Botulinum Toxin Use In Oculoplastics

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Botulinum Toxin use in Oculofacial Plastic Surgery

Botulism

Botulism is a serious illness caused by the toxin of the bacterium Clostridium botulinum that may cause varying degrees of self-limited paralysis of the facial musculature and extremities to life threatening respiratory failure. The toxin can be acquired via ingestion from contaminated food, systemic absorption from infected wounds, or intestinal colonization in infants and adults.

History

The ubiquitous gram-positive anaerobe Clostridium botulinum was first identified as the cause of botulism in 1895 by the Belgian professor Emile Pierre van Ermengem.[1] During the following two decades, numerous other strains of botulinum toxin were isolated and identified. Dr. Herman Sommer produced a crude form of botulinum toxin A at the University of California, San Francisco in 1926 and Dr. Edward Schantz and his colleagues first produced a purified form of botulinum toxin A in 1946. [2] [3] In the 1970s, the first clinical application of botulinum toxin was pioneered by Dr. Alan Scott, an ophthalmologist, who injected botulinum toxin in human extraocular muscles to treat strabismus.[4] Over the past 2 decades, the therapeutic applications of botulinum toxin have greatly expanded to include the treatment of various disorders of muscle hyperactivity, hyperdynamic rhytides, hyperhidrosis and migraine headaches.

Mechanism of Action

The mechanism of action of botulinum toxins utilized in oculofacial plastic surgery involves inhibition of acetylcholine release at the neuromuscular junction, which results in paralysis/paresis of muscle tissue.[5] The toxin is a single 150 kilodalton molecule composed of a heavy and light chain. The heavy chain binds to specific receptors on motor nerve terminals, which subsequently internalize the toxin via receptor-mediated endocytosis. Within these endosomes, the toxin is subjected to an acidic pH around 4-5 which is believed to result in dissociation of the light chain from the toxin and passage of the light chain into the cytosol of the motor neuron. Within the cytosol, the light chain is then able to cleave a specific protein responsible for acetylcholine vesicle exocytosis. These proteins, referred to as the SNARE complex, consist of: 1) synaptosomal associated protein (SNAP-25), 2) vesicle associated membrane protein (VAMP or synaptobrevin); and 3) syntaxin, a docking protein within the synaptic membrane. Botulinum toxin A is known to cleave SNAP-25, and toxin B cleaves synaptobrevin.

Effects of botulinum toxin peak at about 14 days with the duration of effect lasting approximately 3 months. Mechanisms of muscle recovery include sprouting of new terminal axons from affected motor nerve endings and possible up regulation of extrajunctional acetylcholine receptors.


Clinical Applications

The most common oculoplastic applications for botulinum toxin include: benign essential blepharospasm, hemifacial spasm, hyperfunctional facial rhytides, and strabismus. Treatment with botulinum toxin is both safe and effective[6][7][8]; therefore, it is often used as first line treatment in debilitating myoclonic disorders. In addition, hypersecretion of the lacrimal gland secondary aberrant regeneration of the facial nerve can also be successfully treated with botulinum toxin. The mechanism involves inhibition of acetylcholine release from postganglionic parasympathetic nerve endings that supply lacrimal gland acini. Patients with other types of hypersecretion such as hyperhidrosis, gustatory sweating (Frey syndrome), and sialorrhea have also shown clinical improvement from local injections of botulinum toxin.

Surgery

Botox® purified neurotoxin complex is a sterile, vacuum-dried, purified extract of botulinum toxin type A, produced from fermentation of the Hall strain of Clostridium botulinum toxin type A. This strain of C. botulinum is grown in culture medium containing casein hydrolysate, glucose, and yeast extract. It is purified from the culture solution by dialysis and a series of acid precipitations to a complex consisting of the neurotoxin and several accessory proteins. The complex is dissolved in sterile sodium chloride solution containing human albumin and subjected to microfiltration prior to lyophilization. Each vial of Botox® contains 100 units (U) of Clostridium botulinum type A neurotoxin complex, 0.5 milligrams of human albumin, and 0.9 milligrams of sodium chloride in a sterile, vacuum-dried form without a preservative. The toxin must be kept frozen at -5 degrees Celsius or colder until reconstituted. Dysport® brand of botulinum toxin A is also produced in a dried formulation. The dried toxin may be dissolved in sterile, preservative-free saline, in which case it should be kept refrigerated and used within 4 hours of reconstitution. However, some physicians prefer to dissolve the dried toxin in preserved saline to prolong the shelf life after reconstitution. Equal effectiveness to freshly reconstituted botulinum toxin has been demonstrated up to 1 month with preserved toxin.

Myobloc® is a sterile liquid formulation of purified neurotoxin type B approved in 2002 by the FDA for use in the United States. The neurotoxin is produced by fermantation of the bacterium Clostridium botulinum type B (Bean strain) and is associated with hemagglutinin and nonhemagglutinin proteins as a neurotoxin complex. The liquid is produced at a concentration of 5000 U/ml and is slightly acidic at a pH of 5.6. Sterile nonpreserved or preserved saline can be used to dilute the concentration as needed.

Doses of all commercially available botulinum toxin products are expressed in terms of units (U) of biological activity. One unit of toxin corresponds to the calculated medial intraperitoneal lethal dose (LD50) in female Swiss-Webster mice. Despite the fact that this definition applies to all forms of commercially available botulinum toxin, intermanufacturer differences in mouse LD50 assay protocols has led to units that vary in potency between the products. For example, units of Myobloc® required for a specific treatment may be 50 to 100 times higher than Botox®. In addition, a 3-fold higher dose of Dysport® is required to achieve the same clinical effect as Botox®. Therefore, when communicating dose information to others, it is important to specify the particular brand of botulinum toxin being used.

Blepharospasm is effectively treated by injecting directly into the preseptal orbicularis oculi musculature. In patients with hemifacial spasm, injections are tailored specifically to the affected muscles. The most common areas injected for hyperdynamic facial rhytides include the lateral canthal region (crows feet), glabellar folds and forehead.

Post injection follow up

Injection of botulinum toxin results in varying degrees of muscle weakness depending on the concentration and dose of toxin administered. Effects are noticeable within 1 to 14 days, peak after 2 to 6 weeks and begin to subside approximately 10-12 weeks after administration. Patients typically require 3 to 6 months to regain full strength. If the desired clinical response has not been achieved after 2-3 weeks, follow up can be arranged for supplemental injections. Otherwise, most patients usually require retreatment every 3-4 months.

Complications

Although the effects are usually local and self-limited, one must be aware that the possiblity of systemic distribution exists to other types of cholinergic neurons, namely the autonomic ganglia, postganglionic parasympathetic nerve endings and specific postganglionic sympathetic nerve endings that secrete acetylcholine (i.e. that innervate eccrine sweat glands). A list of systemic side effects is provided below.

When used in the ophthalmic area, the most common complications include bruising, swelling, headache, or incomplete results or asymmetry. ptosis secondary to either weakness of the levator or frontalis muscles can occur depending on the sites of injection and dosages. Additionally, patients can develop weakness of the orbicularis muscles, resulting in poor closure of the lids or even paralytic ectropion. Patients with these side effects should be closely monitored to ensure prevention of ocular surface exposure. Patients may also potentially develop diplopia secondary to involvement of extraocular muscles. These side effects can be expected to resolve as the medication loses its effect, which is usually 10-12 weeks after administration.

Over time, patients may develop neutralizing antibodies to botulinum toxin that render the medication ineffective to varying degrees. Development of antibodies agains botulinum toxin is believed to be a function of: 1) dose of toxin administered per session, 2) frequency of treatments; and 3) amount of total protein per unit toxin in the formulation.

Although uncommon, patients may develop type I anaphylactic reactions and rashes after administration of botulinum toxin. Although there are no reports of teratogenicity, use of botulinum toxin in pregant or lactating women is discouraged. Given the increased risk for systemic side effects, it is an absolute contraindication to administer botulinum toxin to patients with a history of neuromuscular disorders (i.e. myasthenia gravis, Eaton-Lambert syndrome). In addition, physicians should be aware that aminoglycoside antibiotics can also interfere with neuromuscular transmission and can intensify the effects of botulinum toxin.

Prognosis

The general literature is conflicted regarding changes in outcomes with chronic treatment.  This is a product of the current, limited understanding of the complex process of BTX-A’s mechanism of action.  As noted above, activity is via direct action on SNAP-25 via the BTX-A light chain’s zinc-endopeptidase specificity[9]. However, the “mechanism of recovery” is not fully understood[10] and therefore the significance of an increase in duration of effect is not immediately attributable to a specific step in the process.

Some insight may be gained by Whitemarsh’s investigation of BTX subtypes in Rat Spinal cord cells:  Treatment with BTX-E ten months following administration of BTX-A on spinal cord cells revealed the presence of enzymatically active BTX-A LC’s in the neuron.  Recovery of a cell after BTX-E treatment is only 14 days.  In a clever experiment by Whitemarsh,  de-novo cleavage of SNAP-25 by BTX-A was detected by further cleavage of a select site on SNAP-25 cleaved only after BTX-E’s administration and recovery, decisively indicating its presence as an active agent 10 months later - long after clinical efficacy diminishes at the established 12 weeks.  Unfortunately, the amount of functional SNAP-25 “required for neurons to perform exocytosis” is not known[10]; though, it is not thought to be a high percentage.  As cited across disciplines including in hand therapy, the temporary effect of BTX-A can in part be attributed to local nerve fiber growth that creates new connections to muscle fibers[11]. It has been noted, and stands to reason, that the new sproutlets do not inherit the BTX LC’s of the primary neuron, allowing for reinnervation of the NMJ. The regrowth of nerve sproutlets occur within weeks, consistent with rapid recovery in spite of extended BTX LC activity in nearby nerves lasting at least 10 months[12].  Therefore, buildup of LC activity in nerves is unlikely to explain the increase in duration of effect found in our patients; and in the clinical setting, increased frequency of treatment even at 6 week intervals did not result in cumulative effects[13].

Spread of botox to the spinal cord was first identified in early research by Habermann[14] in 1974 and most recently in 2014 by Evidente[15] et al. Most definitively, an fMRI study by Opavsky involving seven patients with Cervical Dystonia (CD) showed increased fMRI activity in the contralateral somatosensory cortex after injection with BTX-A[16].  Further, significant novel activity of the contralateral insula and IPL was observed after BTX-A injection with no significant difference in comparison to the control group thus indicating a higher order modulation effect of BTX-A.  This central modulation is newly identified and not yet well understood.

Systemic Side Effects

Skeletal neuromuscular junction

  • Extraocular muscle weakness
  • Ptosis
  • Dysphagia
  • Dysarthria
  • Respiratory failure
  • Generalized muscle weakness

Autonomic Ganglia

  • Mydriasis
  • Cycloplegia
  • Hypotension
  • Constipation
  • Urinary retention
  • Hypolacrimation
  • Hyposalivation
  • Hypohidrosis
  • Reduced gastric secretion

Postganglionic parasympathetic neurons

  • Urinary retention
  • Constipation

Postganglionic sympathetic neurons that release acetylcholine

  • Hypohidrosis

Additional Resources

References

  1. DasGupta BR. Structure of botulinum neurotoxin. In: Simpson LL, ed. Botulinum Neurotoxin and Tetanus Toxin. San Diego, CA: Academic; 1989:53-67.
  2. Snipe PT, Sommer H. Studies on botulinus toxin. 3. Acid preparation of botulinus toxin. J Infectious dis. 1928;43:152-160.
  3. Schantz EJ, Johnson EA. Botulinum toxin: the story of its development for the treatment of human disease. Persp BIol Med. 1997;4-:317-327.
  4. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmology. 1980;87:1044-1049.
  5. Callaway JE, Arezzo JC, Grethlein AJ. Botulinum toxin type B: an overview of its biochemistry and preclinical pharmacology. Dis Mon. 2002;48;367-383.
  6. Huang, L., Costin, B. R., Sakolsatayadorn, N., & Perry, J. D. (2014). Safety of Onabotulinum Toxin A Injection to the Central Upper Eyelid and Eyebrow Regions. Ophthalmic Plastic and Reconstructive Surgery, 1. doi:10.1097/IOP.0000000000000109
  7. Czyz, C. N., Burns, J. A., Petrie, T. P., Watkins, J. R., Cahill, K. V., & Foster, J. A. (2013). Long-term Botulinum Toxin Treatment of Benign Essential Blepharospasm, Hemifacial Spasm, and Meige Syndrome. American Journal of Ophthalmology, 156(1), 173–177.e2. doi:10.1016/j.ajo.2013.02.001
  8. Ababneh, O. H., Cetinkaya, A., & Kulwin, D. R. (2013). Long-term efficacy and safety of botulinum toxin A injections to treat blepharospasm and hemifacial spasm. Clinical & Experimental Ophthalmology, 42(3), 254–261. doi:10.1111/ceo.12165
  9. Montecucco, Cesare, and Glampietro Schiavo. "Mechanism of action of tetanus and botulinum neurotoxins." Molecular microbiology 13.1 (1994): 1-8.
  10. 10.0 10.1 Whitemarsh RCM, Tepp WH, Johnson EA, Pellett S. Persistence of Botulinum Neurotoxin A Subtypes 1-5 in Primary Rat Spinal Cord Cells. Popoff MR, ed. PLoS ONE. 2014;9(2):e90252. doi:10.1371/journal.pone.0090252.
  11. Kalliainen LK, O'Brien VH. Current uses of botulinum toxin A as an adjunct to hand therapy interventions of hand conditions. Journal of Hand Therapy. 2014;27(2):85-95. doi:10.1016/j.jht.2013.12.003.
  12. Borodic, Gary E et al. "Histologic assessment of dose‐related diffusion and muscle fiber response after therapeutic botulinum a toxin injections." Movement Disorders 9.1 (1994): 31-39.
  13. Evidente, Virgilio Gerald H et al. “IncobotulinumtoxinA (Xeomin®) Injected for Blepharospasm or Cervical Dystonia According to Patient Needs Is Well Tolerated..” Journal of the neurological sciences 346.1-2 (2014): 116–120. Web.
  14. Habermann, E. "125I-labeled neurotoxin from Clostridium botulinum A: preparation, binding to synaptosomes and ascent to the spinal cord." Naunyn-Schmiedeberg's archives of pharmacology 281.1 (1974): 47-56.
  15. Evidente, Virgilio Gerald H et al. “IncobotulinumtoxinA (Xeomin®) Injected for Blepharospasm or Cervical Dystonia According to Patient Needs Is Well Tolerated..” Journal of the neurological sciences 346.1-2 (2014): 116–120.
  16. Opavský, Robert et al. "Somatosensory cortical activation in cervical dystonia and its modulation with botulinum toxin: an FMRI study." International Journal of Neuroscience 122.1 (2011): 45-52.