Hyperhidrosis, Developing a Treatment Approach Aims 1 & 2

One objective of the Prosthetic Outcomes Research Award (PORA) is to improve the
understanding of secondary health effects on Service members and Veterans who have undergone
limb amputation and to advance the adoption and implementation of evidence-based
interventions. The investigators will address the important secondary health problem of
excessive residual limb sweating (hyperhidrosis) in amputees.

Successful use of a prosthesis requires a stable interface between the residual limb and the
prosthetic socket. Maintaining healthy skin, therefore, is paramount. However, the closed
environment necessary to provide this stable interface also creates an environment that may
lead to a multitude of skin problems. Amputees regularly deal with skin problems such as
sweating, eczematous itching and redness, infections, and mechanical problems such as
blisters and open wounds. Hyperhidrosis is the single most reported problem. Hyperhidrosis is
reported in up to 70% of amputee and is associated with reduced quality of life, reduced
prosthetic fit and function, decreased satisfaction with their prosthesis and skin
irritation. The investigators own published findings reveal that 66% of prosthetic users
(both veteran and civilian) experienced residual limb sweating that interfered with
activities of daily living. Sweating was rated as most bothersome in warm weather or with
vigorous activity, and the efficacy of treatment strategies was generally reported to be
poor.

Despite the frequency and impact of hyperhidrosis in amputees, there is a lack of evidence
based guidelines for evaluating and treating this problem. A number of knowledge gaps exist,
including no clear standard for assessing the burden of sweating in amputees, and no evidence
base from which to inform treatment decisions for either simple or more elaborate
interventions.

There is no universally accepted standard for assessing the burden and precise location of
sweating in amputee patients. Among the several subjective scales of hyperhidrosis severity
in the dermatology literature, the most commonly used and rigorously validated one is the
Hyperhidrosis Disease Severity Scale (HDSS). The HDSS provides a qualitative measure for the
severity of the patient's condition based on the extent to which hyperhidrosis affects daily
activities. The HDSS is simple to administer and scored as follows:

Hyperhidrosis Disease Severity Scale

Condition:

Score

1. My sweating is never noticeable and never interferes with my daily activities

2. My sweating is tolerable but sometimes interferes with my daily activities

3. My sweating is barely tolerable and frequently interferes with my daily activities

4. My sweating is intolerable and always interferes with my daily activities

In the general hyperhidrosis patient population (non-amputee), the HDSS exhibits moderate to
strong correlations with other quality of life and disease impact metrics, as well as with
gravimetric sweat production. A 1 point improvement on the HDSS correlates with a 50%
reduction in sweat production, while a 2 point improvement correlates with an 80% reduction
in sweat production. The investigators survey data shows the HDSS correlates well with
amputees' perception of the impact of sweating on their prosthesis fit and function, and is
therefore a valid outcome measure in the amputee population.

While the HDSS gives a global, patient-reported outcome of the significance of hyperhidrosis
in the patient's life, it does not inform the treating clinician on the precise location of
the problem. Dermatologists treating hyperhidrosis of other regions (i.e. axillary, palmar,
plantar) use the Minor iodine-starch test to identify the area of hyperhidrosis in order to
guide subsequent treatments. This test consists of an application of iodine, which is allowed
to dry and then dusted with cornstarch. Sweat will react with the iodine and starch and
produce a black/purple color. While this test is primarily used to identify the areas of
hyperhidrosis, a grading scale has been proposed for test interpretation and monitoring
response to treatments. There is scant literature describing the iodine-starch test in
amputees and the investigators early experience suggests that it is insufficient to simply
apply iodine and starch on a residual limb without then donning the patient's prosthesis. It
appears necessary to recreate the environment that produces the excessive sweating by donning
the prosthesis and ambulating. It is not known, however, what method is safe and effective,
without causing harm to the patient's skin and/or prosthetic materials.

As part of the scope of the research proposed herein, the investigators have done pilot work
with 9 subjects and 11 amputation sites, utilizing the iodine-starch test under a variety of
conditions to assess which method is most feasible to allow the patient to use their
prosthesis in the test. Preliminary results suggest that plastic wrap is adequate to protect
the prosthesis from significant iodine stain and does not cause new skin irritation, but is
more often viewed as uncomfortable. It also appears to induce a very rapid and diffuse
pattern sweating, raising concern for creating too much of a false positive effect. A
prosthetic sheath appears to protect the liner from dense stain, though some light iodine
stain has been observed to seep onto the liner in some cases. This method, though, is
generally viewed as comfortable to the patient, does not cause new skin irritation, and does
produce a positive test after 10 - 15 minutes of walking in focal areas more consistent with
the patient's described experience with sweat and sweat location.

The investigators believe that applying the iodine-starch combination, donning a prosthetic
sheath, the patient's own prosthesis, followed by a period of ambulation is the best method
for future studies.

Beyond the assessment of hyperhidrosis, treatment guidelines for this problem have not been
rigorously applied to amputees. In the dermatology literature, guidelines recommend using a
topical antiperspirant such as Aluminum Chloride (AlCl) as first line treatment. For axillary
hyperhidrosis, treatment success with AlCl (defined as a post treatment HDSS score of 1, has
varied from 33% to 72% in clinical trials). However, in the amputee population, there are no
published clinical trials describing the effectiveness or tolerability of a topical
treatment, and if it is ineffective or intolerable, when to consider another option such as
botulinum toxin injections, which are generally considered as second line treatment. The
investigators found through a survey that 50% of respondents had tried either an over the
counter or prescription strength antiperspirant. Of those respondents having tried such an
agent, nearly 50% reported them to have no efficacy, and only about 20% reported them to be
completely or mostly effective. Clearly this data has limitations, due to subject recall
bias, and is not the product of an intervention study. It does, however, illustrate that a
majority of amputees may not have satisfactory options to treat this problem.

There have been a few case reports and/or case series reporting the use of botulinum toxin to
treat this problem in amputees. While these preliminary reports suggest that botulinum toxin
is an effective treatment option, they are limited by the fact that the intervention was
tried on such a small number of patients. Kern et al used botulinum toxin type B (BTX-B) in 9
patients while Charrow et al. used botulinum toxin type A (BTX-A) in 8 patients. Both
reported good effectiveness in treating hyperhidrosis but neither utilized a validated method
to determine effectiveness, nor did the subjects fail a topical treatment prior to botulinum
toxin treatment.

Further, there is no published literature describing the best way to localize botulinum toxin
application for amputee hyperhidrosis. In considering the feasibility of widespread adoption
of botulinum toxin as a treatment for amputee hyperhidrosis, one of the biggest barriers
could be the large surface area involved that needs to be treated.

Dermatologists use the iodine-starch test to identify the hyperhidrotric area that will be
targeted with the botulinum toxin injection. For palmar, axillary, and plantar hyperhidrosis,
it is recommended that every patient be assessed with this method. A single case study has
reported the successful use of the iodine-starch test to help identify hyperhidrotic areas on
a residual limb. However, it has not been well studied to know if the iodine-starch test can
be utilized in amputees to identify potential sites for injection, or even if the pattern of
sweating can be demonstrated to be a focal, not a global, problem. If the iodine-starch test
can be used successfully in amputees, it could help direct botulinum toxin injections to a
focused area, rather than an entire residual limb. This could have significant impact on the
overall tolerability of the procedure and the willingness of both patients and providers to
implement it in usual clinical care.

Aim 1 and Aim 2

Inclusion Criteria:

- Provision of signed and dated informed consent form (ICF)

- Stated willingness to comply with all study procedures and availability for the
duration of the study

- Male or female, age 18 or older

- Have a prosthetic device

- In good general health as evidenced by medical history

- If subject is currently using aluminum chloride participant must be discontinued for
at least one week prior to participation in the study.

Exclusion Criteria:

- Open sores or wounds on the residual limb

- Known sensitivity or allergy to iodine

- Known sensitivity to antiperspirant, aluminum chloride hexahydrate