Published on February 19, 2014
BY DR SIDDHI TIWARI MODERATOR : DR SAROJ PUROHIT
HISTORICAL ASPECT A German poet, doctor and scientist , Dr. Justinus Kerner of Wurttemberg, first explained the disease called botulism (1817 to 1822) caused by ‘sausage poison’. Already imagined that the toxin that caused such a serious disease, could be used to treat diseases like muscular spasms. Dr Emile Pierre van Ermengem (belgium) in 1895 successfully isolated this bacterium, named it Bacillus botulinus. Botulinum toxin was first used to treat human disease (1980) by Drs Alan Scott (opthalmologist) and Edward Schantz, in treating strabismus.
In 1987, ophthalmologist Jean Carruthers observed that frown lines disappeared after the use of botulinum toxin A for blepharospasm. In 1996, they published the first paper on the use of Botox for cosmetic purposes. In 2002, the FDA announced the approval of BOTOX® Cosmetic to temporarily improve the appearance of moderate-to-severe frown lines between the eyebrows (glabellar lines). In July 2004, the FDA approved BOTOX® to treat severe underarm sweating, known as primary axillary hyperhidrosis, that cannot be managed by topical agents.
Microbiology Botulinum toxin (BTX or BoNT) is produced by Clostridium botulinum, a gram-positive anaerobic, spore forming bacillus. BoNT is broken into 7 neurotoxins (labeled as types A, B, C [C1, C2], D, E, F, and G), which are antigenically and serologically distinct but structurally similar. Type A is the most potent toxin, followed by types B and F toxin. Human botulism is caused mainly by types A, B, E, and (rarely) F. Types C and D cause toxicity only in animals.
The BoNT molecule is synthesized as a single chain (150 kD) and then cleaved to form the dichain molecule with a disulfide bridge.
The light chain (~50 kD) acts as a zinc (Zn2+) endopeptidase similar to tetanus toxin with proteolytic activity located at the N-terminal end. The heavy chain (~100 kD) provides cholinergic specificity and is responsible for binding the toxin to presynaptic receptors, it also promotes lightchain translocation across the endosomal membrane.
MECHANISM OF ACTION Botulinum toxins act at four different sites in the body: The neuromuscular junction Autonomic ganglia Postganglionic parasympathetic nerve endings Postganglionic sympathetic nerve endings that release acetylcholine.
Release of acetylcholine at the neuromuscular junction is mediated by the assembly of a synaptic fusion complex. Allows the membrane of the synaptic vesicle containing acetylcholine to fuse with the neuronal cell membrane. The synaptic fusion complex is a set of SNARE proteins, which include synaptobrevin, SNAP-25, and syntaxin. After membrane fusion, acetylcholine is released into the synaptic cleft and then bound by receptors on the muscle cell.
Botulinum toxin binds to the neuronal cell membrane at the nerve terminus and enters the neuron by endocytosis. The light chain of botulinum toxin cleaves specific sites on the SNARE proteins, preventing complete assembly of the synaptic fusion complex thereby blocking acetylcholine release. Botulinum toxins - types B, D, F, and G cleave synaptobrevin -types A, C, and E cleave SNAP-25 -type C cleaves syntaxin. Without acetylcholine release, the muscle is unable to contract.
Induces weakness of striated muscles by inhibiting transmission of alpha motor neurones at the neuromuscular junction. This has led to its use in conditions with muscular overactivity, such as dystonia. Transmission is also inhibited at gamma neurones in muscle spindles, which may alter reflex overactivity. Also inhibits release of acetylcholine in all parasympathetic and cholinergic postganglionic sympathetic neurons. This has generated interest in its use as a treatment for overactive smooth muscles (for eg, achalasia) or abnormal activity of glands (for eg, hyperhidrosis).
The toxin requires 24-72 hours to take effect, reflecting the time necessary to disrupt the synaptosomal process. In very rare circumstances, some individuals may require as many as five days for the full effect to be observed. Peaking at about 10 days, the effect of botulinum toxin lasts nearly 8-12 weeks.
PREPARATION Serotype A is the only commercially available form of botulinum toxin for clinical use, although experience is emerging with development of other serotypes B, C, and F . The products and their approved indications include the following: OnabotulinumtoxinA (Botox, Botox Cosmetic) Botox - Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm, neurogenic detrusor overactivity, chronic migraine, upper limb spasticity Botox Cosmetic - Moderate-to-severe glabellar lines AbobotulinumtoxinA (Dysport) - Cervical dystonia, moderate-to- severe glabellar lines IncobotulinumtoxinA (Xeomin) - Cervical dystonia, blepharospasm Rimabotulinumtoxin B (Myobloc) - Cervical dystonia
The potency of BoNT-A is measured in mouse units (MU). One MU of BoNT-A is equivalent to the amount of toxin that kills 50% of a group of 20 g Swiss-Webster mice within 3 days of intraperitoneal injection (LD50). According to one report, 1 nanogram of toxin contains approximately 20 U of BOTOX® (ie, 1 U of BOTOX® is equal to approximately 0.05 nanogram of the toxin). One unit of BOTOX® has a potency that is approximately equal to 4 unit of Dysport®. one unit of Xeomin® is equal to 1 unit of Botox®
DERMATOLOGICAL INDICATIONS AESTHETIC INDICATIONS Botox® is indicated for all wrinkles produced due to persistent muscular contractions. These include horizontal forehead lines glabellar lines and vertical frown lines crow's feet bunny lines marionette lines dimpled chin platysmal bands. Dynamic wrinkles respond better than fixed wrinkles. NON AESTHETIC INDICATIONS Localized axillary or palmar hyperhidrosis that is nonresponsive to topical or systemic treatment.
THERAPEUTIC USES Cosmetic use Hyperkinetic facial lines (glabellar frown lines, crow's feet) Hypertrophic platysma muscle bands Sweating, salivary, and allergy disorders Axillary and palmar hyperhidrosis Frey syndrome, also known as auriculotemporal syndrome (gustatory sweating of the cheek after parotid surgery) Drooling in cerebral palsy and other neurological disorders Nasal allergy Strabismus and nystagmus Smooth muscle hyperactive disorders Neurogenic bladder – Detrusor hyperreflexia, BPH Achalasia cardia Hemorhoids, Chronic anal fissures Focal dystonias - Involuntary, sustained, or spasmodic patterned muscle activity Cervical dystonia (spasmodic torticollis)[3, 4] Blepharospasm (eyelid closure) Laryngeal, Limb, Oromandibular, Orolingual, Truncal dystonia Spasticity Nondystonic disorders of involuntary muscle activity Hemifacial spasm, trismus Tremors, tics, myoclonus. Chronic pain and disorders of localized muscle spasms Chronic low back pain Tension headache Chronic migrane headache Medication overuse headache Lateral epicondylitis Knee, Shoulder,Neuropathic pain
CONTRAINDICATIONS 1. 2. 3. 4. Patients afflicted with a preexisting motor neuron disease, myasthenia gravis, Eaton-Lambert syndrome, neuropathies, psychological unstability. History of reaction to toxin or albumin. Pregnancy and lactating females. Infection at the injection site. RELATIVE CONTRAINDICATIONS Some medications decrease neuromuscular transmission, generally should be avoided in patients treated with botulinum toxin. Includes aminoglycosides (may increase effect of botulinum toxin) penicillamine, quinine, chloroquine and hydroxychloroquine (may reduce effect) calcium channel blockers, and blood thining agents eg. warfarin or aspirin (may result in bruising).
Preoperative Counseling and Informed Consent Detailed counseling with respect to the treatment, desired effects, and longevity of the results should be discussed . A detailed consent form needs to be completed by the patient. Should include the type of botulinum toxin, longevity expected, need for repeated treatments and possible postoperative complications. Preoperative photography is mandatory.
Reconstitution and Handling 1. 2. 3. 4. 5. Follow all usual precautions of sterility and skin preparation before injection. Seat the patient with chin down and head slightly lower than the physician's. Plastic single use insulin syringes with 30-32 gauge needles are recommended, and toxin is injected into affected muscles or glands Topical anesthetics are generally reserved for the very sensitive. Ice could be used as a numbing agent. Doses are tailored according to the mode of use and individual patients, and the dose depends on the mass of muscle being injected: The larger the muscle mass the higher the dose required.
Electromyograph monitoring Administer injections under the guidance of electromyograph (EMG) monitoring. Technique involves using a 27-gauge (1.5 in) polytef-coated EMG needle connected to an EMG recorder by an alligator clip on its shaft. The patient is asked to contract the muscle in question. The injection is placed where the maximal EMG recording can be found within the muscle. This technique ensures that the injection is at the point of the muscle that is contributing most to the hyperfunctional facial line. As these injections have become routine,. EMG-guided injections remain a useful adjunct in patients who have residual function after their initial injection.
The Glabellar Complex and Vertical Frown Lines Glabella lines are created by the action of 3 muscles: the corrugator supercilli; the procerus; and the depressor superciliis. Before initiating the treatment, Assess facial expression at rest and during animation. Evaluate the range of motion of involved muscles. Palpate muscles during repose and contraction. Assess brow position Injections given into the corrugator (red and blue circles) and procerus (green circle) muscles. Caution : Avoid injecting too low over the orbit. Use caution with lateral brow injections; stay well above the superior orbital rim. Do not completely paralyze the muscles.
The 52-year-old female patient, frowning in both photos, as she looked before and 32 days after treatment
Horizontal Forehead Lines Muscle : frontalis The treatment goal is to achieve a balance between brow elevation with forehead smoothing. Before initiating the treatment, evaluate the patient's anatomy for expressivity, muscle mass, symmetry, lateral v/s medial movement, compensation for brow ptosis, and a narrow or wide brow. injection given at blue circles and optional red Xs. Caution : Less experienced injectors of botulinum toxin type A should stay at least 2 cm above the brow. Ensure that injection sites are lateral enough to avoid a quizzical eyebrow appearance.
The patient is seen rest before and 33 days after treatment. forehead lines are fairly effaced and she now has decent brow position. The same patient is shown with raised eyebrows before and 33 days after treatment. The patient has relatively normal brow position, and softening of rhytids without dropping of the brows.
Crow's Feet Contraction of orbicularis oculi muscle. The treatment goal is reducing dynamic rhytides and softening static rhytides. Before initiating the treatment, Determine the source of the wrinkles - the orbicularis oculi vs zygomaticus major. Assess while the patient animates and while he is at rest. "snap test" to measure skin laxity along the lower lid margin. Injection given in each of the 3 blue circles (photo) on each side and the red X’s. Caution : Treat around the lower third of the canthal area with caution. Avoid the area below the zygomatic arch and the zygomaticus major muscle. Injection into this area has the potential to cause lip and cheek ptosis. Avoid veins, and treating patients who have a history of dry eyes. Keep injections superficial; use intradermal or subdermal blebs with the needle oriented away from the orbit
Patient depicted 17 days after treatment for crow's feet. Smiling without crow's feet wrinkles.
Bunny Lines Contraction in the transverse portion of the nasalis. The treatment goal is to soften the bunny lines on smiling. Before initiating the treatment, Patients should be asked to laugh, sniff, and to squint intensely, only become evident when smiling at maximum contraction. Injections given into the two blue circles. Sometimes an additional dorsal injection is required. Caution : Avoid injecting in the levator labii alaeque nasi and the levator labii superioris to prevent drooping of the upper lip. Do not massage vigorously or in a downward direction, could result in lip ptosis. Keep injections superficial in this vascularized area to avoid bruising.
The patient shown 17 days after treatment for bunny lines, with good result. Patient expression alternates from rest to "scrunching."
Dimpled Chin (Peau D'orange) Contraction of the mentalis : causes a "cobblestone" appearance of the skin and possible deepening of the mentolabial crease. Treatment goal is to reduce the chin dimpling which adds to the rejuvination of lower face. Before initiating treatment, Patient asked to animate which brings out the wrinkles. Typical treatment is via 1 central or 2 lateral injections, about one half to 1 cm above the chin (blue ovals) Injections should be kept at least 1 cm from the lower lip. Caution: Avoid injecting the toxin too high, which can affect the orbicularis oris and cause lower lip incompetence and possibly, drooling. Avoid injection in the depressor labii, which can cause the lower lip to depress. Do not treat the case of dimpled chin who have hypertrophied mentalis.
The patient is shown alternating from rest to full expression 17 days after treatment of the chin. After treatment she is seen unable to flex her mentalis and cause a dimpled chin as she could before treatment.
Platysmal bands Occur due to diastasis of the midline platysmal muscle and loss of submental fat, give the appearance of turkey neck. The treatment aim is to Reducing vertical bands that appear when the patient contracts the platysma. Treated via a series of superficial/intradermal injections directly into the contracted muscular band. The number of injection points depends on length of each band. Grasping the band with the non-injecting hand might be helpful while injecting very superficially in the contracted muscle. Caution : Use caution to avoid dysphagia, dysphonia, and neck weakness; the strap muscles should be avoided. Platysmal band injections do not substitute for surgical procedures and will not correct skin laxity and fat deposits. So patients should be counselled to have realistic expectations.
The patient shown in full expression before and 17 days after treatment. Anterior vertical bands have disappeared.
Marionette Lines/ Depressed anguli oris (DOA) Contraction of the depressor anguli oris or DAO. Deep marionette lines give the impression of being unhappy. The aim of treatment is to reduce the muscular strength of the DAO and the fibers of the platysma and thereby induce a lift of the corners of the mouth while the patient is at rest. Typically treated via 1 injection point into the posterior aspect of each DAO. Injections should be at least 1 cm lateral to the mouth corner to avoid adverse outcomes. A second injection site may be added laterally to target the platysma. Caution: Avoid unintended placement of neurotoxin in the depressor labii inferioris. Titrating the dose, starting with a low dose and titrating up, is advised.
The patient is shown in the photo, in full expression, 28 days after treatment to her DAO. Neurotoxin treatment effectively softens marionette lines.
Botulinum Toxin in the Treatment of Hyperhidrosis Selective, focal chemodenervation may be achieved by injecting botulinum toxin intradermally to combat localized, but severe sweating in areas such as the palms, soles and axillae. Unlike sympathectomy, which renders > 20% of the body surface anhidrotic, thereby triggering compensatory sweating, treatment with botulinum toxin does not precipitate hyperhidrosis elsewhere as the total body surface area treated is < 3%. The extent of excessive sweating can be documented by employing the simple starch-iodine test. This should be carried out prior to regional nerve blocks or the use of topical anesthetics. The test can also help determine the approximate amount of the drug needed.
INJECTION TECHNIQUE The bevel should face upwards as the needle penetrates the skin almost parallel to it, and is then advanced for about 2 mm before injecting intradermally. The thumb is taken off the syringe plunger for a second or two before withdrawal. These measures help prevent backflow of botulinum toxin and its wastage. Avoid subcutaneous injections to prevent diffusion into intrinsic muscles of the palms and soles or beyond the targeted glands in the axillae.
Key considerations Palms and soles: Injections are placed about 1.5 cm apart. The total dose is dependent on the surface area and may range from 50-150 units per palm. Doses on the soles exceed those on the palms. A small zone of visible blanching attests to the deep dermal placement. Duration of effect varies from 3-12 months. Axillae: Injections are placed between 1.5 and 2.5 cm apart in 10-20 sites totaling approximately 50 units per axilla. Tiny intradermal wheals are raised beginning at the periphery of the hair-bearing skin and circling into the center of the axillary vault. Response times for duration of anhidrosis in the axillae range from 4-10 months.
Precautions after botulinum toxin injection Pt. should be instructed to contract the injected area for approximately 90 minutes to two hours, which will help in the uptake of the toxin. Avoid bending for a few hours after treatment to avoid potential diffusion. One should go home immediately and rest after Botox®.Do nothing strenuous for one or two days. Refrain from laser/IPL treatments, facials and facial massage for one to two weeks after injections. This is to minimize toxins dislodging and traveling (due to increased blood circulation or direct pressure) to the surrounding muscles.
Therapeutic failure Some patients do not respond to injections and, having never previously responded, are designated as primary nonresponders. Patients with rhytids that are not dynamic in origin (eg, photodamage, age-related changes) do not respond. Improper injection technique or the denatured toxin may also result into therapeutic failure Some patients may have neutralizing antibodies from prior subclinical exposure, or individual variations in docking proteins may exist Secondary nonresponders respond initially but lose the response on subsequent injections. Most of these patients may have developed neutralizing antibodies.
ADVERSE EVENTS Sequelae that can occur at any site include pain, edema, erythema, ecchymosis, injection site pain, and short-term hypersthesia. Generalised reactions including nausea, malaise, flu-like symptoms and cutaneous eruptions may result from diffusion of neurotoxin into the systemic circulation, and are treated supportively based on symptoms. Systemic reactions are considered hypersensitivity to BoNT or one of the components (i.e. albumin or lactose) in the suspension. Headaches were the most frequently reported adverse event in the initial trials of BoNTA-ONA for the treatment of glabellar lines, it is most likely a result of the injection technique and not the drug itself. Glabellar Region The most common complication in the treatment of the glabellar complex is ptosis of the upper eyelid. injections placed at or under the middle part between the eyebrows in the region of the midpupillary line. Caused by diffusion of the toxin through the orbital septum, where it affects the upper eyelid levator muscle. Occur as early as 48 hours or as late as 7-10 days following injection and can persist for 2-4 weeks. T/t : alpha-adrenergic agonists, apraclonidine 0.5% and phenylephrine hydrochloride (2.5%) eyedrops. The treatment is symptomatic and 1-2 drops three times a day must be continued until ptosis resolves.
Forehead The most significant complication of treatment of the frontalis is brow ptosis. Results from overaggressive treatment with injections being placed too low on the forehead or from poor patient selection. Treatment of the brow depressors (glabellar complex) can elevate the brow from 1-2 mm. Be conservative while treating forehead expression lines. Crow's Feet Complications in this area are bruising, diplopia, ectropion or a drooping lateral lower eyelid and an asymmetric smile caused by injection of the zygomaticus major. Lower face and neck An asymmetric smile, lip ptosis, cheek bite or incompetence of the mouth manifesting as drooling or dribbling, are potential complications resulting from the use of botulinum toxin in the treatment of the complex musculature of the lower face. Platysmal injections in large doses to treat prominent vertical bands and horizontal neck lines, may cause weakness of the neck flexors and dysphagia. Palmo-plantar hyperhydrosis Temporary hand weakness and reduction in fine motor skills which can last several weeks; thus, injection sites should be spaced appropriately and injections should be placed superficially.
TOPICAL BTX BoNTA cream based on commercially viable ionic nanoparticle technology. ( FDA approved in 2008) Other formulations are under development. Advantages over conventional injections : eliminate the need for multiple traumatic injections for better comfort self administration cause only a mild weakening; therefore, it is potentially safer for use in the areas where muscles are highly sensitive to smaller doses of the toxin.
Aesthetic Plast Surg. 2008 Sep;32(5):715-22; discussion 723. doi: 10.1007/s00266-008-9151-9. Epub 2008 May 15. Novel topical BoNTA (CosmeTox, toxin type A) cream used to treat hyperfunctional wrinkles of the face, mouth, and neck. Chajchir I, Modi P, Chajchir A. Abstract BACKGROUND: This study aimed to compare the effect of the stabilized novel topical botulinum neurotoxin type A (BoNTA) cream (CosmeTox) and a placebo cream on subjects, to compare clinician-reported outcomes, and to assess the safety and utility of the novel topical BoNTA cream for treating the entire upper face, chin, and neck areas. METHODS: This study randomized 40 female subjects to receive either topical BoNTA (CosmeTox) cream (2 U/ml) or an identical placebo cream (without BoNTA) on the face, chin, and neck areas. The subjects were followed for 12 weeks. The main outcome measures were the Facial Line Outcomes questionnaire scores and results from the Self-Perception of Age instrument, which assesses age of appearance relative to actual age. RESULTS: The BoNTA topical cream (CosmeTox) treatment produced significant improvements in the Facial Lines Outcome scores, which were maintained throughout the study period and lasted more than 3 months. The BoNTA topical cream treatment also reduced the age of appearance for a majority of subjects. The placebo had no effect on any measure. No serious adverse events occurred during the entire study period. CONCLUSION: Topical treatment with the stabilized BoNTA cream (CosmeTox) to the entire upper facial lines resulted in significantly improved facial features and age appearance, as measured by the subjects and clinicians. The BoNTA cream (CosmeTox) resulted in a significantly younger, more satisfying, relaxed appearance.
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