Introduction

Anhidrosis is the inability to sweat. It is important to recognize anhidrosis as it can be potentially life-threatening due to heat-related illnesses. There are three main causes of anhidrosis, which are peripheral alterations in the eccrine gland itself, idiopathic, and central or neuropathic disease and/or medication that disrupts neural inputs from the anterior hypothalamus to the gland.

Causes of central/neuropathic anhidrosis can occur at any level of innervation. The disturbance can occur at the sweating center in the brain, the descending neural tract, or the sweat gland. A disruption will lead to an absence of sweating. Disruption in the neural input can be due to tumors or infarctions of the hypothalamus, pons, or medulla. Spinal cord tumors, injuries, or infarctions can disrupt the neural tract. Other etiologies such as degenerative syndromes (Shy-Drager syndrome), autoimmune autonomic neuropathy, peripheral neuropathy (diabetes, alcohol use disorder, leprosy), and drugs have all been implicated in central/neuropathic anhidrosis.

Peripheral alterations that cause anhidrosis can be congenital or acquired. In addition, forms of peripheral alterations can be due to genetic abnormalities such as incontinentia pigmenti, due to local destruction, for example, by a tumor, or obstruction by entities such as psoriasis.

As heat intolerance may be due to various underlying disorders, a detailed history is important in establishing the diagnosis. Heat intolerance can cause drowsiness, episodic inability to concentrate while in a hot environment, or fatigue, along with a decrease in the patient's normal sweating, which are clues to the diagnosis of anhidrosis. A detailed history should also include the addition of medications, medical events such as injuries, growths or radiation, alcohol consumption, the presence of autoimmune disease or diabetes mellitus, and family history.

Causes

Central and neuropathic causes of anhidrosis can occur anywhere along the neural track, as previously stated. There are diagnostic clues that will aid in locating the area of the lesion. If there is the involvement of the pons or medulla, the patient will have ipsilateral facial and neck anhidrosis. Neural tracks in the spinal cord have both crossed and uncrossed fibers. Therefore, alterations in the spinal cord will result in anhidrosis of the skin that can be either ipsilateral or contralateral. Peripheral neuropathies tend to be symmetrical as in diabetes mellitus and alcohol use disorder. However, there are cases of asymmetrical peripheral neuropathy leading to anhidrosis, such as in cases of leprosy. A patient with Horner syndrome will present after the disruption of the superior cervical ganglion. Regional anhidrosis can also occur due to the chemical blockade of a selected sympathetic ganglion. Congenital insensitivity to pain with anhidrosis is a rare entity that is autosomal and recessive. It presents with self-mutilation due to a lack of pain, intellectual disability, and recurrent fevers due to anhidrosis.

Drugs that interfere with the synaptic transmission in the autonomic ganglia will lead to anhidrosis:

• Nicotinic acetylcholine receptor antagonists such as hexamethonium and trimethaphan

• Muscarinic acetylcholine receptor antagonists such as atropine or scopolamine

• Calcium channel blockers

• Alpha-adrenergic blockers such as phentolamine

• Alpha2-adrenergic agonists such as clonidine

• 5-fluorouracil

• Topiramate

• Zonisamide

• Quinacrine

There are numerous causes of abnormalities in the sweat gland that cause anhidrosis. Among the various causes are several hereditary and acquired systemic diseases that present with generalized or localized anhidrosis. Males with X-linked hypohidrotic ectodermal dysplasia will have an absence of sweat glands, whereas female carriers will have hypohidrosis or reduced sweating. The other ectodermal dysplasias, such as Rapp-Hodgkin syndrome and Naegeli-Franceschetti-Jadassohn syndrome, can lead to sweat gland abnormalities. Though not an exhaustive list, there are other rare inherited syndromes in which genetic errors result in sweat gland dysfunction such as Bazex-Dupre-Christol syndrome and Fabry disease.

Local tissue destruction can be the culprit of acquired localized anhidrosis. Tumors, radiation therapy, systemic sclerosis, burns, graft-versus-host disease, acrodermatitis chronica atrophicans, and Sjögren syndrome can distort the normal architecture of the skin with subsequent anhidrosis. Entities that lead to obstruction of the glands are also implicated in anhidrosis. Psoriasis, lamellar ichthyosis, miliaria, eczematous dermatoses, porokeratosis, and bullous diseases are examples of obstruction.

Evaluation

Detailed patient history is paramount in determining the possible underlying etiology. The next step would be to determine any potential contributing factors, such as medications. Colorimetric and or gravimetric testing can demonstrate diminished or absent sweating. Injection of local, intradermal cholinergic drugs to promote sweating can be utilized. However, this should only be done in a small area as the side effect profile and its associated risks preclude injection into large areas. If a patient is suspected of having peripheral neuropathy, testing the axon reflex sweating by injecting an intradermal picrate or nicotine sulfate at an appropriate dose may be performed. A skin biopsy from an affected area should always be obtained in patients with suspected anhidrosis to identify abnormalities of the sweat glands.

A quantitative sudomotor axon reflex test (QSART) assesses the autonomic nerves that mediate sweating. Mild electrical stimulation is applied to the skin via electrodes and acetylcholine enters the skin. Acetylcholine results in the stimulation of the sweat glands; and the sweat response is measured.

A silastic sweat imprint test also utilizes electrodes, however, pilocarpine is used to stimulate the sweat glands. indentations appear to mark the sweat droplets on a material formed of silicone rubber.

A thermoregulatory sweat test utilizes the body's core temperature to assess a correlation to sweat production. It assesses the thermo-regulatory sudomotor mechanism of the body.

Treatment / Management

Unfortunately, treatment options for anhidrosis can be limited unless an offending agent can be discontinued. Providers need to stress the importance of maintaining a cool environment for the patient. The use of water spray bottles for purposes of cooling can prove helpful. For those disorders due to clogged sweat glands, frequent and gentle exfoliation is useful. Those with disorders of cornification and overheating, such as lamellar ichthyosis, should be treated aggressively and monitored closely.

Although there is no remarkable evidence to support the use of corticosteroids, many case reports recommend the administration of corticosteroids in the early stages of AIGA. However, if the treatment is delayed or when the destruction of sweat glands has already occurred, then corticosteroids may not be beneficial.

The cornerstone for the treatment of anhidrosis is the management of the underlying cause, such as treating lung carcinoma if that is causing Horner syndrome and resulting in anhidrosis.

Differential Diagnosis

When considering anhidrosis, a differential diagnosis will depend on the underlying etiology.

Central and Neuropathic Anhidrosis

• Tumors, infarctions, or other alterations of the hypothalamus, pons, medulla, or spinal cord

• Horner syndrome

• Degenerative syndromes such as Ross syndrome or Shy-Drager syndrome

• Autoimmune autonomic neuropathy

• Congenital insensitivity to pain with anhidrosis

• Peripheral neuropathy due to diabetes mellitus, alcoholism, leprosy, amyloidosis

• Drugs

Drugs

• Nicotinic acetylcholine receptor antagonists such as hexamethonium and trimethaphan

• Muscarinic acetylcholine receptor antagonists such as atropine or scopolamine

• Calcium channel blockers

• Alpha-adrenergic blockers such as phentolamine

• Alpha2-adrenergic agonists such as clonidine

• 5-fluorouracil

• Topiramate

• Zonisamide

• Quinacrine

Peripheral Causes Due to Sweat Gland Abnormalities

• Genetic disorders such as ectodermal dysplasias, incontinentia pigmenti, Bazex-Dupré-Christol syndrome, Fabry disease

• Destruction from tumors, burns, radiation therapy, systemic sclerosis, morphea, Sjögren syndrome, graft-versus-host disease, acrodermatitis chronica atrophicans

• Obstruction from miliaria, ichthyoses, psoriasis, eczematous dermatoses, bullous diseases

Prognosis

The prognosis of anhidrosis varies depending on the type of anhidrosis. Anhidrosis associated with a genetic syndrome is generally lifelong. In the setting of drug-induced anhidrosis, it is usually reversible with the discontinuation of the medication. Anhydrosis secondary to a treatable cause is generally reversible and has a favorable prognosis.

Complications

Complications will depend on the underlying etiology. Heat-related illnesses are the most grave complications of anhidrosis. Children are more vulnerable because their core body temperature rises faster than adults and their heat loss mechanism is less efficient. Heat-related illnesses are:

• Heat cramps

• Heat exhaustion

• Heatstroke

The most feared complication, no matter the underlying etiology, is heatstroke.

Deterrence and Patient Education

Providers need to stress the importance of maintaining a cool environment for the patient. The use of water spray bottles for purposes of cooling can prove helpful. The patient is advised to wear loose and light clothing when it is warm and monitor their activity level not to overdo it. Frequent and gentle exfoliation is helpful for those disorders due to clogged sweat glands.

Enhancing Healthcare Team Outcomes

An interprofessional approach to anhidrosis is recommended. Anhidrosis and the underlying etiologies can cause severe emotional distress for patients. Quality of life may be low for patients of all ages secondary to societal scrutinization of their underlying condition (i.e., lamellar ichthyosis). Therefore, it is recommended to evaluate and arrange for mental health care in addition to the necessary medical care to address the underlying cause of the anhidrosis, if there is one. The outcome of patients with anhidrosis depends on the cause. There is no cure for those with inherited disorders, and it is a lifelong issue. The outcomes may improve for those with acquired anhidrosis by improving the primary condition or removing the offending medication. Most importantly, the patient should be actively involved in their care as the patient must maintain a cool environment and recognize the signs and symptoms of heat intolerance.