Clinical Use of Botulinum Toxins in Oral and Maxillofacial Surgery

Sanchit GoyalPG Trainee

Contents• Introduction• History• Bacteriology• Structure and Toxicity• Mechanism of Action• Preparations • Cosmetic Uses• Therapeutic Uses• Complications • Contraindications

Introduction

• Botulinum toxin (BTX) is a neurotoxic protein produced by the bacterim Clostridium botulinum and related species.

• Infection with the bacterium may result in a potentially fatal disease called botulism.

• Human median lethal dose(LD50) of 1.3-2.1ng/kg IV or IM and 10-13 ng/kg when inhaled

• Commercially available BTX are Type A and B.• Widely used in cosmetic applications for the

treatment of facial wrinkles, TMJ disorders, sialorrhea, headache and neuropathic facial pain, muscle movement disorders and facial nerve palsy.

Commercial Available Brands

History • Idea of therapeutic use was first developed by

Justinus Kerner; called it ‘sausage poison’.• In 1870, Muller coined the term botulism.• 1897, Emile Van Ermengem isolated the

bacteria from the ham and produced the disease in lab animals.

• BTX was developed as a biological weapon in 20th century by many countries.

• Therapeutic use of BTX-A was studied in primates by Scott et al in 1973.

• In late 1970s toxin was introduced as a therapeutic agent for treatment of strabismus.

• In 1988, used for treating wrinkles and aging skin.

• Niamtu reported on the use of BTX for facial rhytids and dynamic lines in 1999 and 2000.

• During the mid- and late-1990s, BTX was used for lateral canthal lines (crow’s feet), platysmal banding, orbicularis oris injection, masseter muscle injection and the treatment of TMDs.

Bacteriology • Clostridium species bacteria are sporulating,

obligate anaerobic, Gram-positive bacilli.• Spores of C. botulinum are ubiquitous,

distributed widely in soil and marine sediments worldwide and often found in the intestinal tract of domestic grazing animals.

• Under appropriate environmental or laboratory conditions, spores can germinate into vegetative cells that will produce toxin.

• C. botulinum grows and produces neurotoxin in the anaerobic conditions frequently encountered in the canning or preservation of foods.

• Seven different strains of Clostridium have been described (A, B, C (1 and 2), D, E, F and G).

• Humans can be affected by the toxins of 5 strains (A, B, E, F and G)

Structure and Toxicity

• Toxins produced by clostridial bacteria are high-molecular-weight protein complexes that include 3 key proteins: a 150- kDa toxin, a non-toxin hemagglutinin protein, and a non-toxin non-hemagglutinin protein.

• Disulfide and noncovalent bonds link the heavy and light chains, and both chains are required for neurotoxicity.

• BTX is the most toxic material known• It is 4 times more lethal in mice than tetanus

toxin, 1 X1010 more lethal than curare, and 100 X 1010 more lethal than sodium cyanide.

• Based on findings from primate studies, human LD50 for intramuscular BTX injection is estimated at 2500–3000 U for a 70-kg adult (35–40 U/kg).

Mechanism of Action• BTX is a protease that causes temporary chemical

denervation of skeletal muscle by blocking the Ca+2-mediated release of acetylcholine from nerve endings of alpha and gamma motor neurons (myoneural junction), producing a transient dose dependent weakening of the muscle activity rendering it nonfunctional without systemic effects.

• This inhibition of muscular contraction is believed to be followed by the sprouting of new axon terminals, which results in synaptic regeneration and the reestablishment of neuromuscular transmission.

• The area of flaccidity produced may be larger than the area of muscle denervated as a result of postulated paralysis of gamma motor neurones, so the output of the muscle spindles is reduced leading to reduced muscular contraction at adjacent sites within the injected muscle.

• Weakening of surrounding muscles not injected may also occur because of toxin diffusion.

• Animal studies have demonstrated that BTX diffuses across fascial planes to surrounding muscles

• Clinical effect occurs within approximately 3–7 days (typically seen after 1–3 days) after administration, followed by 1– 2 weeks of maximum effect, which then levels off to a moderate plateau until full nerve recovery within 3–6 months (typically at approximately 3 months).

Preparation

Preinjection Check List• Emergency drugs.• An established injection protocol that includes the

specific locations and appropriate doses for the condition to be treated.

• All injection sites should have been evaluated properly.

• The practitioner must be aware of all medications and supplements that are taken by the patient to minimize any effect on the potency of the BTX.

• Medical conditions; vital signs, such as blood pressure, should be noted before injecting.

• Informed consent signed by the patient

Uses1. Cosmetic

- Facial Wrinkles- Maseteric and Temporalis Hypertrophy- Correction of Gummy Smile

2. Therapeutic- TMJ disorders- Salivary Secretory Disorders- Facial Pain- Nerve Palsies- Muscle Movement Disorders- Perioperative use of BTX

Cosmetic Uses1. Facial Wrinkles

• Wrinkles appears as a result of the pulling of the skin by the underlying musculature.

• BTX reduces the mimetic effects of wrinkles and folds, and should therefore be applied in areas of dynamic motion, such as the glabella, frontal region, and peri-orbital lines

Glabellar Wrinkles

Frontal Wrinkles

Peri-Orbital Lines (Crow’s Feet)

Injection Techniques

Masseter Hypertrophy

• Masseteric hypertrophy usually results from anatomical asymmetry of the jaw, clenching, excessive chewing of gum or congenital malformations.

• May by unilateral or bilateral

Temporalis Hypertrophy

• Less common • Can be managed successfully using BTX• With no appreciable side effects.

Proposed locations of botox injection for the temporalis and masseter muscles

Correction of Gummy Smile

• The exposure of more than 3 mm of the gum during the smile is known as gingival or gummy smile (GS).

• GS represents an aesthetic disorder and therefore various correction methods are proposed, including gingivoplasty, orthodontic treatment, orthognathic surgery, and bone resection.

• BTX a simple, fast, and effective method for the aesthetic correction of GS.

• Various causes have been described for GS, including lip length, clinical crown length,and mainly altered passive eruption or vertical maxillary excess.

• Behavior of perioral muscles critically influences the structure of the smile and, patients with GS had at least 20% greater facial muscular capacity to raise the upper lip when smiling (Peck et al 1992)

Muscles Responsible for Gummy Smile

Classification Of Gummy Smile Based On Area Of Gingival Exposure

Type of GS Clinical appearance Main muscles involved

Anterior Major gum exposure (>3 mm) in area

Between canine teeth

LLSAN

Posterior Major gum exposure (>3 mm) posterior to

Canines, with normal exposure (<3 mm)In anterior region

Zm and zmi

Mixed Excessive gum exposure in both areas

(Anterior and posterior)

Llsan, zm, and zmi(Combination of >2)

Asymmetric Excessive or more apparent gum exposure

On one side only

Llsan and/or zm/zmi ipsilateral

Rosemarie Mazzuco et al 2010 J American Academy of Dermatology

Anterior Gummy Smile Posterior Gummy Smile

Mixed Gummy Smile Asymmetric Gummy Smile

Therapeutic Uses

Salivary Secretory Disorders• Xerostomia is one of the first manifestations of

botulism.• Topical injection of BTX-A as a minimally invasive

option for the treatment of drooling has been used for many years in neurological diseases.

• Greatest limitation in this indication is its transient effectiveness (3–4 months), requiring multiple and expensive administrations.

• The therapeutic effect is based on the inhibitory action of the toxin at the cholinergic receptors of the salivary gland cells.

• Treatment is mostly focused on the parotid gland and to a lesser extent on the submandibular gland. The sublingual gland is seldom injected.

• Parkinson’s disease, amyotrophic lateral sclerosis cerebral palsy, and carcinoma of the upper digestive tract.

• Posttraumatic and iatrogenic salivary sialoceles and Cysts or salivary fistulas after sialadenectomy or oropharyngeal cancer surgery.

• Frey’s Syndrome

Areas of BOTOX injection in Major Salivary Glands

10-20 U

10-15 U

TMJ Disorders• BTX is used for treatment of TMJ and masticatory

muscle pain, reduced jaw opening capacity, recurrent TMJ dislocations and masticatory hyperactivity.

• TMDs may be divided into– Myofascial– Arthrogenic

• Joint noise, pain and restricted range of motion are most frequent symptoms.

• The source of chronic myofascial pain is not clear.

• Injection into the masseter and temporalis muscles with TMD reduced subjective pain and tenderness with objective and subjective weakening of the masticatory muscles.

• This is due to action of BTX on nociceptors and the inhibitory effect of specific protein- receptor binding within the intracellular compartment on the release of neuropeptides and inflammatory molecules, such as calcitonin gene-related peptide, substance P, and glutamate

• Patients with reduced mouth opening experienced improvement in mouth opening after BTX therapy.

• Muscular relaxation, reduction of inflammation in the muscle and the TMJ.

• BTX injection into the lateral pterygoid muscle has reduced the clicking associated with TMD.

• BTX injection into the flexor muscles of the mandible produced subjective and objective reductions in the power of muscular contractions.

BTX for Prevention of Post-Traumatic TMJ Ankylosis

Jiewen Dai et al. Journal of Medical Hypothesis and Ideas 2015

Facial Pain ( Other Than Myofacial Pain)

• Use of BTX in pain conditions such as tension headache, myofacial pain, migraine, trigminal neuralgia, bruxism and hemifacial contracture.

• Postoperative wound pain can be managed with BTX but post-dental procedures is asssociated with a poor results.

Facial Nerve Palsy• BTX injection, through an orbital route or a skin

crease, provides a good means of inducing a protective ptosis by temporarily paralyzing the levator palpebrae superioris

• Useful in intensive care patients to prevent desiccation of the cornea.

• BTX-A is commonly used to relieve the symptoms of synkinesis with marked improvement

• In patients with facial asymmetry, chemo-denervation of the normal side with BTX.

• BTX reduces the relative hyperkinesis of the contralateral side to the paralysis, resulting in a more symmetrical function of the face.

Other nerve palsies

• Third nerve palsy – commonly due to trauma.• BTX injection to the lateral rectus muscle for

treatment of third-nerve palsy. BTX injection decreases the likelihood of contracture of the lateral rectus muscle, thereby allowing return of medial rectus muscle function.

• The abducens nerve can be injured during a severe orbital trauma. In such cases, BTX injection of the medial rectus muscle has been studied with variable improvements

Frey’s Syndrome• Frey’s Syndrome (gustatory sweating)

has been drescribed as a secretory alteration of the eccrine sweat glands located in the facial area due to an inappropriate response to cholinergic stimulus from the auriculotemporal nerve fibers. It is most frequently encountered as a complication of parotidectomy.

• Clinically it results in sweating and flushing of facial skin during salivation.

Perioperative Use of BTX

• The presence of postoperative involuntary movements may be detrimental to healing.

• BTX weakens the muscle and in so doing may improve postoperative recovery and healing. Wound healing improves if the muscles involved are injected with BTX prior to surgery.

• Patients undergoing eyelid reconstructive surgery had successful wound healing after adjunct treatment with BTX.

• BTX has been used to immobilize muscles after jaw fractures to reduce the displacing forces on the fracture ends and obtain good immobilization especially if rigid internal fixation is not available or feasible.

• BTX has also been beneficial during the initial osseointegration phase for dental implants.

Potential Therapeutic Uses

Topical Formulations

• For treatment of focal hyperhidrosis of the palms, soles, axillae and facial areas.

Keloid and Hypertrophic Scar

• BTX-A can improve the appearance of hypertrophic scar and inhibit its growth.

• Evidence supporting this potential use arise from BTX’s ability to prevent excessive muscle contraction of the skin near keloid tissue, and its reported influence on cellular apoptosis and cellular proliferation

Complications• Immunogenicity • Allergy• Local complication– Pain– Oedema– Erythema– Ecchymosis– Short-term hypoesthesia

• Other reported adverse effects are : Headache, blepharoptosis and perioral muscular palsy.

• In therapeutic applications, complications are; Pain Erythema Ecchymosis Dry eyes Mouth droop Ptosis and lid oedema Facial muscle weakness Asymmetry of facial expression Xerostomia Transient dysphagia Restricted mouth opening Nasal regurgitation Infection Blurred vision Salivary duct calculi

- Neutralizing antibodies to BTX-A can lead to loss of treatment effect.

- Clinical resistance to BTX-A has been estimated as high as 7%.

- BTX-B is an alternative therapeutic agent.

Contraindications• Contraindications are generally few. • Pregnancy and breast feeding• Disorders of the neuromuscular junction

(myasthenia gravis, amyotrophic lateralizing sclerosis, myopathies)

• Drug interactions (aminoglycoside antibiotics, quinidine, calcium channel blockers, magnesium sulfate, succinylcholine, and polymyxin).

• Other reported contraindications are Eaton–Lambert syndrome and hypersensitivity to BTX or one of its ingredients

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