Can Botulinum Toxin Have An Effect For Hyperhidrosis?

Hyperhidrosis not only predisposes the feet to fungal and bacterial infection, but it can also negatively affect the patient’s quality of life. Accordingly, these authors discuss the treatment of hyperhidrosis with various iterations of botulinum toxin. They also offer pearls on injection techniques and dosing.

Sweating is normal when it is a response to an external stimulus (exercise or high temperature or humidity) or occasional nervousness. It is hyperhidrosis when it is excessive, frequent (at least once a week) and without apparent cause.

   Hyperhidrosis can be generalized or focal. With generalized hyperhidrosis, a medical evaluation may reveal a cause, of which there are many. Focal hyperhidrosis is often confined to the face, axilla, palms or soles of the feet. Focal hyperhidrosis does not usually have an associated disorder. Hyperhidrosis affects an estimated 2.8 percent of the United States population.1

   When it comes to hyperhidrosis of the foot, patients can be “swimming in their shoes.” It creates a warm, moist environment, which is ideal for fungal, viral and bacterial growth. It predisposes patients to bromhidrosis, tinea pedis and fungal nails, bacterial infections, warts and eczema. It can ruin shoes. It also can affect the sufferer’s self image and social life.

   Over the counter or prescription antiperspirants with aluminum chloride may help in mild cases, but they can cause focal rashes and are not always effective. Anticholinergic drugs are usually not used for focal hyperhidrosis and can have systemic side effects. Iontophoresis, low-voltage electrical stimulation of the areas of hyperhidrosis, may help but this must be repeated frequently.

   For severe palmar hyperhidrosis, sympathectomy is usually effective but it is moderately invasive and can result in compensatory hyperhidrosis in other body regions. Although endoscopic retroperitoneal lumbar sympathectomy is less commonly performed, it is reportedly effective for plantar hyperhidrosis. However, one study indicates that compensatory hyperhidrosis occurred in one-half of patients who received the treatment.2

A Closer Look At Botulinum Toxin

Botulinum toxin is an effective treatment for hyperhidrosis. Clostridium botulinum is an anaerobic bacterium, which produces botulin toxins that cause the disease botulism. Originally called “sausage poison” from improperly prepared meat, the condition was first described by the physician Justinus Kerner, who first conceived of the possible therapeutic uses of the toxin.3

   Botulin is one of the most potent naturally occurring poisons. Approximately 110 cases are reported every year in the U.S.3-10 In nature, botulism can be food borne (25 percent of cases), occur in infants (and very rarely in adults) when spores grow in the intestine (75 percent) or result from a wound infection (3 percent).5 In the medical setting, botulism can result from inhalation of the toxin and from complications of medical use. The disease is due primarily to the toxin’s effects on nerve communication with muscles at the synaptic junctions.

   There are seven botulinum serotypes (A, B, C1/C2, D, E, F and G).11 Type A (BTX-A) is the most potent and is used in medicine as Botox (Allergan), Dysport (Medicis) and Xeomin (Merz). Type B is also used in medicine in rimabotulinumtoxinB (Myobloc, Solstice Neuroscience). Botulin binds irreversibly to the pre-synaptic nerve endings and blocks the signal to the muscles and the sweat glands. The effects are temporary due to proteolytic inactivation of the toxin and the growth of new nerve endings.11

   Botox has been in use since the late 1970s for the treatment of strabismus and this treatment of spasticity still accounts for more than half of all doses. The doses used for muscle spasticity are considerably greater than for cosmetic uses and hyperhidrosis.

What You Should Know About Possible Adverse Reactions

When it comes to medical use of botulinum toxin injections, systemic reactions away from the injection site and even fatalities have been associated with the injection. However, cause and effect were never established and these patients had significant neuromuscular problems.12

   According to the Allergan Web site: “There has not been a confirmed serious case of spread of toxin effect away from the injection site when Botox has been used at the recommended dose to treat chronic migraine, severe underarm sweating, blepharospasm or strabismus, or when Botox Cosmetic has been used at the recommended dose to treat frown lines.”13

   Hypersensitivity reactions have been reported but are rare. One fatal case of anaphylaxis may have occurred with Botox or the lidocaine used in the reconstitution.14

   The medical benefits of botulinum toxin justify the risk in most cases.12 Over more than 30 years, clinicians collectively have performed millions of botulinum toxin injections. A 2009 FDA review of all botulinum toxin products identified 10 pediatric deaths and 17 adult deaths.15 All of these patients had underlying neuromuscular disorders. Allergan’s Web site notes “the available evidence does not suggest that Botox treatment is associated with an increased risk of mortality.”13

   It is uncommon for Botox to result in neutralizing antibodies. One study reports a 0.49 percent incidence and this appears to have very little influence on effectiveness.16 Botulinum toxin products now have a FDA required “black box” warning. While one should take care in the administration of botulinum toxin and keep the dose to the minimum effective dose required, some of the worry might be unjustified.17,18

   Relative contraindications to the use of botulinum toxin include: neuromuscular disorders such as amyotrophic lateral sclerosis, myasthenia gravis and Lambert-Eaton syndrome. Known hypersensitivity to ingredients in the product is a rare contraindication.19

Discerning Among The Different Types And Uses Of Botulinum Toxin

Botox, Dysport and Xeomin are all botulinum “A” toxins produced by three different companies. Myobloc is the “B” toxin. Although there is a lack of consensus on this issue, there is little to differentiate between the efficacy of Botox, Dysport and Xeomin. However, the preparations are different and one must keep this in mind when reconstituting the toxins.
While there is some controversy on this, a rough estimate is that between one and three units of Dysport are equivalent to one unit of Botox.20 Again, this is a wide range as there is not yet a consensus on this issue.

   Some studies suggest some differences in the duration of action and likelihood of side effects between the BTX-A toxins.21 Some of the difference might be due to uncertainties in volumes of reconstitution and how the formulations have changed over the past few years.21 Myobloc appears to have a more rapid onset but a shorter duration of action than the “A-toxins.”

   All the toxins come freeze dried and clinicians must reconstitute these agents. We use the recommended preservative free normal saline. About 10 to 25% of the diluent can be 1% lidocaine and this may decrease the pain of the injections.22

   The volume of normal saline (plus 1% lidocaine) to use is controversial. In cosmetic use, 1 cc is the common dose but 2 cc, 4 cc or even more is reasonable. The reason for using the lower amounts is supposedly to decrease the diffusion of toxins into unwanted areas. We have not found this to be a problem at 4 cc dilution. For hyperhidrosis, diffusion is less of a problem and probably helpful in covering a larger area and thus reducing the number of injections needed. Some patients may experience a focal, transient decrease in grip strength with palmar hyperhidrosis but this is minimal.

   It is essential to know the number of toxin units per cc. Botox comes with 100 units per vial. (In terms of “mouse units,” one unit is the median lethal dose (LD-50) in standard mice.) When Botox is reconstituted with 1 cc, this yields 100 units/cc. 4 cc yields 25 units/cc. An advantage of the higher volume is less loss of product due to the inevitable drops left on the skin surface or in the hub of the needle (the hub holds about 0.06 cc).
Botox is freeze dried and one should keep it in the freezer before reconstitution. Allergan now says refrigeration is sufficient although we still keep it in the freezer. One caveat is that before reconstitution, the vial looks empty so it is best not to discard it accidentally.

   The official direction is to mix very gently.23 In reality, the molecule may not be that fragile although we still mix gently. Another recommendation is to use all of the reconstituted toxin within eight hours. In reality, one can keep it in the refrigerator, not the freezer, for days or even longer.23

Key Insights On Injections For Plantar Hyperhidrosis

To assess the extent of hyperhidrosis, one can do a starch-iodine test on the sole and sides of the feet before toxin injection. Dry the foot, paint it with iodine and allow it to dry. The areas of hyperhidrosis will become moist from sweat. After one dusts the area with starch powder and blows off the excess, the powder will stick to the hyperhidrosis areas and turn purplish/blue/black.21,24-26

   Although this test works, it is usually unnecessary as the areas of hyperhidrosis are obvious to both the patient and the doctor. Having said that, it may save a few injections and a small amount of toxin.

   Toxin injections are very painful. While a stoic patient can tolerate injections with only the use of local ice, ethyl chloride spray and/or focal vibration (gate theory nerve block), most patients will require a posterior or anterior tibial tendon block.27,28

   One would inject toxins into all areas of excess sweating (as perceived by the patient and the doctor doing the procedure). We reconstitute with 4 cc of normal saline for a concentration of 25 Botox units (or equivalent units for Dysport) per cc. We inject using a Luer lock with a 1 cc tuberculin syringe and a 30 gauge one-half inch needle. Inject with the flat half of the bevel toward the skin at about a 30-degree angle with spacing of about 1.5 cm side to side and in a heel to toe direction. Injections are intradermal injections or superficial subcutaneous injections.

   We inject about 2.0 units of Botox (or “equivalent” Dysport) per site (0.08 cc with 4 cc of reconstituting fluid). Depending upon foot size and the extent of hyperhidrosis, this adds up to about 40 to 60 injections per foot. We use about 80 to 120 units of Botox (or equivalent) per foot. We do not find it necessary to do the starch-iodine test. We also do not find it necessary to mark a grid on the foot.

   Intradermal injections may cause a tiny, short-lived bleb. When intradermal injections are not possible due to skin thickness, one may perform superficial subcutaneous injections. Be aware that these injections sometimes lead to a small bump. Very minimal bleeding can be visible and this may be helpful in marking prior injection sites. Significant bleeding should not occur. However, if it does, pressure on the site quickly stops the bleeding.

   Patients can walk out of the office soon after the procedure. Use caution if using a foot block (especially if both feet have been blocked). It is better to have patients wait to leave the office until the blocks have started to wear off. Post-procedure foot soreness is uncommon.

   When clinicians use Botox for hyperhidrosis, the onset of effects usually occurs in two to four days with a peak effect in about two weeks. Significant effects then last between five and 15 months. Allergan claims that significant effects last about 200 days.15

   In our practice, patients have repeat injections about once a year. Significant reduction in sweating occurs in almost all patients. However, if one uses conservative amounts of toxin, one can perform a follow-up treatment — using a smaller amount of toxin — after about two weeks (but less than four weeks, which would be a free treatment). Try to avoid the need for “touch-up” treatment because of the likely need for another nerve block. (For some caveats on dosing, see “Pertinent Pointers On Ensuring The Correct Dosage” at right.)

   One can treat plantar hyperhidrosis effectively with either sympathectomy or botulinum toxin. However, sympathectomy can be complicated with compensatory hyperhidrosis in another body part. This is much less common with BTX-A injections. However, a somewhat surprising observation in one paper is that many patients afflicted with both palmar and plantar hyperhidrosis and treated with palmar BTX-A had a worsening in their plantar hyperhidrosis.24

In Conclusion

Topical use of botulinum toxin with nanotechnology is on the horizon. Preliminary studies involving the cosmetic use of botulinum toxin have shown similar efficacy to injections.26,32 If this approach proves to be efficacious, this will eliminate the painful injections into the palms and soles of the feet, the need for a nerve block and the need for skill in performing the procedure.

   Then many more licensed healthcare professionals will be “qualified” to treat hyperhidrosis with botulinum toxin and the cost will probably be less. There will also be marked increase in competition. The good comes with the bad and it is not something you should sweat about.

   Dr. Levine practices at Institute Beauté in New York City and is board-certified in podiatric surgery. She is the co-chair of the International Aesthetic Foot Society.

   Dr. Lautin practices at Institute Beauté in New York City. He is the co-chair of the International Aesthetic Foot Society.

References

1. Strutton DR, Kowalski JW, Glaser DA, Stang PE. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol. 2004; 51(2):241-248.
2. Loureiro M de P, de Campos JRM, Kauffman P, Jatene FB, Weigmann S, Fontana A. Endoscopic lumbar sympathectomy for women: effect on compensatory sweat. Clinics (Sao Paulo). 2008; 63(2):189-196.
3. Erbguth FJ. Historical notes on botulism, Clostridium botulinum, botulinum toxin, and the idea of the therapeutic use of the toxin. Mov Disord. 2004; 19(Suppl 8):S2-6.
4. Dhaked RK, Singh MK, Singh P, Gupta P. Botulinum toxin: bioweapon & magic drug. Indian J Med Res. 2010; 132(5):489-503.
5. Sobel J. Botulism. Clin Infect Dis. 2005; 41(8):1167-1173.
6. Smith LA. Botulism and vaccines for its prevention. Vaccine. 2009; 27(Suppl 4):D33-39.
7. Cherington M. Clinical spectrum of botulism. Muscle Nerve. 1998; 21(6):701-710.
8. Hambleton P. Clostridium botulinum toxins: a general review of involvement in disease, structure, mode of action and preparation for clinical use. J Neurol. 1992; 239(1):16-20.
9. Torrens JK. Clostridium botulinum was named because of association with “sausage poisoning.” BMJ. 1998; 316(7125):151-151.
10. Ting PT, Freiman A. The story of Clostridium botulinum: from food poisoning to Botox. Clin Med. 2004; 4(3):258-261.
11. Dolly JO, Aoki KR. The structure and mode of action of different botulinum toxins. Eur J Neurol. 2006; 13(Suppl 4):1-9.
12. O’Flaherty SJ, Janakan V, Morrow AM, Scheinberg AM, Waugh M-CA. Adverse events and health status following botulinum toxin type A injections in children with cerebral palsy. Dev Med Child Neurol. 2011; 53(2):125-130.
13. Medication Guide Botox® Cosmetic(onabotulinum toxin A) for Injection. 2010; Available from: https://www.allergan.com/products/medical_dermatology/botox.htm
14. Li M, Goldberger BA, Hopkins C. Fatal case of BOTOX-related anaphylaxis? J Forensic Sci. 2005; 50(1):169-172.
15. Available at https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2009/ucm17501…
16. Naumann M, Carruthers A, Carruthers J, Aurora SK, Zafonte R, Abu-Shakra S, Boodhoo T, Miller-Messana MA, Demos G, James L, Beddingfield F, VanDenburgh A, Chapman MA, Brin MF. Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications. Mov Disord. 2010; 25(13):2211-2218.
17. Kuehn BM. FDA requires black box warnings on labeling for botulinum toxin products. JAMA. 2009; 301(22):2316.
18. Narayanan UG. Botulinum toxin: does the black box warning justify change in practice? Dev Med Child Neurol. 2011; 53(2):101-102.
19. Botox Product Information: BOTOX® Cosmetic(onabotulinumtoxinA)for injection [Internet]. Available from: https://www.allergan.com/products/prescribing_information.htm
20. Wohlfarth K, Kampe K, Bigalke H. Pharmacokinetic properties of different formulations of botulinum neurotoxin type A. Mov Disord. 2004; 19(Suppl 8):S65-67.
21. Simonetta Moreau M, Cauhepe C, Magues JP, Senard JM. A double-blind, randomized, comparative study of Dysport vs. Botox in primary palmar hyperhidrosis. Br J Dermatol. 2003; 149(5):1041-1045.
22. Güleç A. Dilution of botulinum toxin A in lidocaine vs. in normal saline for the treatment of primary axillary hyperhidrosis: a double-blind, randomized, comparative preliminary study. J Eur Acad Dermatol Venereol. 2011; Epub ahead of print.
23. Shome D, Nair AG, Kapoor R, Jain V. Botulinum toxin A: is it really that fragile a molecule? Dermatol Surg. 2010 ;36(Suppl 4):2106-2110.
24. Gregoriou S, Rigopoulos D, Makris M, Liakou A, Agiosofitou E, Stefanaki C, Kontochristopoulos G. Effects of botulinum toxin-a therapy for palmar hyperhidrosis in plantar sweat production. Dermatol Surg. 2010; 36(4):496-498.
25. Lowe N, Campanati A, Bodokh I, Cliff S, Jaen P, Kreyden O, Naumann M, Offidani A, Vadoud J, Hamm H. The place of botulinum toxin type A in the treatment of focal hyperhidrosis. Br J Dermatol. 2004; 151(6):1115-1122.
26. Glogau RG. Topically applied botulinum toxin type A for the treatment of primary axillary hyperhidrosis: results of a randomized, blinded, vehicle-controlled study. Dermatol Surg. 2007; 33(1 Spec No.):S76-80.
27. Smith KC, Comite SL, Storwick GS. Ice minimizes discomfort associated with injection of botulinum toxin type A for the treatment of palmar and plantar hyperhidrosis. Dermatol Surg; 2007; 33(1 Spec No.):S88-91.
28. Richards RN. Ethyl chloride spray for sensory relief for botulinum toxin injections of the hands and feet. J Cutan Med Surg. 2009; 13(5):253-256.
29. Li Yim JFT, Weir CR. Botulinum toxin and pregnancy-a cautionary tale. Strabismus. 2010; 18(2):65-66.
30. El-Sayed YY, Caughey AB. Medical treatment for pregnant women: balancing risks and benefits. J Perinatol. 2009; 29(9):589-590.
31. Wataganara T, Leelakusolvong S, Sunsaneevithayakul P, Vantanasiri C. Treatment of severe achalasia during pregnancy with esophagoscopic injection of botulinum toxin A: a case report. J Perinatol. 2009; 29(9):637-639.
32. Howl J, Jones S. Transport molecules using reverse sequence HIV-Tat polypeptides: not just any old Tat? (WO200808225). Expert Opin Ther Pat. 2009; 19(9):1329-1333.

   Editor’s note: For those interested in training for botulinum toxin injections, the authors suggest the Web site of the IAFS (www.IAFS.com ) as a possible resource.

   For further reading, see “What You Should Know About Managing Hyperhidrosis” in the October 2004 issue of Podiatry Today.