustak H, Gupta AA, et al. Role of retrobulbar hyaluronidase
in filler-associated blindness: evaluation of fundus perfusion and electroreti-
nogram readings in an animal model. Ophthalmic Plast Reconstr Surg 2019;
35:33–37.
46. Ramesh S, Fiaschetti D, Goldberg RA. Orbital and ocular ischemic syndrome
with blindness after facial filler injection. Ophthalmic Plast Reconstr Surg
2018; 3:e108–e110.
47. Sharudin SN, Ismail MF, Mohamad NF, et al. Complete visual recovery of filler-
induced visual loss following subcutaneous hyaluronidase injection. Neuro-
Ophthalmology 2018; 43:.
48. Thanasarnajsorn W, Cotofana S, Rudolph C, et al. Severe vision loss caused
by cosmetic filler augmentation: case series with review of cause and therapy.
J Cosmet Dermatol 2018; 17:712–718.
49. Humzah DM, Ataullah S, Chiang C, et al. The treatment of hyaluronic acid
&& aesthetic interventional induced visual loss (AIIVL): a consensus on practical
guidance. J Cosmet Dermatol 2019; 18:71–76.
The most recent guideline on how to manage visual loss after filler. We recommend
this article to everyone using fillers in the periocular area.
Volume 30  Number 5  September 2019