Neurotoxin Mechanisms of Action

The strains of the anaerobic bacterium Clostridium botulinum produce eight distinct serotypes of botulinum neurotoxin (BoNT) designated A–H. All serotypes produce chemodenervation of skeletal muscles by blocking acetylcholine release from presynaptic motor neurons at the neuromuscular junction. There are differences in how they affect the intracellular “molecular machinery” and produce their clinical effect.

BoNT type A (BoNT-A) was the first serotype that Dr. Alan Scott, a pioneering San Francisco ophthalmologist, developed for use in humans to treat strabismus and blepharospasm. ¹⁰ Cosmetic use followed the use in blepharospasm. ¹¹ Since the Food and Drug Administration (FDA) approval in 1990 of onabotulinumtoxinA (Botox/Botox Cosmetic), additional A formulations have been approved by the U.S. FDA and Health Canada: abobotulinumtoxinA (Dysport/Reloxin) and incobotulinumtoxinA (Xeomin). BoNT type B (BoNT-B) is also available in North America. RimabotulinumtoxinB (Myobloc/NeuroBloc) was FDA approved in 2000 for the treatment of cervical dystonia but has been used off-label to treat facial wrinkles. ¹²

BoNT-A preparations have remained the preferred treatment for cosmetic applications, as BoNT-B has a shorter duration of effect, greater pain during injection, and other side effects compared to BoNT-A. ¹² The onset of action is usually 24 to 48 hours after injection, with the full effect being noted at 5 to 7 days, peak effect at 30 days, and reduced effect over 3 to 6 months in most subjects. All approved neuromodulators differ in potency and clinical effect, and therefore, their units are not interchangeable. It is helpful to consult the product inserts and the peer-reviewed literature for further information.

Adverse Effects of Neurotoxin Treatment

The greatest complication of neurotoxin treatment is overcorrection or undercorrection. Overcorrection resolves over time, while further injection can address undercorrection.

Mechanism of Action: Space-Filling and Neocollagenesis

The efficacy of HA fillers has been initially attributed to their space-filling effect. More recent research suggests that HA may also induce neocollagenesis via changes in the structure and function of the cutaneous fibroblasts in the extracellular matrix. ¹⁶ ID#b1a750a014_17 ^{– 18} Other non-HA fillers such as Radiesse and Sculptra are more commonly used in the mid- and lower face and other nonface areas such as chest and hands. The addition of 0.3% lidocaine to the HA fillers has become standard practice to improve patient comfort and tolerability.

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  Gel hardness (G′): G′ is a measure of the amount of gel displaced based on the degree of stress applied to the gel. Hard gels (high G′) exhibit greater resistance to deformation, require greater injection pressure, and tend to provide a firmer feel under the skin. Soft gels may be beneficial for the treatment of areas with thin skin, such as the periorbital area or lips.

  
  
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  Degree of cross-linking: The amount of uncross-linked (soluble) and cross-linked (insoluble) HA in a gel influences gel viscosity. Less cross-linked HA allows a smoother flow during injection but may contribute to a shorter duration of effect. Decreasing the amount of cross-linked HA also decreases the hardness of a gel.

  
  
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  Particulate versus nonparticulate gels: Initial HA fillers were noncohesive biphasic fillers, characterized as cross-linked particles suspended in a noncross-linked HA matrix acting as a lubricant. These products (Restylane and Restylane Lyft [formerly Perlane]) have HA concentration of 20 mg/mL and are manufactured with nonanimal-stabilized HA technology where the gel is sized to a uniform particle volume and then mixed with uncomplexed HA to ensure that the material will flow on injection into tissue. ¹⁹

Nonparticulate gels are characterized by a uniform, smooth consistency and so are monophasic. Juvéderm Ultra, Ultra Plus, Voluma, Volift, and Volbella are monophasic monodensified fillers, and in contrast to biphasic particulate gels, do not undergo sizing, a process that breaks down the gel. They contain a single phase of HA with a single density. Different families of monophasic monodensified fillers exist, depending on the manufacturing technology, such as the Hylacross technology (Juvéderm Ultra, HA concentration 24 mg/mL) or the Vycross technology (Juvéderm Voluma, HA concentration 20 mg/mL; Juvéderm Volift, HA concentration 17.5 mg/mL; and Juvéderm Volbella, HA concentration 15 mg/mL). Cohesive monophasic polydensified gels (Belotero range) were more recently introduced. In contrast to monodensified fillers, they are manufactured with the cohesive polydensified matrix (CPM) technology, resulting in a gel with nonuniform cross-linking and molecular weight and a viscosity that is lower than that of other fillers (comparing fillers targeting the same indication). These properties may allow for a more homogeneous intradermal distribution of the material. ^{20 ,​ 21}

The cross-linking technology, the uniformity and size of the particles, and the gel formulation and the HA concentration of the filler determine its viscoelastic properties, and therefore its clinical effect. Fillers with high viscosity (G′) such as Restylane and Restylane Lyft are good solid support but do not spread as well for superficial filling. Belotero Balance has excellent spreadability and tissue integration due to having the lowest elasticity and viscosity. The Hylacross fillers (Juvéderm family) have intermediate viscosity and elasticity. Vycross fillers such as Juvéderm Voluma have low elasticity like Restylane and Restylane Lyft and are suitable for structural support, whereas the more elastic fillers such as Juvéderm Ultra and Belotero Basic are more elastic and spreadable and also helpful for more superficial application. ²¹

Adverse Events and Hyaluronidase

The most frequent adverse effects associated with HA fillers are transient and mild, including pain, bruising, edema, and erythema at the injection site. Another common adverse event is the Tyndall effect in which blue light is reflected after a bolus of HA filler is placed superficially, particularly in the thin skin of the periocular region. Often a small dose of hyaluronidase is enough to reduce the nodule. Hyaluronidase can also be helpful for the restoration of symmetry.

Delayed inflammatory nodules may also occur. Our group conducted a retrospective chart review of our clinic patients who we treated with Juvéderm Voluma (HA-V) between February 1, 2009 and September 30, 2014 to evaluate for delayed onset nodules. ²² Of the 4,702 treatments using 11,460 mL of HA-V, 23 patients (0.5%) experienced delayed onset nodules. The median time from injection to reaction was 4 months, and median time to resolution was 6 weeks. Importantly, 9/23 (39%) had an identifiable immunologic trigger such as flu-like illness prior to the nodule onset. In our experience, effective treatments included oral prednisone, intralesional corticosteroids, and hyaluronidase. None of our nodules were of infectious etiology, and we feel they are largely immune-mediated responses to the short chains in HA-V. While delayed nodules are uncommon from HA-V (0.5%), it is important to be aware of this adverse effect and have a management protocol in place.

Inadvertent intravascular injection is also possible in superficial vasculature such as the supratrochlear vessels, but because they are arborizing with adjacent vasculature, the ischemic effects are much more limited. Intravascular injection can occur in a facial vessel where the flow is reversed, and the filler bolus canalized can block the central retinal artery. There is limited time to restore retinal circulation before the retinal tissue succumbs. There have been several cases now reported in the literature where periocular hyaluronidase in large doses has been injected in a retrobulbar, supratrochlear, and supraorbital approach where some or all vision was recovered. ²³ ID#b1a750a014_24 ^{– 25}

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  Needle versus cannula: The theoretical risk of arterial wall perforation and emboli with cannulas is lower, but these complications can still occur with cannulas as with needles. Slow, small aliquot injection technique along with knowledge of the underlying vascular anatomy is essential. With both injection methods, the authors prefer to use an anterograde injection technique so that the soft bolus of filler rather than the tip of the needle or cannula pushes encountered vasculature gently aside. While both needles and cannulas are useful in practice and achieve excellent cosmetic results, cannula use in the deeper compartments among practitioners is encouraged to minimize complications. ²⁶

  
  
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  Avoiding vascular complications: There are 98 reported cases of filler-induced blindness from 1906 to 2015. ²⁷ There were over 3 million total reported aesthetic filler injections by the American Society of Aesthetic Plastic surgeons and the American Society for Dermatologic Surgery in 2016 and 2017. ^{28 ,​ 29}

Although thankfully a rare event, physicians injecting in the periocular region and midface should be prepared with detailed knowledge of facial and vascular anatomy and have learned sophisticated injection techniques to prevent and if necessary treat inadvertent facial and periocular intravascular injection. ³⁰