|Year : 2005 | Volume
| Issue : 4 | Page : 279-288
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
Milind N Naik
Division of Ophthalmic Plastic Surgery, L. V. Prasad Eye Institute, Hyderabad - 500 034
Source of Support: None, Conflict of Interest: None
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
|How to cite this article:|
Naik MN, Soparkar CN, Murthy R, Honavar S G. Botulinum toxin in ophthalmic plastic surgery. Indian J Ophthalmol 2005;53:279-88
|How to cite this URL:|
Naik MN, Soparkar CN, Murthy R, Honavar S G. Botulinum toxin in ophthalmic plastic surgery. Indian J Ophthalmol [serial online] 2005 [cited 2020 Oct 22];53:279-88. Available from: https://www.ijo.in/text.asp?2005/53/4/279/18915
| Botulism|| |
Botulism has accompanied mankind since the beginning. In the medieval times, it was known that production of sausages bears a high risk of food poisoning. In 1822, Justinus Kerner, a German physician described the clinical picture of Botulism, and ascribed it to botulinum toxin, which is an exotoxin produced by the naturally ubiquitous bacterium Clostridium botulinum , a gram-positive, spore-forming, anaerobic rod commonly found on plants, in soil, water and the intestinal tracts of animals and fish. Botulism may develop hours to days (usually 18-36 h) after ingestion of toxin, the symptoms consist of progressive weakness, dizziness, blurred vision, difficulty in speech and swallowing, and finally respiratory distress. While mere nanograms of toxin may cause symptoms, the lethal dose in an adult human is estimated to be 0.1 mg injected intravenously, 1.0 mg inhaled, or 70 mg ingested orally.
| From terror to treatment|| |
Botulinum toxin, once touted as the 'most poisonous poison' is now one of the most frequently used medications in ophthalmic plastic surgery, and the far-sighted innovators of this poison-turned-medication certainly bear recognition. The organism C. botulinum was originally isolated by Professor E Van Ermengem in 1895. In the 20 years that followed its initial discovery, different strains of the organism were identified which produced distinct forms of botulinum toxin. Dr Conrad Behrens perhaps first conceived the concept of injecting pharmacological agents into extraocular muscles to paralyse them as an alternative to strabismus surgery. In 1973, Dr Alan Scott and co-workers attempted to paralyse the extraocular muscles of rhesus monkeys with multiple materials, such as alcohol, di-isopropyl flurophosphate, alpha-bungarotoxin and botulinum type A toxin. He demonstrated the effectiveness of botulinum toxin type A for the management of strabismus in humans. Later, botulinum toxin was subsequently approved for the treatment of numerous disorders of spasticiy including blepharospasm, hemifacial spasm and Meige's syndrome in 1989. Over the subsequent 30 years, botulinum toxins have been used to treat a host of other conditions, and are currently used in almost every sub-specialty of medicine [Table - 1]. Its various applications in ophthalmic plastic surgery are listed in [Table - 2].
| Pharmacology|| |
Types of botulinum toxin
C. botulinum elaborates eight antigenically distinguishable exotoxins (A, B, C1, C2, D, E, F and G), and types A, B and E are commonly associated with systemic botulism in humans. Type A is the most potent toxin, followed by types B and F toxin. These also represent the most commonly used commercial preparations of botulinum toxin.
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. ,, 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. 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. Botox“ (Allergan Inc., Irvine, CA, USA) and Dysport“ (Ipsen Pharmaceuticals, France) are the type A toxins. Myobloc“ (Elan Pharmaceuticals, San Diego, CA, USA) is the type B toxin. Botulinum toxin type B is also marketed in Europe by the name Neurobloc“ by Elan Pharma International Limited, Ireland. Type A toxin is easily producible in culture in a highly purified, stable and crystalline form. Type A toxin also has the longest duration of action, and a favourable ratio between biologically active and inactive neurotoxin. Botox“ 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 Botox“ 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. Dysport“ is also produced in a dried formulation. This dried toxin A has to be stored at -5įC until reconstitution. Myobloc“ is a sterile liquid formulation of purified neurotoxin type B produced by fermentation of Bean strain of the bacterium C. botulinum type B. Myobloc“ 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 Myobloc“ vials are stable for 30 months when refrigerated, and for 9 months at room temperature. 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, the greater acidity of its storage medium translates to greater discomfort upon injection. Moreover, Botox“ is 50-100 times more potent than Myobloc“ 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.
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 Dysport“ to Botox“ has been suggested to be 3: 1 or 4: 1 by various studies in patients with Blepharospasm and hemifacial spasm.,, Therefore, when communicating dose information about botulinum toxins, it is very important to specify the particular brand of toxin being used.
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. This has also been linked to early re-injection into muscles. Others have reported absence of antibody production. 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. Botox“, Dysport“ and Myobloc“ contain human serum albumin (HSA) to stabilise neurotoxin complex and prevent it from aggregating onto surfaces., 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. 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 Botox“, has reduced from 25 to 5 ng per 100 U vial, thereby reducing the total albumin load and its attendant risks (Data on File, Botox“, Allergan). The ophthalmologists using botulinum toxin should however be aware of the presence of HSA and its implications.
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 Botox“ to be used within 4 hours of reconstitution, and earlier reports 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, to 6 weeks. 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.
Botulinum toxins have revolutionised the treatment of patients with facial dystonias. The success rate is reported to be over 90%.
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. 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. ,,, The aetiology of blepharospasm is considered to be an organic dysfunction of the rostral brainstem.,, 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.
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. 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. It generally results from mechanical-vascular compression of the seventh cranial nerve root in the cerebello-pontine angle. Less than 1% are caused by posterior fossa tumours, therefore a magnetic resonance imaging may be indicated in patients with HFS. Although neurosurgical microvascular decompression procedure may be the definitive form of treatment, 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 Botox“ (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. 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.
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. 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. Apraxia of lid opening is often associated with blepharospasm, and botulinum toxin injection has been shown to improve lid opening delays in ALO.
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,, 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., Heyworth in 1994 reported three cases of persisting hypotropias following temporary induction of ptosis with botulinum toxin. A recent report using 5 U of Botox“ reported onset of ptosis in an average of 4 days, and duration lasting 46 days. 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 Botox“ 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. ,,
Lower eyelid senile entropion
One of the aetiologies of lower eyelid senile entropion is the overriding of preseptal orbicularis muscle over pretarsal orbicularis muscle. Several reports have shown the effectiveness of botulinum toxin injection into the lower orbicularis muscle for temporary control of lower eyelid entropion.,,, 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,, and toxin therapy had no adverse effects on results of surgical entropion repair.Approximately 10-20 U of Botox“ 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, 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), Hofmann (15 U of Botox“), Keegan et al. (20 U of Dysport“), and Montoya et al. (20 U of Dysport“) with intra and periglandular injection of botulinum toxin. Ptosis and superior rectus underaction are common side effects.
Frey's syndrome or 'auriculo-temporal syndrome' is characterised by ipsilateral excessive facial sweating while eating. This typically follows parotid surgery, 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 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 Botox“,, and 10 or 20 U/cm2 for Dysport“. There is some evidence to suggest that neuronal regeneration may take much longer within the autonomic nervous system., 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. Botulinum toxin has also been successively used for treatment of idiopathic craniofacial hyperhidrosis, and diabetic autonomic gustatory sweating. 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.
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. 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. This can prove to be a useful adjunct in the management of dry eye patients.
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. 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.,,
A consensus panel has recently published guidelines and recommendations for the use of botulinum toxin in a wide range of aesthetic applications.
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 (Botox“) are injected at five to seven sites into both corrugators and into the procerus muscle. ,,
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].,,
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. Injection into the zygomaticus major can cause ipsilateral lip ptosis, and should thus be avoided. Lower eyelid injection with 2 U of botox can widen the eye with reduction in infraorbital wrinkles.
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.,
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,, and Tension type headache. 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.
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. 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.
| 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.
| References|| |
Stephen S. Arnon. Botulinum Toxin as a Biological Weapon: Medical and Public Health Management. JAMA
Lamanna C. The most poisonous poison.Science 1959;130:763-72.
Klein AW. Botulinum toxins. Introduction. Semin Cutan Med Surg
Scott AB. Botulinum toxin injection of eye muscles to correct strabismus. Trans Am Ophthalmol Soc
Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology
Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ
: Ellenhorn MJ, Barceloux DG, editors. Medical Toxicology. Diagnosis and Treatment of Human Poisoning. New York: Elsevier; 1988. p. 1185-7.
Melling J, Hambleton P, Shone CC. Clostridium botulinum toxins: nature and preparation for clinical use. Eye
Sellin LC. The pharmacological mechanism of botulism. Trends in Pharma Sci
Stanley EF, Drachman DB. Botulinum toxin blocks quantal but not non-quantal releasee of ACh at the neuromuscular junction. Brain Res
Angaut-Petit D, Molgo J, Comella JX, Faille L, Tabti N. Terminal sprouting in mouse neuromuscular junctions poisoned with botulinum type A toxin: morphological and electrophysiological features. Neuroscience
Schantz EJ, Scott AB. Use of crystalline type A botulinum toxin in medical research. In
: Lewis GE, editor. Biomedical aspects of Botulism. New York: Academic Press; 1981. p. 143-9.
Botulinum toxin advancement. Dermatology times
Flynn TC, Clark RE 2nd edn. Botulinum toxin type B (MYOBLOC) versus botulinum toxin type A (BOTOX) frontalis study: rate of onset and radius of diffusion. Dermatol Surg
Hoffman RO, Helveston EM. Botulinum in the treatment of adult motility disorders. Int Ophthalmol Clin
Krack P, Deuschl G, Benecke R, Ceballos-Baumann AO, Marion MH, Oertel WH, et al
. Dose standardization of botulinum toxin. Mov Disord
Marion MH, Sheehy M, Sangla S, Soulayrol S. Dose standardization of Botulinum toxin. J Neurol Neurosurg Psychiatr
Sampaio C, Ferreira JJ, Simoes F, Rosas MJ, Magalhaes M, Correia AP, et al
. Dysbot: a single blind, randomized clinical trial to compare two different formulations of botulinum toxin type A. Mov disord
Frueh BR, Felt DP,Wojno TH, Musch DC. Treatment of Bepharospasm with Botulinum Toxin. A preliminary report. Arch Ophthalmol
Scott KB, Kennedy RA, Harrison AS. Botulinum A toxin injection as a treatment for blepharospasm. Arch Ophthalmol 1985;103:347.
Biglan AW, Gonnering R, Lockhart LB, Rabin B, Fuerste FH. Absencee of Antibody production in patients treated with Botulinum A Toxin. Am J Ophthalmol
Ludlow CL, Hallett M, Rhew K, Cole R, Shimizu T, Sakaguchi G, et al
. Therapeutic use of type F Botulinum toxin. N Engl J Med
Botox. Irvine, Calif: Allergan Inc; 2001.
Dysport. Slough, Berkshire, England: Ipsen Ltd; 2001.
Nunnery A. Risk of Infectious Amyloid transmission with the use of allografts and xeografts. Presented at: Annual Meeting of the American Society of Ophthalmic Plastics and Reconstructive Surgery 2000.
Dunlop D, Pittar G, Dunlop C. Botulinum toxin in ophthalmology. Aust NJ Ophthalmol
Klein AW. Dilution and storage of Botulinum toxin. Dermatol Surg
Lowe NJ. Botulinum toxin type A for facial rejuvenation: United States and United Kingdom perspectives. Dermatol Surg
Hexsel DM, De Almeida, Rutowitsch M. Multicenter, Double-Blind Study of the Efficacy of Injections With Botulinum Toxin Type A Reconstituted Up to Six Consecutive Weeks Before Application. Dermatol Surg
De Almeida, Kadunc BV, Chiacchio ND. Foam During Reconstitution Does Not Affect the Potency of Botulinum Toxin Type A. Dermatol Surg
Dutton JJ, Buckley EG. Long term results and complications in the treatment of blepharospasm. Ophthalmology
Jankovic J, Orman J. Blepharospasm: Demographic and clinical survey of 250 patients. Ann Ophthalmol
Scott AB. Botulinum treatment for blepharospasm, In
: Smith BC, editors. Ophthalmic Plastic and Reconstructive Surgery. St Louis: CV Mosby; 1987. p. 609-13.
Wirtschsfter JD. Clinical doxorubicin chemomyectomy. An experimental treatment for benign essential blepharospasm and hemifacial spasm. Ophthalmology
Malinovsky V. Benign essential blepharospasm. J Am Optometric Assoc
Jankovic J, Nutt JG. Blepharospasm and cranial-cervical dystonia (Meige's syndrome: Familial occurrence. Adv Neurol
Jankovic J, Ford J. Blepharospasm and orofacial-cervical dystonia: Clinical and pharmacological findings in 100 patients. Ann Neurol
Janati A, Metzer WS, Archer RL, Nickols J, Raval J. Blepharospasm associated with olivopontocerebellar atrophy. J Clin Neuro-ophthalmol
Anderson RL, Patel BC, Holds JB. Blepharospasm: past, present and future. Ophthal Plast Reconstr Surg
Digre K, Corbett JJ. Hemifacial spasm: differential diagnosis, mechanism, and treatment. Adv Neurol
Loeser JD, Chen J. Hemifacial spasm: treatment by microsurgical facial nerve decompression. Neurosurgery
Sprik C, Wirtschafter JD. Hemifacial spasm due to intracranial tumor. An international survey of botulinum toxin investigators. Ophthalmology
Cakmur R, Ozturk V, Uzunel F. Comparison of pre-septal and pre-tarsal injections of botulinum toxin in the treatment of blapharospasm and hemifacial spasm. J Neurol
Defazio G, Abbruzzese G, Girlanda P, Vacca L, Curra A, De Salvia R, et al
. Botulinum toxin A treatment for primary hemifacial spasm: ten year multicenter study. Arch Neurol
Jordan DR, Anderson RL, Digre KB.Apraxia of lid opening in blepharospasm. Ophthalmic Surg
Tozlovanu V, Forget R, Iancu A, Boghen D. Prolonged orbicularis oculi activity: a major factor in apraxia of lid opening. Neurology
Forget R, Tozlovanu V, Iancu A, Boghen D. Botulinum toxin improves lid opening delays in blepharospasm-associated apraxia of lid opening. Neurology
Magoon EH. Botulinum toxin for treatment of blepharospasm, corneal exposure, and entropion. J Ocul Ther Surg
Kirkness CM, Adams GG, Dilly PN, Lee JP. Botulinum toxin-A induced protective ptosis in corneal disease. Ophthalmology
Adams GG, Kirkness CM, Lee JP. Botulinum toxin a induced protective ptosis. Eye
Heyworth PL, Lee JP. Persisting hypotropias following protective ptosis induced by botulinum neurotoxin. Eye
Ellis MF, Daniell M. An evaluation of the safety and efficacy of botulinum toxin type A (BOTOX) when used to produce a protective ptosis. Clin Exp Ophthalmol
Scott AB. Injection treatment of endocrine orbital myopathy. Doc Ophthalmol
Traisk F, Tallstedt L. Thyroid associated ophthalmopathy: botulinum toxin A in the treatment of upper eyelid retraction - a pilot study. Acta Ophthalmol Scand
Uddin JM, Davies PD. Treatment of upper eyelid retraction associated with thyroid eye disease with subconjunctival botulinum toxin injection. Ophthalmology
Clarke JR, Spalton DJ. Treatment of senile entropion with botulinum toxin. Br J Ophthalmol
Carruthers J, Stubbs HA. Botulinum toxin for benign essential blepharospasm, hemifacial spasm, and age-related lower eyelid entropion. Can J Neurol Sci
Magoon EH. Botulinum toxin for treatment of blepharospasm, corneal exposure, and entropion. J Ocul Ther Surg
Steel DH, Hoh HB, Harrad RA, Collins CR. Botulinum toxin for the temporary treatment of involutional lower lid entropion: a clinical and morphological study. Eye
Riemann R, Pfennigsdorf S, Riemann E, Naumann M. Successful treatment of Crocodile tears by injection of botulinum toxin into the lacrimal gland. Ophthalmology
Hofmann RJ. Treatment of Frey's syndrome (Gustatory sweating) and 'Crocodile tears'(Gustatory epiphora) with purified botulinum toxin. Ophthalmic Plast Reconstr Surg
Keegan DJ, Geerling G, Lee JP, Blake G, Collin JR, Plant GT. Botulinum toxin treatment for hyperlacrimation secondary to aberrant regenerated seventh nerve palsy or salivary gland transplantation. Br J Ophthalmol
Montoya FJ, Riddell CE, Caesar R, Hague S. Treatment of gustatory hyperlacrimation (crocodile tears) with injection of botulinum toxin into the lacrimal gland. Eye
Eckardt A, Kuettner C. Treatment of gustatory sweating (Frey's syndrome) with botulinum toxin A. Head Neck
Beerens AJ, Snow GB. Botulinum toxin A in the treatment of patients with Frey syndrome. Br J Surg
Guntinas-Lichius O. Increased botulinum toxin type A dosage is more effective in patients with Frey's syndrome. Laryngoscope 2002;112:746-9.
Shelley WB, Talanin NY, Shelley ED. Botulinum toxin therapy for palmar hyperhidrosis. J Am Acad Dermatol
Odderson IR. Axillary hyperhidrosis:treatment with botulinum toxin A. Arch Phys Med Rehabil
Boger A, Herath H, Rompel R, Ferbert A. Botulinum toxin for treatment of craniofacial hyperhidrosis. J Neurol
Restivo DA, Lanza S, Patti F, Giuffrida S, Marchese-Ragona R, Bramanti P, et al
. Improvement of diabetic autonomic gustatory sweating by botulinum toxin type A. Neurology
Putterman AM. Botulinum toxin injections in the treatment of seventh nerve misdirection. Am J Ophthalmol
Whittaker KW, Matthews BN, Fitt AW, Sandramouli S. The use of botulinum toxin A in the treatment of functional epiphora. Orbit
Sahlin S, Chen E, Kaugesaar T, Almqvist H, Kjellberg K, Lennerstrand G. Effect of eyelid botulinum toxin injection on lacrimal drainage. Am J Ophthalmol
Carruthers J, Carruthers A. Treatment of glabellar frown lines with C. Botulinum toxin A exotoxin. J Dermatol Surg Oncol
Cather JC, Cather JC, Mentor A. Update on Botulinum toxin in facial aesthetics. Dermatol Clin
Foster JA, Wulc AE, Holk DE. Cosmetic indications for Botulinum toxin. Sem Ophthalmol
Carruthers J, CArruthers A.Botulinum toxin (Botox) chemodenervation for facial rejuvenation. Facial Plast Surg Clin N Am
Caruthers J, Fagien S, Matarasso SL. Consensus Recommendations on the use of Botulinum toxin type. A in Facial Aesthetics. Plast Reconstr Surg
Ozsoy Z, Aydm G, Genc B. Two plane injection of botulinum toxin for the treatment of glabellar frown lines. Plast Reconstr Surg
Carruthers JA, Lowe NJ, Menter MA, Gibson J, Nordquist M, Mordaunt J, et al
. A multicenter, double blind, randomized, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol
Heckmann M, Schon-Hupka G. Quantification of the efficacy of botulinum toxin type A by digital image analysis. J Am Acad Dermatol
Lowe NJ, Lask G, Yamauchi P, Moore D. Bilateral, double-blind, randomized comparison of 3 doses of botulinum toxin type A and placebo in patients with crow's feet. J Am Acad Dermatol
Matarasso SL, MAtarasso A. Treatment guidelines for botulinum toxin type A for the periocular region and a report on partial upper lip ptosis following injections to the lateral canthal rhytids. Plast Reconstr Surg
Flynn TC, Carruthers JA, CArruthers JA. Botulinum-A toxin treatment of the lower eyelid improves infraorbital rhytides and widens the eye. Dermatol Surg
Huang W, Rogachefsky AS, Foster JA. Browlift with botulinum toxin. Dermatol Surg
Huigol SC, Carruthers A, Carruthers JD. Raising eyebrows with botulinum toxin. Dermatol Surg
Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM. Botulinum toxin type A in the treatment of migraine headaches:an open label study. Otolaryngol Head Neck Surg
Silberstein SD, Mathew N, Saper J, Jenkins S. Botulinum tosin type A as a migraine preventive treatment. Headache
Relja MA, Korsic M. Treatment of Tension type headache by injection of botulinum toxin type A: double blind placebo-controlled study. Neurology
Cosmetic and Clinical Applications of Botulinum toxin. William J Lipham. Slack Inc
Kauffman JA, Way JF Jr, Siegel LS, Sellin LC. Comparison of the action of types A and F botulinum toxin at the rat neuromuscular junction. Tox Appl Pharmacol
Mezaki T, Kaji R, Brin MF. Combined use of type A and F botulinum toxins for blepharospasm: a double-blind controlled trial. Mov Disord
[Figure - 1], [Figure - 2], [Figure - 3], [Figure - 4], [Figure - 5], [Figure - 6], [Figure - 7], [Figure - 8], [Figure - 9], [Figure - 10], [Figure - 11], [Figure - 12]
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5], [Table - 6]