Essential Primary Hyperhidrosis is a disorder of unknown etiology, characterized by excessive uncontrollable sweating in a specific body area. It is most often found on the palmar surfaces on hands (40%), feet (40%), armpits (10%), and groin (10%), due to increased firing of sympathetic cholinergic sudmoter nerves(Naumann et al, 2004). Essential Primary hyperhidrosis is estimated at 2.8% of the population in the United States, affecting men and women equally, and most commonly occurring among people aged 25–64 years (Haider, 2005). About 30–50% have another family member afflicted (implying genetic predisposition).
While Essential Primary Hyperhidrosis is not considered a serious or life threatening condition, it has a tremendous impact in a person’s overall quality of life regardless of where it occurs, to the point where people with excessive seating may be stereotyped as anxious, nervous, socially awkward or lacking self-confidence (Claes, 1994). Palmar hyperhidrosis (HH) seems to be by far the most debilitating affliction of them all, since basic chores of life become problematic. Some everyday examples include: shaking someone’s hand, attempting to write with a pen or simply trying to eat with a fork and knife. While there are many varying treatments available for Palmar HH , ranging from internal treatments (iontophoresis) to external treatments(essential mineral oils) to full blown surgery (endoscopic thoracic sympathectomy), this report will focus on the main 2 strategies for optimizing treatment outcomes for palmar HH, which are: Aluminum Chloride Hexahydrate and Botulimun Toxin A (Botox©).
To better understand why hyperdydrosis occurs, it is best to understand that sweat is a required function of the body, to serve as a coolant against overheating. Your body has several million sweat glands, the bulk of which are eccrine glands which secrete an odorless, clear fluid that help regulate body temperature through evaporative heat loss. These sweat glands become activated due to variety of stimuli, including: heat, stress, and physical exercise. Hyperhidrosis involves overactive sweat glands, producing more sweat than needed. While the cause of overactive sweat glands is relatively unknown, it is most commonly attributed to: nervousness, extreme excitement, nicotine, certain smells, and caffeine. A doctor can diagnose hyperhidrosis using a variety of tests at hand, including but not limited to a starch-Iodine test, paper test and laboratory tests. A Starch-Iodine test is performed, where an iodine solution is applied to the sweaty area, covered lightly over with a starch solution. The starch-iodine combination will turn a dark blue color, indicating where there is excess sweat production. A paper test, is performed by placing a special paper over the affected area, and then weighted to determine the amount of sweating that occurs. A third test includes a few laboratory tests that may be performed (such as thyroid function tests, blood glucose and uric level acid measurements), to rule to more serious medical conditions that may be associated with excessive sweating.
Uses and function of Botulimun Toxin A
In the early 19th century, Justinus Kerner (1786–1826) was the first to speculate about the potential therapeutic uses of Botulinum toxin in muscle hyperactivity disorders (Dressler, 2007). The first therapeutic use of Botox was proposed during the late 1960’s by Alan B. Scott of the Smith-Kettlewell Eye Research Institute. In 1997, Scott was the first to therapeutically inject these Botox preparations directly into overactive muscles to treat children with strabismus. After the successful treatment of these patients, physicians began using focal injections of Botox for other conditions involving overactive contraction of muscle. (Hallet, 2009)
While several strains of Botulimun toxin exist, the most commonly used to treat HH is Botulimun toxin A. Botulimun toxin A is commercially manufactured as Botox© and Dysport©. These are 2 different agents, with one unit of Botox being approximately equivalent to three units of Dysport. The toxin is licensed as a treatment for a number of indications, mainly dystonia and spasm, but is also very commonly used for cosmetic purposes to reduce the effects of ageing. When Botox is injected into the skin, the treatment affects the signal between the nerve endings and the sweat glands in the dermis. The Botulinum toxin binds itself to the nerve endings near the injection site and acts like a roadblock. It blocks the release of the neurotransmitter acetylcholine, a chemical our nerve cells use to communicate with each other, and this disrupts the message sent from the nerve endings to stimulate the production of sweat. The chemical makeup of Botulinum toxin A is bacterium Clostridium Botulimun.
The toxin is composed of a heavy chain and a light chain joined by a disulphide bond(Dolly, 1997).Action of Botulinum toxin at cholinergic nerve terminals. The heavy chain of the toxin binds selectively and irreversibly to high affinity receptors at the presynaptic surface of cholinergic neurons, and the toxin-receptor complex is taken up into the cell by endocytosis. The disulphide bond between the two chains is cleaved, and the toxin escapes into the cytoplasm. The light chains of the seven serotypes interact with different proteins (synaptosomal associated protein (SNAP) 25, vesicle associated membrane protein (VAMP) and syntaxin) in the nerve terminals to prevent fusion of acetylcholine vesicles with the cell membrane and thereby impeding its release (Moore, 1995).
Method- Botox is injected via a very small needle (most commonly used is a 30-gauge tuberculin syringe with a ½-inch needle) deep into the skin. The optimal depth of injection for the needle is between dermis and subcutaneous tissue layer, where most of the essential eccrine glands are located. Failure of the syringe to be injected properly (such as inserting the needle at a perpendicular angle and not an oblique angle) will create is a strong possibility that the Botox will diffuse and travel into the intrinsic muscles of the hand, causing severe hand weakness (Saddia et al, 2007). For mild-to-moderate palmar HH, approximately 40-50 injections of .05 -.01 ml. spaced 1.5 cm apart are injected into the palm, for a total dosage of approximately 100U (Hornberger et al, 2004). Most patients receiving this many needles injected will experience some degree of hand weakness that begins 1-3 days after treatment and will persists for approximately 2 weeks following treatment (Swartling et al, 2000). For those that rely on their hand for their profession such as dentists, musicians, and surgeons, the two options given is that the treatment will be given at with less incisions or the treatment will be extended over a longer period of time, thus minimizing hand weakness.
Aluminum Chloride Hexahydrate
The vast majority of antiperspirants used to treat hyperhidrosis will use some form of an aluminum based compound as being the central active ingredient. Historically, aluminum chloride hexahydrate is the primary aluminum of choice. Aluminum chloride Hexahydrate(AlCl3•6H2O) is a compound composed of aluminum and chlorine .The solid has a low boiling and melting point, and is bonded ionicly with significant covalent character. Aluminum Chloride Hexahydrate (ACH) functions as an antiperspirant in a way that it is absorbed into the top layer of the applied skin. As the aluminum ions absorb into the cells, water is absorbed with them, causing the cells to swell. Metal ions precipitate with mucopolysaccharides, damaging epithelial cells along the lumen of the duct and forming a plug that blocks sweat output. The swelling of the cell causes it to increase in size, thereby closing the sweat glands, and trapping the fluid in the cell and not allowing it to escape outside the body (Kim, 2000).
Some of the more common medications that use the Aluminum Chloride Hexahydrate formula are Hypercare, Drysol, and Maxim. These different types of medications will have varying amounts of ACH, with Hypercare and Maxim using 20- 25 % ACH, while the Drysol solution uses closer to 40% ACH. The medication is administered externally either via a cream/spray or through a gel. When using the topical antiperspirant, the palms should be cleaned and properly dried. The skin has to be dried before application, since if moisture is present; irritating hydrochloric acid may form (Stolman, 2003).A thin filmy coating covering the affected areas of the palms should be applied and subsequently be allowed it to dry. The optimal time of applying the medication is prior to bedtime, as you'll want the solution to permeate the skin for a maximum time period without getting messed up. It is recommended that following application, to cover their hands in a plastic glove, thus increasing the likelihood of maximum penetration of the solution into sweat gland pores.
Dosages and Effectiveness: While all seem to agree that Botulinum Toxin is an effective treatment for hyperhidrosis, there seems to be varying schools of thought concerning the proper dosage to be given. In a prospective, single blind, randomized trial, Dr. H. Kaufmann of Mount Sinai School of Medicine (Saadia el al, 2001) observed a study of 24 patients with severe palmar hyperhidrosis, with each receiving either a low (50 U) or a high dose (100 U) of Botulimun toxin type A, divided equally in 20 injection sites following a predefined grid drawn in the hand, with the patients being blinded as to the dose received. The study lasted 6 months, with patients being evaluated every 2 weeks during the first month, and then every subsequent month until the end of the study. Botulimun toxin was diluted in 0.9% saline solution to achieve a concentration of 2.5 U per 0.15 mL in the low dose (50 U) group and 5U per 0.15 mL in the high dose (100 U) group. The overall result of the study was that those with 50U injections received a more than satisfactory result compared to those with the large dose of 100U.
There are countless studies that can attest to the effectiveness of Botulimun Toxin as an effective treatment plan for palmar HH. In fact a recent study released by Bodokh and Branger compared the effectiveness of treatment with Botox in one hand compared to no treatment in the other control hand. This study showed a 75% improvement in sweat reduction in the hand of the patient that was treated with the Botox (Bodokh, 2003). In a similar study by Solomon and Hayman, all 20 patients with Palmar HH that were treated with Botox saw reduced sweat production significantly in the treated areas with anhidrosis (deficiency/absence of perspiration) lasting from 4 to 9 months ( Rayner et al, 2000). In yet a third study, a multicenter placebo controlled trial injections of Botulinum toxin (100 to 200 units of Botox) in 145 patients with hyperhidrosis reduced sweat production six fold (Heckmann et al, 2001). However there are serious side effects as well as risks in the use Botox.
Aluminum Chloride Hexahydrate dosage-The proper dosage of ACH to treat palmar HH varies with the individual. Generally patients prescribed with ACH start off with 40% solution (ex: drysol), eventually upping their way up to 55%.However these formulations of ACH in an alcohol solution have been limited by patient tolerance. In one study, up to 26 percent of patients found the associated solution accompanied with dryness of the skin and internal pain (Scholes et al, 1978).Maxim and Hypercare have lower concentrations of ACH and is used as a lower concentration to treat HH. If this lower concentration of 20-25% ACH does not work, it’s possible to go even lower dose of ACH to achieve anhidrosis. Observations from a busy hyperhidrosis practice revealed decreased irritation and increased efficacy with a novel therapy that combines 15% aluminum chloride hexahydrate with 2% salicylic acid in a gel base. This combination of 15% aluminum chloride hexahydrate with 2% salicylic acid offers patients who have failed aluminum chloride hexahydrate in the past, due to increased irritation excellent efficacy with minimal irritation (Heather, 2009). In a study entitled: Palmar and plantar hyperhidrosis: a practical management algorithm (Benohanian et al, 2007) 456 patients being treated for palmar all used different amounts of ACH to achieve anhidrosis(Table 4). In conclusion, the proper ACH dosage varies by the patient and can be fluctuated until optimal results occur. Damage to clothing may also occur, so expensive clothing should be avoided, when applying ACH (Tögel, 2012)
Disadvantages, risks, and adverse side effects:
The main reported drawback of Botulimun toxin treatment was pain during the injection and a weakness in the intrinsic hand muscles following treatment. The pain of multiple injections can be minimized by local median and ulnar nerve blockade (Almeida, et. al., 2001). To accomplish doctors will inject lidocaine (a local anesthetic and antiarrhythmic drug) in a subcutaneous infiltration to the radial artery and extends toward the dorsum of the wrist (Ramamurthy et al, 1993). In conclusion, although there is pain involved in Botox injections, the use of anesthetics will turn the previously very painful Botulinum toxin treatment of palmar hyperhidrosis into a more comfortable procedure.
While there are possible temporary side effects stemming from Botox injections (bruising at the injection site, headache, indigestion, and nausea), there is a serious side effect (which is permanent), and that is known as botulism. This happens when the Botulinum toxin spreads to other body areas beyond where it was injected to, paralyzing/weakening the muscles used for breathing and swallowing, causing a potentially fatal (Kuehn, 2009). In September 2005, a paper published in the Journal of American Academy of Dermatology reported from the FDA saying that use of Botox has resulted in 28 deaths between 1989 and 2003 (Mohan et al, 2005) .On February 8, 2008, the FDA announced Botox has "been linked in some cases to adverse reactions, including respiratory failure and death, following treatment of a variety of conditions using a wide range of doses", due to its ability to spread to areas distant from the site of the injection(Food and Drug Administration, 2008). Due to this phenomenon, the US Food and Drug Administration currently requires manufacturers to label Botulinum Toxin products with black box warnings about the possible risk of botulism like symptoms associated with the toxin (Food and Drug Administration, 2009)
There are those that voice concerns that Botox injections in the palm may impede the release of acetylcholine at the neuromuscular junctions, thereby decreasing muscle tone and motor function in the hand. This however has not been found to be the case(Haton et. al.,2003).In a controlled study of the use of Botox treatment in 19 patients concluded that patients experienced a significant decrease of anhidrosis without a concomitant decrease in grip strength, significant finger dexterity, or the occurrence of notable adverse events(Lowe et al 2002).However, in a recent counter study entitled “Side-effects of intradermal injections of Botulinum A toxin in the treatment of palmar hyperhidrosis: a neurophysiological study”, Swartlinga, FaÈrnstr, Abt and Naverc measured the amount of hand weakness in 3 hand muscle as well as muscle power in the fingers, over various time periods following the injection of Botox. As seen in the table below (Table 5), muscle weakness and muscle function does initially decrease following treatment, but decreases intermittingly, and is nearly obsolete at 37 weeks
The most common adverse effects of using a aluminum chloride treatment, are itching and stinging immediately following application. This however is short and not lasting. In a sample test of 702 patients, the recorded pain was slight and short in duration in 70%, moderate in 21%, and severe in 9% (Hölzle, 2002). There are also some reported cases of ongoing skin irritation that cause dermatitis. This also can simply solved (as stated previously) by lowering the percentage of the aluminum chloride in the solution.
Cost effectiveness vs. remission time: While each treatment typically works for four to six months at a time, costs are high: In 2009, the American Society of Plastic Surgeons estimated national surgeons' average fee was $405 for a single dose of Botulinum toxin treatment (Naumann, et. al, 1999). Using simple math, a patient requiring this treatment every 6 months to achieve acceptable sympathetic relief, would over a ten year period ,be spending over $8000 in out of pocket costs to cover his treatment. On the flip side, an expensive bottle of aluminum chloride solution can be purchased for as little as $15. Even if you were to use an entire bottle every 2 month, the total cost over a ten year period will come out to less than $1500, thus a clear advantage in using Aluminum Chloride over Botox.
Tolerance
All patients will develop some level of tolerance to Botox injections. This is caused by the development of neutralizing antibodies to the toxin. Patients who receive higher individual doses or frequent booster injections seem to have a higher risk of developing antibodies. Studies have shown that 3-5% of the patients develop neutralizing antibodies against the toxin that lead to resistance (Zuber et al, 1993). More so, the effects of a Botox injection are temporary. It’s very possible for symptoms may return completely in little as 3 months following initial treatment. After repeat injections, it may take less and less time before your symptoms return, especially if your body develops antibodies to the Botulinum toxin. Aluminum Chloride Hexahydrate however has no way to develop a tolerance level based on the mechanism of the medication. However, normal sweat gland function returns with epidermal renewal, necessitating retreatment of the ACH once or twice a week (Hölzle).
Conclusion:
Excessive sweating of the palms has massive consequences on a person’s quality of life. Recognition of the fact that there are medications and treatment options available is the first necessary step towards a complete recovery. That being said, Aluminum Chloride Hexahydrate should be used as the first line of therapy in the treatment of palmar hyperhidrosis. This is based on the fact that it is an inexpensive treatment, it is relatively simple to use, is nearly painless, has very limited side effects, and its all-around effectiveness has been proven from multiple studies. Furthermore the dosage can be heightened or lowered on a daily basis making the medication extremely flexible and simple to use.
While ACH is the preferred method of use, the use of Botox is still commercially used worldwide. One should be aware that there are serious side effects as well as risks in the use Botox, which include but are not limited to; the pain of multiple needles, decreased muscle function following the treatment and of course the possibility of botulism. Long term cost effectiveness and immunoresistance from repeated injections of Botox should also be taken into account before opting for this treatment modality.
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