The Multispecialty Toxin: A Literature Review of Botulinum Toxin

Karen Bach, BS; Richard Simman, MD, FACS, FACCWS

Disclosures

Plast Reconstr Surg Glob Open. 2022;10(4):e4228 

In This Article

Results and Discussion

A detailed description of all the conditions for which BoNT has been shown to be effective in treating is beyond the extent of this article. Only conditions for which BoNT is commonly used will be discussed (Table 2). In addition to indication-specific dosages and administration recommendations of Botox for FDA-approved conditions, the most common adverse reactions will also be discussed (Table 3).

Ophthalmology

As previously mentioned, the therapeutic potential of BoNT was first recognized in 1981 by Scott following their studies of injecting the toxin into ocular muscles to treat strabismus.[4] In 1989, the FDA approved this agent for the treatment of strabismus, blepharospasms, and hemifacial spasm in patients aged younger than 12 years. The current recommended Botox dose for strabismus is based on the prism diopter correction or prior treatment response.[20] For blepharospasm, 1.25–2.5 U is recommended for each of the approved three sites per affected eye.[20] The role of BoNT therapy in ophthalmology has since expanded to treat several other conditions, including eyelid retraction due to thyroid disease, apraxia of lid opening, entropion, exposure keratopathy, lacrimal hypersecretion, and chronic dry eyes.[21,22]

Complications with BoNT use in ophthalmology arise as a result of toxin diffusion or inadvertent placement into the adjacent muscles. Ptosis of the eyelid is the most common complication of BoNT treatment of strabismus and blepharospasms.[23] Although this effect is almost always temporary and self-resolving, apraclonidine 0.5% (Iopidine) or phenylepherine hydrochloride 2.5% (Neosynephrine) ophthalmic solution may be used. These eye drops are adrenergic agonists that help contract Müller's muscles located beneath the levator muscle and elevate the lash margin.[24,25] Other complications include diplopia, dry eye, blurred vision, and very rarely, acute angle closure glaucoma, and retinal detachments.[26–28] Acute angle closure glaucoma is an interesting adverse effect, as BoNT has been shown to be beneficial in alleviating pain from acute angle closure glaucoma.[29] The exact mechanism behind this is unclear, although BoNT has demonstrated antinociceptive effects through the inhibition of peripheral sensitization in prior studies.[30]

Neurology

BoNT has many neurological applications in the management of movement disorders and painful conditions. In 2000, the FDA approved its use for the treatment of cervical dystonia in patients 16 and older. The recommended Botox dose for cervical dystonia is dependent on the patient's presentation, including the head and neck position, pain, and degree of muscle.[20] It is advised to use a lower dose initially if there has been no prior treatment and adjust the dose accordingly based on response. Other movement disorders treated with BoNT besides dystonia include hemifacial spasm, tremor, tics, bruxism, myokymia, neuromyotonia, palatal myoclonus, and spasticity, in addition to synkinesis.[31] Synkinesis refers to abnormal involuntary muscle contraction that occur with voluntary contraction of other muscle groups and in rare cases, such as oculonasal synkinesis, Botox may provide a nonsurgical treatment option to address the paroxysmal contraction.[32] Botox is FDA approved for the treatment of spasticity in both adult and pediatric populations. The recommended dose for spasticity is divided among affected muscles and is as follows: adult upper limb (max 400 U), adult lower limb (300–400 U), pediatric upper limb (3–6 U/kg with a max of 200 U), and pediatric lower limb (4–8 U/kg with a max of 300 U).[20] BoNT therapy has also been proven effective in treating debilitating conditions such as tension headaches, migraines, myofascial pain, temporomandibular joint syndrome, and trigeminal neuralgia.[31] The FDA-approved BoNT in 2010 for the prevention of headaches in adults suffering from chronic migraines who have 15 or more headache days each month, with each episode lasting four hours or more a day.[33] The recommended total Botox dose for chronic migraines is 155 U, with 5 U (0.1 mL) injections per site divided across seven head or neck muscles.[20] The mechanism behind its therapeutic effects relates to the blockade of pain neurotransmission. BoNT has also shown beneficial in treating brachial plexus birth injuries (BPBIs). Administration of the toxin into muscles, such as the pectoralis major, latissimus dorsi, subscapularis, and teres major, help reduce muscle imbalances and excessive inappropriate contractures in brachial plexus birth injuries.[34]

The side effect profile of BoNT use in neurology is generally benign and well-tolerated. For the treatment of cervical dystonia, the most common reported effect is resistance to therapy, with an incidence as high as 6.5%.[35] Other reactions include dysphagia, upper respiratory infection, increased cough, and rhinitis. For the treatment of chronic migraine, adverse reactions of bruising, pain, ptosis, and diplopia have been reported.[36]

Plastic Surgery and Dermatology

In 2002, BoNT was approved by the FDA for cosmetic use to improve the appearance of vertical eye furrows (glabellar lines) when injected into the corrugator or procerus muscles. Injections into the lateral orbicularis oculi can help eliminate lateral canthal wrinkles (crow's feet) and was granted approval in 2013. Injection into the frontalis muscle targets the horizontal forehead lines while injection into the platysma muscle can improve the appearance of age-related platysma muscle bands. Botox Cosmetic injections are FDA approved only for the glabellar lines, lateral canthal lines, and forehead lines. Wrinkles are caused by dermal atrophy that occurs with aging and repeated contractions of the underlying muscles. When BoNT is injected into these muscles, it causes relaxation of the muscle and improve appearance of overlying lines. The recommended dose for glabellar lines is 4 U (0.1 mL) into each of the five sites, 4 U (0.1 mL) into each of the three sites per side for lateral canthal lines, and 4 U (0.1 mL) into each of the five sites for forehead lines, adding up to a final total of 40 U.[37] Figure 2 provides a brief overview of the frequently injected sites on the face. Other off-label applications in facial rejuvenation include but are not limited to eyebrow depression, nasal bridge lines, perioral rhytids ("smokers lines"), and mesolabial folds ("marionette lines"). Conditions such as migraines, vascular spasms of the hand, and facial paralysis secondary to interventions such as a facelift may also be treated by plastic surgeons. In addition to cosmesis, BoNT has proven therapeutic benefit for the treatment of hyperhidrosis, a condition characterized by excessive sweating in areas such as the axillae, palms, and soles. As of 2004, BoNT is FDA approved for the treatment of severe primary axillary hyperhidrosis refractory to other topical therapeutics. The recommended Botox dose for axillary hyperhidrosis is 50 U per axilla.[20] In a similar manner, BoNT also exerts a therapeutic effect in patients with gustatory sweating of the cheek, also known as Frey's syndrome.[38] Masseter hypertrophy, although seldom presents a significant issue, may cause pain in some individuals, especially those with TMJ dysfunction or bruxism. BoNT injection into the masseter muscle has reportedly improved pain, and also reduced the size and volume of the muscle.[39] BoNT use for this clinical phenomenon is not FDA-approved yet, and further studies are needed to assess its efficacy and safety.[39]

Figure 2.

Frequently treated areas on the face and neck with BoNT. Figure created with BioRender.com.

Complications of cosmetic use of BoNT are typically self-limited and localized to the site of injection. These include the aforementioned pain, erythema, and bruising effects. Diffusion of the toxin during treatment of glabellar lines or periorbital wrinkles may result in eyelid ptosis, with the most severe cases interfering with vision and requiring treatment with mydriatic agents such as apraclonidine 0.5% (Iopidine) or phenylepherine hydrochloride 2.5% (Neosynephrine) ophthalmic drops.[25] Other adverse reactions associated with Botox treatment of axillary hyperhidrosis include injection site pain and ecchymosis, nonaxillary sweating, pharyngitis, and flu syndrome.

Orthopedic Surgery

A broad range of clinical disorders in orthopedics may be addressed with BoNT therapy. However, many have underlying pathophysiology similar to that of muscle overactivity and/or spasticity and thus, may also be considered as neurological in nature. The first report of BoNT use in orthopedics was published in 1993 and it described the use of Botox injection to treat spasticity in children with cerebral palsy.[40] Spasticity related to other etiologies, such as multiple sclerosis, head injury, or spinal injury, may also be treated with BoNT injection. FDA approval and dosage recommendations for spasticity have already been discussed in the neurology section above. BoNT has also been reported to be useful in the treatment of piriformis syndrome, brachial plexus palsy, congenital talipes equinovarus, idiopathic toe walking, and sports-related or other posttraumatic injuries.[41,42] It is important to be cognizant of toxin diffusion into surrounding tissues leading to weakness or paralysis of unwanted musculature. Major serious adverse events are of low incidence, but several accounts of incontinence and respiratory complications have been reported in children with cerebral palsy treated with BoNT.[43,44] The other mentioned BoNT applications are novel and limited in data availability. Subsequent studies are needed to evaluate the long-term complications, if any, of BoNT use in orthopedics.

Gastrointestinal

BoNT has proven to be effective in the management of several gastrointestinal conditions, in particular, those characterized by spasticity of the smooth muscle. Injection into the lower esophageal sphincter has demonstrated impressive results in patients with achalasia and provided a useful alternative treatment in patients who are not candidates for invasive procedures.[45] The use of BoNT in treating anal fissures has also been extensively studied and injection into the anal sphincter has been shown to improve the resolution of chronic anal fissures.[46] Other conditions treated may include diffuse esophageal spasm, gastroparesis, Sphincter of Oddi dysfunction, anismus, anal fissures, and rectal spasms or Proctalgia fugax.[47,48] Many trials have attempted to use BoNT injection into the antrum or body of the stomach to slow down gastric emptying for weight loss in patients with morbid obesity; however, the results have not been statistically significant.[49,50] Although gastroenterologists routinely use BoNT, the FDA has not yet approved its use for any gastrointestinal indications.

Injections of BoNT into the esophagus for relief of symptoms in achalasia and other spastic esophageal motility disorders have been associated with mild side effects related to the injection itself or from decreased lower esophageal pressure. However, a few rare complications of acute mediastinitis and acute urinary retention have been reported.[51] There has been one reported case of systemic botulism toxicity secondary to BoNT treatment for gastroparesis.[52] However, it should be noted that the patient had a type of muscular dystrophy known as Emery-Dreifuss and in general, BoNT injection is contraindicated in those with existing neuromuscular disorders due to a baseline reduction in acetylcholine responsiveness. Short term incontinence of gas or stool is a self-resolving side effect in the treatment of chronic anal fissure.[47] Overall, the adverse effects are transient and reversible with use of BoNT in the treatment of esophageal, gastroduodenal, anorectal, and biliary disorders.

Urology and Gynecology

BoNT therapy is currently FDA approved for the treatment of neurogenic detrusor overactivity, which results in presentations such as urinary incontinence, overactive bladder syndrome, and non-neurogenic overactive bladder syndrome.[53] For adult detrusor overactivity with an underlying neurologic condition, the recommended Botox dose is approximately 6.7 U (1 mL) injections across 30 sites in the detrusor muscle for a total of 200 U, and 0.5 mL injections across 20 sites in the detrusor muscle (total dose 200 U if ≥34 kg and 6 U/kg if <34 kg) for pediatric detrusor overactivity with an underlying neurologic condition.[20] In contrast, the recommended Botox dose for overactive bladder alone without an underlying neurologic condition is 5 U (0.5 mL) injections across 20 sites in the detrusor muscle for a total dose of 100 U.[20] Off-label use of the toxin is also commonly done for a variety of other genito-urological conditions, including detrusor sphincter dyssynergia, prostatic obstruction, painful bladder syndrome, and other pelvic floor disorders like vaginismus and chronic pelvic pain.[54–56]

For treatment of overactive bladder syndrome and detrusor overactivity, the most common adverse effects are urinary tract infection and urinary retention.[57] These complications could possibly be avoided with screenings for acute urinary tract infections before treatment and prophylactic antibiotic use. The reported complications of BoNT injections for gynecologic indications vary from urinary retention to constipation.[58] In general, use of BoNT in the treatment of multiple urological and gynecological disorders appears to be safe and effective.

Rheumatology

In recent years, BoNT has garnered increasing interest for its use in Raynaud's phenomenon, a condition characterized by an exaggerated vasoconstrictive physiological response of the extremities provoked by cold exposure or emotional stress. The first application for this purpose occurred in 2004, which demonstrated improved blood flow. Subsequently, further studies have proved BoNT's ability to increase blood flow, relieve painful symptoms of vasospasms, and prevent ischemic ulcerations in these patients. The proposed mechanism of action of BoNT efficacy in Raynaud's revolves around the agent's ability to inhibit arteriolar vasoconstriction in a dose-dependent manner via cleavage of SNAP-25 in sympathetic neurons, thus blocking the release of norepinephrine.[59] The most common complication reported is a transient intrinsic weakness of the hand.[60]

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