Botulinum toxin in oculoplastics
Botulinum neurotoxin type A (BTX-A) molecule

Botulinum toxin in oculoplastics

August 1, 2017 Dr James Slattery and Dr Brian Sloan

Once touted as the most toxic poison known, Clostridium botulinum neurotoxin (BoNT) has revolutionised the treatment of a broad array of periocular diseases. Its efficacy and low risk mean it is now one of the most frequently used medications in ophthalmic plastic surgery1.

First recognised as a safe and efficacious therapeutic agent by Allan Scott in the 1970s for treatment of strabismus via extraocular muscle injection, the use of BoNT has since evolved to become standard therapy for movement disorders such as blepharospasm and other facial dystonias to many neurologic and non-neurologic disorders1-3.

BoNT type A is the strongest of seven serotypes identified. It paralyses muscle by inhibiting the release of acetylcholine (Ach) from vesicles at the presynaptic nerve terminal of the neuromuscular junction, decreasing contraction of the motor unit. There is some evidence suggesting BoNT may also modify sensory and proprioceptive input via an effect on central motor neurones. Continued release of Ach for several days means the onset of effect may be two to four days. From a therapeutic point of view, treatment generally remains effective for three to four months after injection and restoration of muscle activity is thought to be secondary to regeneration of new motor end plates, reduced levels of acetylcholinesterae and extra-junctional acetylcholine receptors1,4.

There are currently four neurotoxin formulations available for injection, OnabotulinumtoxinA (Botox, Allergan), AbobotulinumtoxinA (Dysport, Ipsen), IncobotulinumtoxinA (Xeomin, Merz) and RimabotulinumtoxinB (Myobloc, Solstice)3,5.

Although BoNT is a foreign protein, secondary non-response with production of antibodies against botulinum toxin A is extremely rare. There is very little evidence of tachyphylaxis.

BoNT “units” are defined by mouse toxicity trials and while comparative efficacy is fairly similar in regards to potency, speed of onset, therapeutic duration and immunogenicity, there is no true “equivalent” dosing paradigm between different BoNT preparations.

The lethal dose of Botox is estimated to be 2500-3000 units for a 70kg person. Typical periocular treatments are in the order of 20-50 units1.

Facial dystonias

Benign essential blepharospasm and hemifacial spasm are two of the most common disorders affecting the face. These facial dystonias can render patients functionally blind and adversely affect quality of life; causing depression, anxiety, ocular pain and difficulties with driving.

Benign essential blepharospasm (BEB) is a bilateral pattern of focal dystonia involving the muscles surrounding the eyes that manifests clinically as sustained spasms of the eyelid protractors resulting in excessive blinking, photophobia and persistent eye closure in the absence of any adnexal cause. BEB affects 32/100,000 people, typically in the fifth to sixth decade of life; affecting women more frequently than men in a 3:1 ratio. The aetiology is unknown4,6.

A subset of blepharospasm patients display forceful contraction of jaw and tongue, as well as chin thrusting, consistent with oromandibular dystonia, a combination commonly described as cranial dystonia or “Meige syndrome”.

A patient with hemifacial spasm

A patient with hemifacial spasm

Hemifacial spasm (HFS) is characterised by unilateral intermittent sustained contractions of the muscles of facial expression supplied by the facial nerve. Hemifacial spasm commonly is of insidious or subacute onset, peaking in middle age, although it can occur anywhere from the third to seventh decade of life but is less common than BEB. Women are affected more frequently than men, 2:1. It is usually chronic and progressive and may cause patients significant social disability.

The most commonly identified aetiology is vascular compression of the intracranial portion of the facial nerve. Neurosurgical treatment options are available but because of potential complications, patients may elect for a less invasive treatment modality.

High-level evidence exists for the treatment of facial dystonias with BoNT and clinical response rates are reported to be greater than 90% and to clinically correlate with improved quality of life.

Studies show persisting efficacy over a 15-year period in patients treated for BEB, HFS and Meige syndrome, with very low incidence of adverse effects. The average duration of effect and dose required for treatment remains unchanged in short and long duration follow-up studies, once an effective dose has been established by titration.

Subcutaneous injections into orbicularis oculi of upper and lower lids and the corrugator supracilii muscles of the eyebrows are performed. Patients with blepharospasm are typically injected every three to four months while those with hemifacial spasm every four to six months.

Efficacy can be evaluated two to four weeks after initial injection and the sites and doses titrated to response for subsequent injections1,6.

Cosmesis

The past 15 years have seen an explosion in the use of BoNT for the treatment of facial wrinkles or rhytids. The superficial facial mimetic muscles insert directly into the under surface of the skin; repetitive contraction therefore causes characteristic furrows perpendicular to the direction of contraction. These so called “dynamic” rhytids contrast with “static” rhytids, caused by thinning of the dermis. Dynamic rhytids commonly occur in the upper third of the face (brow and periorbital regions) and are amenable to management with chemodenervation agents. It is important to recognise that chemodenervation will not treat static rhytids, which may require other facial rejuvenation techniques such as peels, laser resurfacing and fillers.

Glabellar furrows are primarily caused by contraction of the corrugator supracilii, procerus muscles and medial orbicularis muscles, and respond very well to BoNT injections. Effects may last up to six months. A “chemical brow lift” may be achieved by combining with injection of the lateral orbicularis, which is a lateral depressor of the brow.

Horizontal forehead wrinkles arise from contraction of the twin belly frontalis muscle. BoNT injections are placed evenly 2-3cm above the orbital rim with care not to cause a brow ptosis especially in patients with blepharoptosis and Asians with particularly heavy lids5.

Aberrancy

Involuntary co-contraction of the orbicularis oculi and the orbicularis oris muscle when the patient speaks, smiles, laughs or opens the jaw, secondary to ocular facial synkinesia, results in pseudo-ptosis, otherwise known as Marin Amat syndrome. This synkinesia is secondary to aberrant regeneration of the facial nerve after palsy of various aetiologies, including trauma, Bells palsy, Ramsay Hunt syndrome, polyneuritis and surgery.

The frequency of such aberrant regeneration phenomena is not well documented, but mild forms are probably quite common. The abnormal facial movements are often undesirable to the patient, causing visual obstruction, and are cosmetically displeasing, causing unintended social cues.

The use of BoNT to correct the symptomatic blepharospasm component of the synkinesis, as well as biofeedback is now the mainstay of treatment4.

Lacrimation

Watering results from either lacrimal obstruction (epiphora) or hypersecretion of tears from the lacrimal gland (lacrimation).  Hypersecretion may be reflex in nature, secondary to adnexal disease or due to aberrant regeneration of the facial nerve, particularly while chewing or talking (crocodile tears).

Invasive treatment options include dacryocystorhinostomy, with or without Lester-Jones tube placement, partial lacrimal gland excision, sphenopalatine block and radiotherapy, but Botox injected into the palpebral lobe of the lacrimal gland can also be very effective. Studies have shown nearly 75% of patients have subjective elimination of epiphora,17% improved but still had tearing, and 9% little or no effect. A temporary induced ptosis was the commonest side effect, occurring in approximately 11%.

This procedure can easily be performed in a clinical setting with few transient adverse effects and a high-patient satisfaction7.

Adverse effects

Primary non-response is uncommon and may be due to misdiagnosis, adnexal disease causing sensory blepharospasm, inadequate or inappropriate treatment and handling errors.

Thankfully, contraindications to BoNT injection are rare, but should be avoided in pregnancy and lactation. Neuromuscular disorders such as myasthenia gravis, Eaton-Lambert syndrome and amyotropic lateral sclerosis can theoretically be worsened by neurotoxin injections5.

The clinical safety of BoNT injections has been well established in large series studies and thankfully most adverse events are minor and self-limiting, occurring in around 5-10% of cases. The titration period carries a risk of both under and overtreatment, but this reduces as the effective treatment regimen is identified.

Bruising, swelling and haematoma formation are the most common adverse events. Injections into periocular area can cause blepharoptosis, diplopia, lower-lid malpositions including entropion and ectropion. Excessive weakening of orbicularis can lead to lagophthalmos and corneal epitheliopathy, making artificial lubricants essential in the early post-injection period. An early review after initial treatments is usually prudent. The injection technique is extremely important in minimising side effects and maximising therapeutic effect.

Summary

BoNT has revolutionised treatment of periocular facial movement disorders, virtually eliminating the extensive surgery that used to be patients’ only treatment option. The increasing use of BoNT for cosmesis carries risks of corneal exposure and it should be considered as a possible cause in all patients seen with ocular surface symptoms. Fortunately, such side effects are almost always transient, mild and respond well to conservative management.

References

  1. Harrison AR. Chemodenervation in facial dystonias and wrinkles. 2003. Current Opinion in Ophthalmology;14(5):241-245
  2. Hallet M, Albanese A, Dressler D, Segal KR, Simpson D, Truong D, Jankovic J. Toxicon 2013:67:94-114
  3. Erikson BP, Lee WW, Cohen J, Grunebaum LD. The role of neurotoxins in the periorbital and midface ares. Facial Plast Surg Clin N Am 2015; 243-255
  4. McElhinny ER, Reich I, Burt B, Mancini R, Wladis E, Durairaj VD, Shinder. Treatment of pseudoptosis secondary to aberrant regeneration of the facial nerve with botulinum toxin type A. Ophthal Plast Reconstr Surg 2013;29 (3):175-178
  5. Chundury RV, Couch SM, Holds JB. Comparison of preferences between OnabotulinumtoxinA (Botox) and IncobotulinumtoxinA (Xeomin) in the treatment of benign essential blepharospasm. (2013) Ophthal Plast Reconstr Surg 29(3): 205-7
  6. Czyz CN, Burns JA, Petrie TP, Watkins KV, Foster JA. 2013. American Journal of Ophthalmology 156:173-177
  7. Wojno TH. Results of lacrimal gland botulinum toxin injection for epiphora in lacrimal obstruction and gustatory tearing. Ophthal PLast Reconstr Surg 2011; 27:119-121

About the author
Dr James Slattery MBBS, PhD, B Sci (Biomed) is an oculoplastics fellow at the University of Auckland. He completed his ophthalmology training in Adelaide, South Australia.