Anhidrosis

Etiology

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.[6] 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.[7] 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.[8][9]

Drugs that interfere with the synaptic transmission in the autonomic ganglia will lead to anhidrosis:[10]

• 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.[11][12] The other ectodermal dysplasias, such as Rapp-Hodgkin syndrome and Naegeli-Franceschetti-Jadassohn syndrome, can lead to sweat gland abnormalities.[13] 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.[14]

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.[15]

Epidemiology

Anhidrosis is a clinical finding and not a distinct entity. The exact epidemiology will depend on the underlying etiology. In the majority of anhidrosis cases, men and women are equally affected, with a few exceptions. The age of presentation will vary based on the underlying etiology. Horner syndrome is one of the causes of anhidrosis and is an uncommon condition, occurring with a frequency of approximately 1 per 6,000. It may occur at any age or with any ethnic group.[16][17] 

Another cause of hypohidrosis/anhidrosis is hypohidrotic ectodermal dysplasia, in which patients either do not have eccrine sweat glands or are sparse and rudimentary. In the US, the prevalence of hypohidrotic ectodermal dysplasia is estimated to be 1 per 100,000 births. Internationally, the prevalence is reported at 7 cases per 10,000 births. 

Naegeli-Franceschetti-Jadassohn (NFJ) syndrome is also a rare cause of anhidrosis and is reported to have an international prevalence of around 1 case in 2-4 million population.[18][19] Fabry disease is another disorder where there is a lack of sweat glands, and its prevalence has been observed to be 1 per 40,000 people.[20] There are many other disorders that present with anhidrosis and have variable epidemiological indicators.

Pathophysiology

The pathophysiology of anhidrosis varies depending on the etiology, as anhidrosis is a clinical finding and not a distinct entity. For central and neuropathic anhidrosis, interruption of innervation at any level along the pathway from the sweating centers located in the brain to the sweat glands can result in absent sweating. Drugs that interfere with the synaptic transmission in the autonomic ganglia can inhibit sweating. Peripheral alterations can result in the absence of sweating. Peripheral alterations include genetic disorders, destruction, or obstruction. Genetic abnormalities underlie several types of anhidrosis, and the pathogenesis may be unknown. Other etiologies may have a known cause, such as local tissue destruction by prior radiation therapy. The clinical presentation and history can help delineate the pathophysiology.[21] 

As anhidrosis is a clinical presentation of an underlying disorder, it is beyond the scope to describe the pathophysiology of each disorder separately. However, for instance, Horner syndrome, which is a common cause of ipsilateral anhidrosis, depends on the level of interruption of the sympathetic supply. Anhidrosis with first-order neuron lesions affects the ipsilateral side of the body as the sympathetic supply from its central origin. The ipsilateral face is involved in lesions involving the second-order neurons. Postganglionic third-order neuron lesions occurring after the vasomotor and sudomotor fibers have branched off show very limited involvement of the face (area adjacent to the ipsilateral brow).[22]

Histopathology

The histopathology will vary depending on the etiology. Males with X-linked hypohidrotic ectodermal dysplasia will have an absence of sweat glands, whereas female carriers will have reduced glands. The clinical presentation and or a skin biopsy will help identify those with local destruction or obstruction.[23]

Light microscopy may not reveal marked morphological changes in sweat glands in patients with acquired idiopathic generalized anhidrosis (AIGA) due to idiopathic pure sudomotor failure (IPSF). Still, there may be lymphocytic infiltration around sweat glands.[24] Some cases of AIGA may reveal swollen secretory cells of the sweat glands and hyperkeratotic horny layer due to sweat gland failure.

History and Physical

History and physical exam findings for anhidrosis will differ between the various underlying etiologies. A thorough history should be obtained, including past medical history, medications, medical treatments (i.e., radiation therapy), and family history. A careful and detailed history will yield clues to a potential diagnosis.[9]

A patient may complain of heat intolerance, fatigue, drowsiness, or inability to concentrate in warm environments. A patient with central/neuropathic anhidrosis may have accompanying neurological symptoms such as ptosis and miosis in Horner syndrome. Although very rare, a patient with congenital insensitivity to pain with anhidrosis will present with self-mutilation.

Those with anhidrosis due to destruction will have the physical exam findings of the underlying etiology, such as scarring from a prior burn or sclerotic changes as in morphea.

Anhidrosis caused by obstruction will likewise have the physical exam findings associated with the underlying etiology, such as psoriatic plaques or lamellar ichthyosis.

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.[25] 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.[26]

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.[27]

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.[28] However, if the treatment is delayed or when the destruction of sweat glands has already occurred, then corticosteroids may not be beneficial.(B3)

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.