Botulinum toxin in ophthalmic plastic surgery

Milind N Naik, Charles NS Soparkar, R Murthy, SG Honavar
Division of Ophthalmic Plastic Surgery, L. V. Prasad Eye Institute, Hyderabad, India

Correspondence Address:
Milind N Naik
Division of Ophthalmic Plastic Surgery, L. V. Prasad Eye Institute, Hyderabad - 500 034
India

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1

Abstract

Botulinum toxin chemodenervation has evolved greatly over the past 30 years since its introduction in the 1970s for the management of strabismus. Among ophthalmic plastic surgeons, botulinum toxins are often used as the first line treatment for facial dystonias. These toxins are also efficacious for the temporary management of various other conditions including keratopathies (through so called chemo-tarsorraphy), upper eyelid retraction, orbicularis overaction-induced lower eyelid entropion, gustatory epiphora, Frey's syndrome, and dynamic facial rhytids such as lateral canthal wrinkles (crow's feet), glabellar creases and horizontal forehead lines. This article describes the pharmacology, reconstitution techniques and common current applications of botulinum toxins in ophthalmic plastic surgery.

Keywords: Botulinum toxin, chemodenervation

Botulism

From terror to treatment

Pharmacology

Molecular biochemistry

All botulinum neurotoxins are produced as relatively inactive, single polypeptide chains of about 150 kDa weight with a high degree of amino acid sequence homology among the toxin types [Figure - 1]. The parent polypeptide chain consists of a heavy (H) chain and a light (L) chain of roughly 100 and 50 kDa respectively, linked by a disulfide bond.

The botulinum toxin neurotoxin complex is also associated with various other nontoxic proteins, which could be either with or without haemagglutinating properties.

Mechanism of action

Botulinum toxins act at four different sites in the body: the neuromuscular junction, autonomic ganglia, postganglionic parasympathetic nerve endings and postganglionic sympathetic nerve endings that release acetylcholine (Ach). Intramuscular administration of botulinum toxin acts at the neuromuscular junction to cause muscle paralysis by inhibiting the release of Ach from presynaptic motor neurons [Figure - 2].

At the neuromuscular junction, its mechanism of action involves three discrete steps: binding, internalisation and inhibition of neurotransmitter release through inactivation of SNARE (Soluble N -ethylmaleimide-sensitive factor Attachment protein receptor) proteins. [8],[9],[10] The peak of the paralytic effect occurs 4-7 days after injection. Approximately 2 months after the administration of botulinum toxin, the axon begins to expand, and new nerve terminal sprouts emerge and extend towards the muscle surface.[11] These new nerve sprouts re-establish the motor nerve unit and the muscle paralysis is reversed within 2-4 months.

Commercial preparations

Three preparations of botulinum toxin are commercially available at present. BotoxÒ (Allergan Inc., Irvine, CA, USA) and DysportÒ (Ipsen Pharmaceuticals, France) are the type A toxins. MyoblocÒ (Elan Pharmaceuticals, San Diego, CA, USA) is the type B toxin. Botulinum toxin type B is also marketed in Europe by the name NeuroblocÒ by Elan Pharma International Limited, Ireland. Type A toxin is easily producible in culture in a highly purified, stable and crystalline form.[12] Type A toxin also has the longest duration of action, and a favourable ratio between biologically active and inactive neurotoxin. BotoxÒ purified neurotoxin complex is a sterile vacuum-dried purified extract of botulinum toxin type A, produced from fermentation of the Hall strain of C. botulinum type A. Each vial of BotoxÒ contains 100 units (U) of C. botulinum type A neurotoxin complex, 0.5 mg of human albumin, and 0.9 mg of sodium chloride in a sterile vacuum-dried solid without preservatives. DysportÒ is also produced in a dried formulation. This dried toxin A has to be stored at -5°C until reconstitution. MyoblocÒ is a sterile liquid formulation of purified neurotoxin type B produced by fermentation of Bean strain of the bacterium C. botulinum type B. MyoblocÒ is packaged as a liquid formulation at a concentration of 5000 U/ml. It is available in 0.5 ml (2500 U), 1 ml (5000 U) and 2 ml (10 000 U) vials and does not require reconstitution. Studies have shown that unopened MyoblocÒ vials are stable for 30 months when refrigerated, and for 9 months at room temperature.[13] It is slightly acidic with a pH of 5.6. Although botulinum toxin type B has a faster onset of action, and a larger area of diffusion,[14] the greater acidity of its storage medium translates to greater discomfort upon injection. Moreover, BotoxÒ is 50-100 times more potent than MyoblocÒ for any given specific treatment. Contraindications for the use of botulinum toxin are listed in [Table - 3]. Doses of all commercially available botulinum toxins are expressed in terms of units of biologic activity. One unit of botulinum toxin corresponds to the calculated median intraperitoneal lethal dose (LD₅₀) in female Swiss-Webster mice.[15]

Although the definition of unit applies to all forms of commercially available toxins, inter-manufacturer differences in mouse LD₅₀ assay protocols has led to units that vary in potency between products. Thus the bio-equivalence ratio of DysportÒ to BotoxÒ has been suggested to be 3: 1 or 4: 1 by various studies in patients with Blepharospasm and hemifacial spasm.[16],[17],[18] Therefore, when communicating dose information about botulinum toxins, it is very important to specify the particular brand of toxin being used.

Antibody production
Even today, much remains unresolved about the issue of production of antibodies against botulinum toxin. Botulinum toxin is capable of inducing formation of humoural antibodies in humans leading to decreased effect of the toxin over time.[19] This has also been linked to early re-injection into muscles.[20] Others have reported absence of antibody production.[21] Direct comparison of the results of these various studies is complicated. Antibody production is a function of cumulative dose, antigenic load per dose, and time interval between injections. Prudence would therefore dictate that the smallest therapeutic dose be given with maximum time interval between two injections. However, in patients who develop antibodies to type A toxin, successful treatment with type F toxin has been reported.[22] BotoxÒ, DysportÒ and MyoblocÒ contain human serum albumin (HSA) to stabilise neurotoxin complex and prevent it from aggregating onto surfaces.[23],[24] HSA is derived from a screened pool of donors monitored by the US Food and Drug Administration (Rockville, MD, USA). Prions are normal (helical) or abnormal (helical) proteins with toxic effects, and can accompany HSA that is derived from the donors. Concerns have been raised about the potential risk of human-to-human transmission of prion disease by the HSA used in commercially available botulinum toxin products.[25] Although this theoretical risk exists, there have been no reports of transmission of Hepatitis A, B or C, human immunodeficiency virus or Creutzfeldt-Jacob disease through HSA. The human albumin load in BotoxÒ, has reduced from 25 to 5 ng per 100 U vial, thereby reducing the total albumin load and its attendant risks (Data on File, BotoxÒ, Allergan). The ophthalmologists using botulinum toxin should however be aware of the presence of HSA and its implications.

Toxin reconstitution

The type A toxin has to be reconstituted with sterile, nonpreserved 0.9% saline prior to injection [Figure - 3]. The toxin concentration per 0.1 ml of diluent is dependent on the volume of diluent used [Table - 4]. The reconstituted solution should be clear, colourless and free of particulate matter, and should be stored in a refrigerator at 4⁰subC until use. The dose recommendations for common therapeutic indications of botulinum toxin are given in [Table - 5]. The reconstituted toxin is drawn into a tuberculin syringe via a fine gauge needle (30G or 32G) for final injection. The manufacturer recommends BotoxÒ to be used within 4 hours of reconstitution, and earlier reports[26] have mentioned about deterioration of the toxin within few hours after reconstitution. However, several recent reports suggest storing the vial in the refrigerator after reconstitution to be reasonable for 1 week[27],[28] to 6 weeks.[29] The fragile toxin molecules are susceptible to damage by mechanical stress, hence it would be prudent to avoid rapid injection and frothing during reconstitution. A recent report however has demonstrated no adverse effect of frothing on the toxin action or duration.[30]

Facial dystonias

Botulinum toxins have revolutionised the treatment of patients with facial dystonias. The success rate is reported to be over 90%.[31]

Facial dyskinesias presenting to the ophthalmologist include Benign Essential Blepharospasm (BEB), Hemifacial spasms (HFS), Orbicularis myokimia, Meige syndrome and Apraxia of lid opening (ALO).

BEB is an involuntary and repetitive bilateral spasmodic contraction of the orbicularis oculi muscle [Figure - 4], and is often progressive.[32] It usually presents in the fourth to sixth decade with an increase in the blink rate, which increases in 1 or 2 years to forceful involuntary closure of eyelids. Symptoms are often exacerbated by environmental conditions like bright light, dusty air or optokinetic stimulus. [33],[34],[35],[36] The aetiology of blepharospasm is considered to be an organic dysfunction of the rostral brainstem.[35],[37],[38] Treatments that have been tried for BEB include central nervous system depressants (diazepam and clonazepam), orbicularis myectomy and selective facial nerve neurectomy. However, patient acceptance is highest with botulinum toxin chemodenervation.[39]

Reflex blepharospasm, caused by dry eye or ocular surface pathology can mimic BEB. It can be associated with spastic lower eyelid entropion that in turn induces ocular surface damage, and the vicious cycle continues. It is typically relieved by instillation of topical anaesthetic. Botulinum toxin injection helps to break the vicious cycle, by inducing temporary paralysis of orbicularis oculi.

Meige Syndrome was first described in 1910 by Henry Meige, as 'spasm facial median'. It is a form of cranial dystonia characterised by the presence of bilateral blepharospasm with concurrent dystonia of the lower face, in the form of lip pursing, chewing, or jaw opening movements. Dysarthria, and dysphonia may also be seen.[37] The most common and disabling manifestation of Meige syndrome is blepharospasm, which can render the patient functionally blind.

HFS [Figure - 4] is characterised by repetitive unilateral periodic tonic contractions of ipsilateral facial muscles. It begins in middle age, and is more common in females.[40] It generally results from mechanical-vascular compression of the seventh cranial nerve root in the cerebello-pontine angle.[41] Less than 1% are caused by posterior fossa tumours,[42] therefore a magnetic resonance imaging may be indicated in patients with HFS. Although neurosurgical microvascular decompression procedure may be the definitive form of treatment,[40] botulinum toxin injections are effective in controlling HFS.

Orbicularis myokimia generally occurs in younger individuals, and involves involuntary twitching of the upper or lower eyelid, resulting from spasm of individual bundles of muscle fibres. It is related to stress, fatigue, use of alcohol, or excess caffeine.

For chemodenervation of facial dystonias, a pre-injection evaluation involves examination of the muscles involved in the spasms, and assessment of the muscle mass. Videography of spasms before and after injection may allow identification of the involved muscles, and help in planning future treatment. Patients with BEB typically require repeat injections every 3-4 months, whereas those with HFS have a longer spasm-free interval of 4-6 months. Patients are evaluated 2-4 weeks after their initial injections to assess the efficacy, and side effects or complications if any [Table - 6]. Further injections may be given at that time, or a note may be made to inject more or less toxin into the areas that are under or over paralysed, respectively.

We commonly use BotoxÒ (Allergan, Irvine, CA, USA) by diluting 100 U vial to obtain a dilution of 2.5 or 5 U per 0.1 ml. For the treatment of BEB, subcutaneous injection of botulinum toxin is given into the orbicularis oculi of upper and lower eyelids as well as the eyebrows [Figure - 5]. The sites injected vary for each patient and subsequent injections are modified based on patient's response to treatment. For HFS, the periocular injection sites and dosage remains similar to that of BEB. Additional injections into the involved lower facial muscles may be required in HFS.

Patients with HFS demonstrate a longer duration of action than BEB, because HFS demonstrates less of nerve and muscle hyperactivity. Moreover, the facial nerve progressively degenerates in HFS, leading to a longer spasm free interval. Injection into the pretarsal muscle has been shown to produce a significantly better response compared to preseptal injection in blepharospasm and HFS patients.[43] Meige syndrome is more difficult to control than BEB, requires a higher total toxin dose, and has a shorter spasm free interval. Orbicularis myokimia if persistent, requires focal toxin injection into the involved muscle bundle. Injection of botulinum toxin has been shown to be efficacious and safe over a 10 year period in one study.[44]

Apraxia of lid opening is a nonparalytic motor abnormality characterised by difficulty in initiating the act of lid elevation. It has been reported with extrapyramidal disorders, including Parkinson's disease, Huntington's chorea, progressive supranuclear palsy, and  Shy-Drager syndrome ^{More Details}.[45] Abnormal persistence of orbicularis oculi activity detectable electromyographically but not clinically, has been suggested to be the main factor contributing to the delay in lid opening in these patients.[46] Apraxia of lid opening is often associated with blepharospasm, and botulinum toxin injection has been shown to improve lid opening delays in ALO.[47]

Chemo-tarsorrhaphy

Traditionally, tarsorrhaphy has been used in cases of corneal exposure due to facial nerve palsy, persistent epithelial defects, and indolent corneal ulcers. Botulinum toxin chemodenervation of levator muscle is a quick and easy procedure for induction of temporary ptosis for corneal protection,[48],[49] thereby avoiding surgical tarsorrhaphy and subsequent scarring of eyelid margin. Electromyographic guidance though helpful, is not mandatory for botulinum toxin injection procedure [Figure - 6]. Transient superior rectus underaction lasting for 6 weeks has been reported to occur in 68-80% of treated patients.[49],[50] Heyworth in 1994 reported three cases of persisting hypotropias following temporary induction of ptosis with botulinum toxin.[51] A recent report using 5 U of BotoxÒ reported onset of ptosis in an average of 4 days, and duration lasting 46 days.[52] Till date, there have been no studies addressing the dose requirement to achieve complete ptosis, and doses ranging from 2.5 U up to 20 U of BotoxÒ have been used. Its use however, should be limited to corneal conditions that are likely to be temporary.

Upper eyelid retraction.

Botulinum toxin injection into the levator can be an effective treatment for upper eyelid retraction associated with thyroid eye disease [Figure - 7]. Though the amount of resultant ptosis is unpredictable, recent reports suggest that it is easy to administer, well tolerated by patients, effective in reducing symptoms and improves the cosmetic appearance. [53],[54],[55]

Lower eyelid senile entropion

One of the aetiologies of lower eyelid senile entropion is the overriding of preseptal orbicularis muscle over pretarsal orbicularis muscle.[55] Several reports have shown the effectiveness of botulinum toxin injection into the lower orbicularis muscle for temporary control of lower eyelid entropion.[56],[57],[58],[59] Surgical treatment of senile lower eyelid entropion is definitive and persistent. However, botulinum toxin chemodenervation is a quick outpatient procedure [Figure - 8] for patients who are unfit or waiting for surgery. The mean duration of action has been reported to range from 12 to 15 weeks,[56],[59] and toxin therapy had no adverse effects on results of surgical entropion repair.[59]Approximately 10-20 U of BotoxÒ is required for the desired effect.

Facial nerve palsy and aberrant regeneration

Aberrant regeneration of facial nerve can lead either to 'crocodile tears' (gustatory epiphora), Frey's syndrome (gustatory sweating) or abnormal facial movements. These late effects of facial nerve regeneration can be treated effectively with botulinum toxin.

Gustatory epiphora

Gustatory epiphora, is characterised by excessive lacrimation while eating or smelling food. This usually follows a Bell's palsy or stroke, involving the proximal facial nerve or its nucleus. Abnormal lacrimation in gustatory epiphora can be treated with intraglandular injection of botulinum toxin [Figure - 9]. Successful treatment of gustatory epiphora has been reported by Riemann et al. (2.5 U of Botox),[60] Hofmann (15 U of BotoxÒ),[61] Keegan et al. (20 U of DysportÒ),[62] and Montoya et al. (20 U of DysportÒ)[63] with intra and periglandular injection of botulinum toxin. Ptosis and superior rectus underaction are common side effects.[62]

Frey's syndrome

Frey's syndrome or 'auriculo-temporal syndrome' is characterised by ipsilateral excessive facial sweating while eating. This typically follows parotid surgery,[64] where subcutaneous dissection disrupts the sympathetic fibres innervating the sweat glands of the face and parasympathetic fibres innervating the parotid gland. Aberrant innervation of the sweat glands by the parasympathetic salivary gland fibres results in Frey's syndrome. Hofmann[61] reported a case of Frey's syndrome treated with intradermal injection of botulinum toxin using the method described by Drobik et al. The Minor's iodine starch test is performed to reveal hypersecreting areas of the skin, which are treated with intracutaneous injection of botulinum toxin. The required dose reported in literature varies widely, ranging from 16 to 150 U for BotoxÒ,[64],[65] and 10 or 20 U/cm2 for DysportÒ.[66] There is some evidence to suggest that neuronal regeneration may take much longer within the autonomic nervous system.[67],[68] Thus, the effect of treatment may last for 4-5 months for crocodile tears, whereas it may last up to a year for Frey's syndrome.[61] Botulinum toxin has also been successively used for treatment of idiopathic craniofacial hyperhidrosis,[69] and diabetic autonomic gustatory sweating.[70] Further work is however required to address the optimal injection parameters and dosage.

Synkinetic facial movements

Patients with partially regenerated facial nerve may have other anomalous facial movements. Synkinesis between orbicularis oculi and lower facial muscles would lead to narrowing of palpebral aperture on smiling, creating a cosmetic deformity [Figure - 10]. Putterman reported successful treatment of synkinesis with botulinum toxin injection into the orbicularis oculi given in a manner similar to that for HFS.[71]

Lacrimal gland hypersecretion and dry eye

Injection of botulinum toxin into the lacrimal gland [Figure - 9] has been described for the treatment of gustatory epiphora. However, it can also be used for primary lacrimal gland hypersecretion, and secondary causes such as functional epiphora. Whittaker et al.[72] reported intraglandular injection of the toxin for functional epiphora, and demonstrated subjective improvement without strong correlation with Schirmers test. Transient mild ptosis and diplopia were the main side effects. Once the optimum doses and long term efficacy of multiple injections has been proved, it could prove beneficial to patients with irreparable damage to the lacrimal drainage system.

Injection of botulinum toxin into the medial eyelid decreases lacrimal drainage by paralysing the lacrimal pump mechanism.[73] This can prove to be a useful adjunct in the management of dry eye patients.

Cosmetic oculoplasty.

Facial wrinkles or rhytides may be categorised as static or dynamic. Dynamic wrinkles are the result of activity of underlying muscles. On the other hand, static wrinkles result from thinning of the dermis due to age, sun exposure, and smoking. Repeated, prolonged effect of dynamic wrinkles can lead to loss of subcutaneous fat, hyaluronic acid and collagen leading to static wrinkles. The dynamic wrinkles are most common over the upper third of the face (brow and peri-orbital regions), and are amenable to management with chemodenervation agents.

Carruthers et al. reported the use of botulinum toxin injection for dynamic wrinkles in the glabellar area.[74] Since then, over the past few years, its use has expanded to the midface, perioral and neck regions. In addition to its primary use, it has also been used to augment other procedures like chemical peels, laser resurfacing, brow lift and fillers.[75],[76],[77]

A consensus panel has recently published guidelines and recommendations for the use of botulinum toxin in a wide range of aesthetic applications.[78]

Glabellar frown lines: the glabellar wrinkles [Figure - 11] are caused by the actions of corrugator supercilli, depressor supercilli and procerus muscles. Injection into these areas has been shown to cause temporary paralysis that lasts up to 6 months [Figure - 12], thereby eliminating these wrinkles. For treatment, 2.5-5 U of botulinum toxin type A (BotoxÒ) are injected at five to seven sites into both corrugators and into the procerus muscle. [79],[80],[81]

Horizontal forehead wrinkles: the action of the frontalis muscle may, over years, lead to the development of horizontal forehead wrinkles. Injection of botulinum toxin type A (Botox) in four to eight sites spaced evenly over the forehead may relax the muscle and soften these lines. The injections are typically given 2-3 cm above the orbital rim using 2.5-5 U per injection sites [Figure - 12].[75],[76],[77]

Periocular crow's feet: the contraction of the lateral orbicularis fibres, zygomaticus and risorius muscles gives rise to dynamic wrinkles spreading out from the lateral canthus, known as the crow's feet [Figure - 11]. Three to four injections of 2.5-5 U of Botox into lateral orbicularis oculi are required for effective treatment of crow's feet [Figure - 12]. A study comparing 6, 12 and 18 U of botulinum toxin into the periocular area found no significant difference in the clinical response.[82] Injection into the zygomaticus major can cause ipsilateral lip ptosis, and should thus be avoided.[83] Lower eyelid injection with 2 U of botox can widen the eye with reduction in infraorbital wrinkles.[84]

Chemical brow lift: botulinum toxin can be used to create a chemical browlift by selectively paralysing the depressors of the eyebrow. Botulinum toxin injections are given into the glabellar area (as described earlier) and lateral orbital orbicularis muscle [Figure - 12] below the eyebrow.[85],[86]

Other aesthetic facial applications of botulinum toxin include 'bunny lines', peri-oral treatment, dimpled chin, 'marionette lines' and platysmal bands.

Botulinum toxin has also been found to be useful in the management of Migraine,[87],[88] and Tension type headache.[89] When injected into the neck or facial muscles(temporalis, frontalis, corrugator-procerus complex and occipitalis), it is believed to block the release of nociceptive neuropeptides involved in the chronic inflammatory pain response, such as substance P and glutamate. This theoretically inhibits both peripheral and central sensitisation, thereby down regulating pain.[90]

Future research

Type A botulinum toxin has widened its clinical range of applications, but the risk of developing antibodies limits the repeated use of high-dose injection. Other serotypes of botulinum toxin are being investigated as useful alternatives to botulinum toxin type A. Botulinum toxin type F differs from type A, mainly by its lower potency, efficacy and shorter duration of action.[91] Botulinum toxin type F blocks a different SNARE protein as compared to type A toxin. Therefore, a combination of toxins A and F has been suggested to reduce the total units required, and therefore the overall antigenic dose.[92]

Conclusion

The use of botulinum toxins has revolutionised the treatment of various ophthalmic plastic disorders from facial dystonias to periocular wrinkles. In future, we are likely to see the development of new potent toxins with increasing effectiveness and duration of effect. The ophthalmologist should be aware of this expanding and interesting field of chemodenervation, and use it to the fullest potential.

 

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Figures

[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10], [Figure - 11], [Figure - 12]

Tables

[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]

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