Continuing Education Activity

Hyperhidrosis is a disorder of excessive sweating due to the overstimulation of cholinergic receptors on eccrine glands. This disorder is characterized by sweating beyond what the body uses for homeostatic temperature regulation. Eccrine glands are concentrated in areas such as the axillae, palms, soles, and face; therefore, these are the areas most commonly associated with hyperhidrosis. This activity describes the pathophysiology of hyperhidrosis and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of hyperhidrosis.
• Recall the workup of a patient with hyperhidrosis.
• Summarize the treatment options for hyperhidrosis.
• Review the importance of improving care coordination among interprofessional team members to improve outcomes for patients affected by hyperhidrosis.

Introduction

Hyperhidrosis is a disorder of excessive sweating due to the overstimulation of cholinergic receptors on eccrine glands. This disorder is characterized by sweating beyond what the body uses for homeostatic temperature regulation.[1] Eccrine glands are concentrated in areas such as the axillae, palms, soles, and face; therefore, these are the areas most commonly associated with hyperhidrosis.[2] The acetylcholine negative feedback loop is likely impaired in these patients, which may help explain how a physiologic response can become pathologic.[3] Studies have shown the prevalence of this disorder to be approximately 3% in the United States. Hyperhidrosis can result in emotional, psychological, social, and occupational impairment.[4]

Hyperhidrosis is classified as primary and secondary, and the management and treatment can significantly differ for each. The primary disease typically presents earlier in life with more localized symptoms. The secondary disease typically presents due to adverse effects of medications or systemic disorders, particularly neurologic.[3][5] The diagnosis most often is made clinically, and grading scales and tests are available to assist in determining the severity and localization. Laboratory workup may be indicated if a secondary cause is suspected to rule out infection, hyperthyroidism, diabetes mellitus, neurologic disorder, or a medication side-effect.[2] There are several treatment options for hyperhidrosis, including topical aluminum chloride and oral anticholinergic medications, which are sufficient in patients with mild to moderate disease.[6] Botulinum toxin A injections, sympathectomy, and local excision are also effective but reserved for patients that are resistant to conservative therapy.[7][8]

Etiology

Hyperhidrosis can be categorized as either primary or secondary. This distinction is important to make because treatment and management may significantly differ between the two groups. The etiology of primary hyperhidrosis remains unknown despite multiple literature reviews.[1] Genetic factors are believed to play a role in excessive neural stimulation, although this is not well understood. Secondary causes are usually easier to identify because they are associated with medications such as dopamine agonists, selective serotonin reuptake inhibitors (SSRIs), antipsychotics, and insulin; systemic disorders such as diabetes mellitus, hyperthyroidism, Parkinson disease, and other neurologic disorders; and tumors such as pheochromocytoma and lymphoma.[3]

Almost any febrile illness can cause hyperhidrosis. Chronic excessive alcohol consumption and tuberculosis are also associated with hyperhidrosis.

Developing segmental or localized hyperhidrosis is rare. The condition can present on the forehead, axilla, palm, feet, or forearm in some adults. Some postmenopausal women develop moderate to severe hyperhidrosis around their face and scalp. Unilateral hyperhidrosis tends to be more common on the right side of the face or arm, with anhidrosis on the left side.

Epidemiology

Hyperhidrosis affects approximately 3% of the United States population and is most common in patients between 20 to 60 years of age. There has been no evidence showing that either men or women are at increased risk.[4] The palmar region is the most commonly affected area.[2]

Hyperhidrosis affects all races, but data show that the Japanese are more affected than any other ethnic group.

Pathophysiology

Eccrine sweat glands receive sympathetic innervation via cholinergic fibers that send impulses as a physiologic response to core body temperature control during times of physical or psychological stress. The thermoregulatory center of the hypothalamus mediates sympathetic innervation to the sweat glands. Cholinergic stimulation of muscarinic receptors induces sweating. Hyperhidrosis involves hyperactivity of the sympathetic nervous system, causing excessive release of acetylcholine from the nerve ending. It is believed that the negative feedback mechanism to the hypothalamus may be impaired, causing the body to sweat more than what is needed to cool the body. This pathologic reaction can be triggered by medications that increase the release of acetylcholine from the neuron or systemic medical disorders, which also upregulate a sympathetic response.[3][6]

Histopathology

On histologic examination, eccrine glands appear normal in size and number compared to those without the disorder. However, the sympathetic ganglia in these patients are usually larger.[3] This supports the theory that hyperhidrosis is a disorder of excessive cholinergic stimulation instead of a problem with the eccrine glands themselves.

History and Physical

Patients with hyperhidrosis will report excessive sweating, usually in areas with the highest density of eccrine glands, including the palms, soles, face, head, or axillae. Primary hyperhidrosis is more commonly seen in the younger population, those with symptoms for more than six months, those with a family history of the disorder, and those with bilateral involvement.[2] Symptoms that present later in life should be more concerning for a secondary cause, and a workup to rule out medication side effect or systemic disease is warranted. Diagnosis is usually made from clinical assessment, and thus, a visual inspection of the common sites is recommended. There are visual scales available to quantify the severity of palmar sweat. When localization is in question, an iodine-starch test can help localize the areas of concern, which will also be beneficial at the time of treatment.[3]

Diagnostic criteria for primary hyperhidrosis:

1. Excessive sweating for 6 or more months
2. Sweating involves axilla, palms, soles, and/or face
3. Sweating is bilateral and symmetric
4. Decreased or no sweating at night
5. Sweating episodes last at least 7 days
6. The individual is 25 years of age or younger
7. There is a family history
8. Sweating impairs daily living activities

Evaluation

It is important to first determine whether the source is primary or secondary, and a thorough history will help differentiate. If a secondary cause is suspected, providers should consider ordering a complete blood count, basic metabolic panel, thyroid-stimulating hormone, sedimentation rate, antinuclear antibody, hemoglobin A1C, and chest x-ray.[2][5] These tests will assist in ruling out infection, kidney dysfunction, malignancy, diabetes mellitus, thyroid disease, an inflammatory disorder, or connective tissue disease, which can all be associated with hyperhidrosis. Providers can also thoroughly evaluate the severity of the disease by assessing the amount of palmar involvement using a measuring scale or determining the disease pattern using a starch-iodine test. These are not widely used because visual assessment alone is usually sufficient to make the diagnosis.[3]

Treatment / Management

Treating hyperhidrosis has become easier for clinicians as more treatment options have become available, and a stepwise approach is often effective. There are many topical and systemic agents available to treat hyperhidrosis.

First-line therapy for hyperhidrosis includes over-the-counter aluminum chloride hexahydrate 20% for 3 to 4 nights, then nightly as needed. Skin irritation can occur, and patients often become intolerant of it in the long term.[6]

Recently topical glycopyrronium tosylate (premoistened cloth containing 2.4% glycopyrronium solution) was approved to treat sweating.

Axillary sweating can be managed with aluminum chloride gel. While it does work, it is a potent irritant.

All topical agents can cause skin sensitization, and some, like tannic acid and potassium permanganate, can also cause skin discoloration. These agents appear to decrease sweating by denaturing keratin and thus occluding the pores of the sweat glands. The duration of the effect is very short.

If a patient does not respond to topical treatment or there are more generalized symptoms, oral anticholinergic medications, including oxybutynin 5 mg to 10 mg per day or topical glycopyrrolate 0.5% to 2.0%, should be considered.[7] Anticholinergic agents can cause dry eyes, dry mouth, urinary retention, and constipation.

Iontophoresis two to three times weekly and botulinum toxin A injections every 3 to 4 weeks are effective if patients fail topical and oral drug therapy. Iontophoresis is a long-term treatment, and at best, its effects are mild. Many agents can be added to the water, but compliance with this treatment is low.[8]

Botulinum toxin is effective; however, it is expensive, and repeat treatments are required. Some experts recommend botulinum toxin plus lidocaine for injection into the axilla. Botulinum toxin A acts by cleaving the SNAP-25 protein. This prevents the binding and presynaptic fusion of the acetylcholine vesicles with the nerve terminus and thus blocks the release of acetylcholine. It is the most appropriate treatment after failing topical antiperspirants and oral anticholinergics. Decreased perspiration can last from 6 to 24 months. Injections are usually performed in both axillae; however, they also can be useful in the palms and soles. These locations are less practical and will likely require local anesthesia to limit discomfort.

More invasive therapeutic measures are available, including sympathectomy or local excision as a last resort. Many surgical procedures have been developed to manage hyperhidrosis, including sympathectomy, radiofrequency ablation, subcutaneous liposuction, and surgical excision of affected areas. Of all these, sympathectomy appears to be the best treatment that is somewhat permanent. It involves excision of the ganglia (T2-T4) responsible for sweating. Resection of T1 ganglia is done for facial sweating, T2 and T3 for palmar sweating, and T4 for axillary sweating. The procedure can be done thoracoscopically, but complications are common. Compensatory sweating, gustatory sweating, Horner syndrome, pneumothorax, pain, and intercostal neuralgia have all been reported.

If a secondary cause is suspected, treatment of the underlying disorder or discontinuing the suspected medication is recommended in addition to regular therapy.[9]

Differential Diagnosis

• Thyrotoxicosis
• Neuropathy
• Hypoglycemia
• Pheochromocytoma
• Menopause
• Lymphoma
• Tuberculosis
• Alcohol use disorder

Prognosis

The prognosis of hyperhidrosis is guarded. While not life-threatening, it can be cosmetically unacceptable and may even lead to difficulties with work. The quality of life for patients with severe hyperhidrosis is poor. No treatment works reliably, and the recurrence of hyperhidrosis is common with all currently available treatment options. Newer surgical treatments offer hope but do not always provide a cure.

Complications

• Social embarrassment
• Emotional distress
• Psychological distress
• Work or school-related disability

Pearls and Other Issues

Hyperhidrosis can affect not only a patient's physical health but also their psychological health. Patients, particularly those within the pediatric population, may suffer from social embarrassment leading to a lower quality of life than their peers.[4][10] It is important for healthcare providers to screen for this condition.

Enhancing Healthcare Team Outcomes

Hyperhidrosis is a common complaint in clinical practice, and while there are many treatments available, many are unsatisfactory. Thus, the disorder is best managed by an interprofessional team that includes the primary care provider, nurse specialist, thoracic surgeon, plastic surgeon, and internist. The goal is to reduce sweating with minimal complications.

The pharmacist should educate the patient on all the topical and systemic products available to manage sweating. The patient should be aware of the adverse effects and potential complications.

A dermatologist should be consulted if the cause is unknown.

For recalcitrant cases, a thoracic surgeon should be consulted.

A mental health nurse and psychiatrist should assist with mental health support as the disorder can cause severe emotional distress.

Most topical and nonsurgical treatments do not work reliably. Surgery can be done, but recurrences are not uncommon. Patients need to be educated about all the potential treatments, including their effectiveness and any associated morbidity. A team approach can deliver the optimal treatment for hyperhidrosis and improve outcomes.