Hyperhidrosis

Etiology

Hyperhidrosis can be categorized as either primary or secondary. This distinction is important 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 poorly 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 some adults' forehead, axilla, palm, feet, or forearm. 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. No evidence shows 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, sending impulses as a physiologic response to core body temperature control during 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 endings. 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.

History and Physical

Patients with hyperhidrosis 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 6 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 effects or systemic disease is warranted. Diagnosis is usually made from clinical assessment; 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 is also beneficial during treatment.[3]

Diagnostic criteria for primary hyperhidrosis:

1. Excessive sweating for 6 or more months
2. Sweating involves the 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 first to determine whether the source is primary or secondary, and a thorough history helps 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 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

As more treatment options have become available, treating hyperhidrosis has become easier for clinicians. A stepwise approach is often effective, and many topical and systemic agents are available.

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 for treating sweating. Aluminum chloride gel can be used to manage axillary sweating. While it does work, it is a potent irritant.

All topical agents can cause skin sensitization; some, like tannic acid and potassium permanganate, can also cause skin discoloration. These agents appear to decrease sweating by denaturing keratin, thus occluding the sweat glands' pores. The duration of the effect is very short. If a patient does not respond to topical treatment or has more generalized symptoms, oral anticholinergic medications should be considered, including oxybutynin 5 mg to 10 mg daily or topical glycopyrrolate 0.5% to 2.0%.[7] Anticholinergic agents can cause dry eyes, mouth, urinary retention, and constipation.

Iontophoresis 2 to 3 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; 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 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 somewhat permanent treatment. 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 discontinuation of the suspected medication is recommended in addition to regular therapy.[9](B3)

Differential Diagnosis

The differential diagnosis for hyperhidrosis includes the following:

• 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

The complications that can manifest with hyperhidrosis include the following:

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