Chapter 84. Disorders of the Eccrine Sweat Glands and Sweating

Disorders of eccrine sweating can occur for many different reasons, including dysfunction of the thermoregulatory centers in the brain's central autonomic network, changes in the spinal sympathetic preganglionic, ganglionic, or postganglionic neurons/axons or in the muscarinic (M3) cholinergic synapse on sweat glands. Abnormalities of eccrine sweat formation by the secretory coil and sweat ductal cells may occur or ductal disruption or occlusion may develop, preventing delivery of sweat to the skin surface.

A review of the normal anatomy and physiology of eccrine sweat glands and sweating may be found in Chapter 83. This chapter focuses on neurologic and dermatologic disorders that cause focal or generalized abnormalities of sweating, highlighting an exciting interface where disorders are better understood, diagnosed, and treated based on recognition of the integrated function of nerves, skin, and the immune system (Fig. 84-1). There are a variety of techniques that can be used clinically and in research of sweating that are discussed online. Table 84-1 is a comprehensive table based on disorders with increased or decreased sweating—some diseases are discussed in this text–the others are discussed online. Many are disorders related to nervous system structural, functional and inherited disorders; therefore any patient with a sweating disorder should be evaluated carefully for internal medicine diseases and neurologically by consultants in some cases.

The physical examination continues to be important in the diagnosis of sweating disorders. For example, the skin of an infant with cystic fibrosis is much saltier than infants without cystic fibrosis and when collected sweat is dried, it forms fern-like crystals. Infants with widespread sweat loss may present with “fever of unknown origin.” Taking note of the beads of sweat on the palms and soles of a young adult goes a long way to making a diagnosis of primary focal (essential) hyperhidrosis. In uremia, the evaporation of sweat with high urea concentrations results in the deposition of urea on the skin, referred to as uremic frost. Patients with craniofacial hyperhidrosis may develop a darkened hue to their skin known as chromhidrosis. Focal or segmental compensatory hyperhidrosis may be apparent on examination. Dry, atrophic skin may be seen in areas affected by small-fiber neuropathy. Disorders affecting the sweat duct (miliaria or psoriasis, for example) are often diagnosed via visual inspection of the skin.

Table 84-1 organizes disorders of sweating into the six categories discussed in this chapter.

Clinical Manifestations and Pathomechanism

Primary focal (essential) hyperhidrosis is one of the most common disorders of eccrine sweating.16 This condition is defined as focal visible, excessive sweating of at least 6-months’ duration without apparent cause with at least two of the following characteristics: (1) bilateral and relatively symmetric sweating; (2) the sweating impairs daily activities; (3) a frequency of at least one episode per week; (4) an age of onset before the age of 25 years; (5) a positive family history; (6) cessation of sweating during sleep.17 A national survey estimated that hyperhidrosis affects 2.8% of the US population, and that half of those affected experience excessive sweating of the axillae.18 Hyperhidrosis of the palms, soles, axillae, and, to a lesser extent, craniofacial and groin regions may occur at any time irrespective of temperature, stress, or pleasure. Primary focal hyperhidrosis does not manifest when the patient undergoes general anesthesia and augmentation with thermal stimuli and physical exertion is not uncommon. Sweating may be continuous or phasic; when continuous, sweating is most troublesome in summer. Phasic outbursts with minor emotional activity are similar year round.

Severe primary focal hyperhidrosis interferes with many activities of daily living and patients report a reduced quality of life.19 Avoiding a handshake can lead to professional embarrassment, and avoidance of touch can lead to social or interpersonal seclusion and other symptoms of social anxiety disorder. Symptoms begin in childhood or around puberty and affect either sex equally. A family history is present in approximately one-fourth of patients. The disorder persists for years with occasional spontaneous improvement after 35 years of age.

The central autonomic network control of emotional sweating is distinct from the preoptic-anterior hypothalamic controller of thermoregulatory sweating. The anterior cingulate cortex, which orchestrates the sweat response from the palms and soles, may modulate hypothalamic output inappropriately. These patients have less reflex bradycardia than control subjects in response to the Valsalva maneuver or facial immersion, but a higher degree of cutaneous vasoconstriction in response to finger immersion in cold, suggesting that they have increased sympathetic outflow passing through the T2–T3 ganglia.20 Ventilated capsule recordings of palmar sweating provide further evidence of emotionally triggered, centrally derived sweat output. Such sweating is augmented at rest, bilaterally synchronous, and pulsatile (eFig. 84-3.1).

The severity of primary focal hyperhidrosis ranges from intermittent, slightly moist palms and soles to daily sweat drippage from hands and feet, requiring the frequent use of towels.

Treatment

Treatment involves determining the severity and distribution of the disorder, ruling out other causes of hyperhidrosis, and selecting a modality of therapy appropriate to age of the patient and severity of the disorder. Some current treatment methods are shown in Box 84-1. Treatment begins with discussing the nature of the disorder and discerning patient wishes and expectations. Mild cases of axillary and palmar sweating are controlled via topical application of aluminum chloride hexahydrate or glycopyrrolate, an anticholinergic agent. Care should be taken to have the aluminum chloride applied to completely dry skin as use of the agent on moist skin can result in the formation of a weak hydrochloric acid that can result in discomfort, and burning and peeling of the skin surface. This irritation can be managed by cessation of therapy for a few days and the use of a class VII topical steroid cream. Oral glycopyrrolate, oral or transdermal clonidine, transdermal scopolamine, or oral topiramate21 can be administered if topical agents alone are not helpful or are too irritating. Control of palmar-plantar sweating is sometimes possible using tap water (or a solution of glycopyrrolate) iontophoresis. Intradermal injection of botulinum toxin (BTX), (onabotulinumtoxinA) is appropriate for treatment of focal areas, such as axillae, palms of hands, soles of feet and groin, and is effective for 2–8 months per treatment.22 Facial hyperhidrosis can be treated with oral or topical23 glycopyrrolate.

Immunohistochemical studies show sweat glands appear structurally normal in hyperhidrotic patients before BTX therapy, whereas after therapy the luminal area of the gland and protein gene product 9.5 (neural marker) staining is diminished. This suggests that BTX therapy induces long-standing functional denervation of the sweat glands. However, growth-associated protein 43, indicative of axonal sprouting, is increased, suggesting reinnervation may eventually take place.24

Repeat BTX injections do not demonstrate a diminished duration of efficacy.25 Pain with palmar botulinum injections is common and several techniques are in use to minimize this.26,27 Iontophoresis of BTX in solution has been successfully tried with better control of sweating than with water alone.28,29 However, the cost effectiveness of this has been questioned.

Only the most severe cases of palmar hyperhidrosis not responding to conservative treatment may be considered for surgical management. Many patients have been successfully treated with endoscopic, upper thoracic sympathectomy30 (eFig. 84-3.2); however, the best procedure to use is still being investigated.10,30–36 These surgical procedures carry the risk of creating minor to severe compensatory hyperhidrosis in body segments below the treated area (see eFig. 84-3.3) as well as much less common surgical complications of wound infection, Horner's syndrome, pneumo- or hemothorax, and atelectasis. Long-term surveys of patients having undergone thoracic sympathectomy for treatment of palmar hyperhidrosis have illustrated that many patients wish they had not undergone the procedure due to the compensatory sweating that developed after the surgery.37,38

Another surgical option for axillary hyperhidrosis is tumescent suction curettage, which is performed in an outpatient setting. In one limited study of 63 subjects, greater than 75% were still satisfied with their reduction in sweating 2 years after treatment.39

(Secondary causes of localized hyperhidrosis are discussed in the next section.)

Cerebral Infarction

Spinal Cord Injury and Autonomic Dysreflexia

Other Central Nervous System Disorders

Cold-Induced Sweating Syndrome.46,47

Peripheral Nervous System Disorders

 Intrathoracic Neoplasms

 Compensatory Segmental Hyperhidrosis

Gustatory Sweating

Localized sweating on lips, forehead, scalp, and nose while eating hot and spicy foods occurs physiologically in many people via a trigeminovascular reflex. Pathologic gustatory hyperhidrosis is asymmetric, intense, and may produce patches of sweating on the trunk and even extremities. The cause is aberrant regeneration of damaged and undamaged facial parasympathetic fibers, destined for salivary glands, which instead supply facial sweat glands that have been sympathetically denervated. Thus, gustatory stimuli that previously caused parotid, salivary gland, or gastric secretion now also cause sweating in the distribution of the damaged sympathetic nerve. The most common occurrence is in Frey syndrome, in which sweating occurs in the distribution of the auriculotemporal nerve after an injury, abscess, or surgery in the parotid region.50 Frey syndrome can be seen in infants and children, often following birth trauma with forcep delivery, but two cases of familial, bilateral Frey syndrome without birth trauma have also been reported.51 Gustatory sweating may follow upper thoracic and cervical sympathectomy,50,52–54 facial herpes zoster, or chorda tympani injury and has been reported in cluster headache, diabetic neuropathy,55–57 encephalitis, syringomyelia, and invasion of the cervical sympathetic trunk by a tumor.58 The exact distribution can be delineated with indicator powder on the face, neck, and upper trunk while the subject chews and is photographed. Treatment with topical scopolamine, clonidine,53 glycopyrrolate,59,60 aluminum chloride, or BTX injection61,62 can be effective; rarely, intracranial section of the glossopharyngeal nerve or tympanic neurectomy is needed.

Lacrimal Sweating63

Harlequin Syndrome64

Idiopathic, Localized Hyperhidrosis

 Paroxysmal Localized Hyperhidrosis

Localized Hyperhidrosis Associated with Skin Disorders

Central Autonomic Nervous System Disorders

 Episodic Hypothermia with Hyperhidrosis

 Generalized Hyperhidrosis Without Hypothermia

Fever and Chronic Infection

Malaria, tuberculosis, brucellosis, and subacute bacterial endocarditis may present with fever and generalized hyperhidrosis due to exogenous bacterial pyrogens that stimulate phagocytic leukocytes to produce endogenous pyrogen [interleukin 1 (IL-1) and IL-6, tumor necrosis factor (TNF), and γ-interferon]. These cytokines act not only as circulating hormones, but also as intrinsic modulators in the brain. Signals that stimulate IL-1 production in the brain include humoral factors, such as circulating IL-6 and activation of peripheral C fibers and vagal afferents. These effects can raise “set-point” temperature (producing fever), while simultaneously activating antipyretic mechanisms (eventually producing drenching sweats).75

Metabolic and Systemic Medical Problems

Increased sweating has been reported in diabetes mellitus, hypoglycemia, congestive heart failure, thyrotoxicosis, hyperpituitarism, dumping syndrome, carcinoid syndrome, and alcohol and drug withdrawal. Sweating is increased (especially in males) in acromegaly (in which the size of sweat gland acini and the density of innervation to the sweat glands is greater than in controls) and is decreased in growth hormone deficiency (GHD).

Some studies of GHD pre- and posttreatment, using histochemistry for acetylcholinesterase and immunohistochemistry for the neuropeptide vasoactive intestinal polypeptide and protein gene product 9.5, a general neural marker, have shown increased sweat gland acinar size and periacinar innervation and pilocarpine iontophoresis sweat rate after GH therapy. However, other studies have shown that even treated GHD subjects still sweat less than controls implying permanent eccrine gland hypofunction and androgen deficiency as a cofactor of reduced sweating.

Hyperhidrosis and Malignancy

Hodgkin disease is characterized by the triad of fever, sweating, and weight loss; night sweats may be the only symptom and 31 of 100 patients present with “B”-cell symptoms (fever, weight loss, sweating).76 The excessive production of IL-1 by activated macrophages is implicated as the cause of temperature instability.77 IL-1 is known to induce an abrupt increase in the synthesis of prostaglandin E2 in the preoptic anterior hypothalamic region, causing an elevation of the temperature “set point.” Excessive production of IL-6 by Hodgkin lymphoma cells78 is also implicated as cause of fever and subsequent night sweating. Advanced solid tumors may also cause sweating via immunologic mechanisms relating to TNF-α and effect of ILs on central thermoregulation.

The symptomatic triad of excessive and inappropriate paroxysmal sweating, tachycardia, and pounding headaches (associated with increased blood pressure) almost assures the diagnosis of pheochromocytoma as the cause of hyperhidrosis. Anti-α- and β-adrenergic therapy is a mainstay of this disorder, with a rare patient developing sweat gland necrosis during preoperative therapy.

Generalized Hyperhidrosis Due to Medications/Toxins

Hyperhidrosis is frequently associated with serotonin (5-hydroxytryptamine) reuptake inhibitors, opioids, and sometimes with prostaglandin inhibitors (naproxen). The serotonin syndrome and the neuroleptic malignant syndrome include hyperthermia, labile blood pressure, hyperhidrosis, rigidity, agitation and confusion. The mechanisms may relate to 5-hydroxytryptamine (2A) and dopamine receptor antagonism. The hyperhidrosis that commonly occurs during acute and chronic administration of opioids is mainly due to stimulation of mast cell degranulation, resulting in the release of histamine.79 Excessive sweating can occur in as much as 45% of patients taking methadone.80 Hyperhidrosis is also a recognized side effect of transdermal fentanyl.81 Sweating in combination with hypertension, nausea, and mydriasis characterizes acute opioid and alcohol withdrawal. Despite their well-recognized anticholinergic effects, tricyclic antidepressants occasionally cause hyperhidrosis due to their sympathomimetic effect. The presumed mechanism is inhibited reuptake of norepinephrine, leading to stimulation of peripheral adrenergic receptors and a generalized diaphoretic response. Cholinergic agonists such as pilocarpine and bethanechol and reversible cholinesterase inhibitors such as pyridostigmine can increase sweating directly or indirectly via activation of M3 cholinergic receptors on sweat glands. See Table 84-2 for an abbreviated listing by drug class, example, and mechanism of hyperhidrosis and Table 84-3 for a complete listing of medications reported to cause hyperhidrosis.

Disorders with Central and Peripheral Nerve Abnormalities

Primary Autonomic Disorders with Acquired Idiopathic Anhidrosis

 Acquired Idiopathic Generalized Anhidrosis

Chronic Idiopathic Anhidrosis.85

 Segmental Type of Acquired Idiopathic Anhidrosis

Ross Syndrome

Pure Autonomic Failure (Bradbury–Eggleston Syndrome) and Autoimmune Autonomic Neuropathy

Autoimmune Autonomic Ganglionopathy

Disorders of the Central Nervous System

Degenerative Disorders

Peripheral Nerve Disorders Causing Anhidrosis

 Hereditary Sensory and Autonomic Neuropathy Types I, II, and IV

 Guillain–Barré Syndrome

 Diabetic Neuropathy

 Amyloid Neuropathy

 Leprosy

 Lambert–Eaton Myasthenic Syndrome

 Alcoholic Neuropathy

Fabry Disease

 Idiopathic Small-Fiber Neuropathy

 Erythromelalgia

 Postsympathectomy

Harlequin Syndrome

Anhidrosis Due to Toxins and Pharmacologic Agents

Botulinum Toxin

BTX type A (onabotulinumtoxinA) and B both exhibit a dose-responsive suppression of sweating when injected intra- and subcutaneously (see Chapter 255). This chemodenervation of sweat glands is caused by the structural architecture of BTX with its heavy chain binding to the nerve cell, and its light chain catalyzing the proteolysis of one of the three SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) proteins preventing vesicle membrane fusion and therefore the release of ACh and transmission of the nerve impulse. This unique property has made BTX (especially type A) very popular for the treatment of localized hyperhidrosis of the axilla and palms and skin areas affected by gustatory sweating. More widespread anhidrosis can occur with BTX as well as organophosphate ingestion as a consequence of bioterrorism.114

Pharmacologic Agents

Many pharmacologic agents can cause anhidrosis, especially those that are anticholinergic and interfere with the binding of ACh at M3 muscarinic receptor on sweat glands. Blockade at the sympathetic ganglionic level can inhibit sweating and cause orthostatic hypotension. Recently, oligohidrosis in children has been reported in those taking the carbonic anhydrase (CAII) inhibitors zonisamide and topiramate and studies show reduction in axon reflex-mediated sweating compatible with an effect on the sweat gland. Such observations and the location of CAII in the secretory coil clear cells and at the apex of the ductal cells suggest that the formation of HCO3− and H+ by CAII plays a significant role in sweat fluid secretion.115,116

μ-Opioid Agonists

μ-Opioid agonists (e.g., morphine) tend to inhibit warm-sensitive neurons in the hypothalamus. This action raises the body's set-point temperature, allowing core temperature to rise substantially. This results in anhidrosis even in a hot environment. After opioid drug levels drop, set-point temperature drops below the elevated core temperature, producing profuse sweating.79 Clonidine and α2-adrenergic agonists can suppress sweating, probably by reducing norepinephrine's effect on hypothalamic thermoregulatory neurons. The drug can be effective in Shapiro syndrome, essential hyperhidrosis, and postmenopausal sweating.

Heat Hyperpyrexia and Heat Stroke

Heat hyperpyrexia and heat stroke are states of thermoregulatory failure of sudden onset that are characterized by general anhidrosis, hyperpyrexia [rectal temperature greater than 40.5°C (105°F)], and disturbances of the central nervous system. The exact cause of this disorder is unknown. The picture is generally one of environmental stress, too severe for the thermoregulatory system, which suddenly collapses. In the early stages, sweating may still be present and the patient rational, but the rectal temperature may be greater than 40.5°C (105°F). Within minutes, anhidrosis, mental confusion, coma, and/or seizures may appear. The diagnosis should be suspected from the clinical setting of activity in extreme heat and rectal temperature greater than 40.5°C (105°F); it should be accepted with the additional presence of anhidrosis, hot, dry skin, and any degree of central nervous system manifestations. If untreated, the disorder is uniformly fatal. In treated cases, the mortality is approximately 35%.

Anhidrosis Due to Damage from Physical Agents

Localized anhidrosis can occur whenever sweat glands are damaged by surgery or trauma, scar formation, cutaneous neoplasms, radiation therapy, infection, inflammation of the skin, granulomatous lesions, scleroderma, or vasculitis. Delivery of sweat to the skin surface may be impaired in a variety of dermatoses and papulosquamous diseases, presumably because of poral occlusion. Blister formation with sweat gland necrosis has been reported during intoxication with barbiturates, methadone, diazepam, carbon monoxide, amitriptyline, and clorazepate. Similar changes may occur in coma induced by hypoglycemia and other neurologic events, suggesting the changes are due in part to pressure over skin areas not usually subject to pressure. Radiation-induced dermatitis can abolish eccrine function in a dose-dependent fashion. Mantle irradiation (usually in the 25- to 50-Gy range) often produces a permanent loss of eccrine gland function, which tends to be discovered incidentally when previously treated patients undergo autonomic testing (see eFig. 84-4.2). Keratotic changes blocking the eccrine duct with or without syringoma-like ductal proliferation have been described. Similar changes have been noted with breast cancer radiation therapy. Congenital ectodermal dysplasia (see Chapter 142), acantholytic dermatosis (Grover disease; see Chapter 51), cholinergic urticaria (see Chapter 38), and various forms of ichthyosis (see Chapter 49) may also be associated with altered sweating.

Anhidrosis Due to Congenital and Acquired Skin Diseases

Storage Diseases

Sweat gland cellular inclusions that can be identified on skin biopsy include membrane-bound vacuoles in secretory cells in the mucopolysaccharidoses, intracytoplasmic lipid in Niemann–Pick and Sandhoff storage diseases, inclusions in adrenoleukodystrophy, maltase deficiency, and periodic acid-Schiff (PAS)-positive granules in the outer duct cells in Lafora myoclonic epilepsy.

Neutrophilic Eccrine Hidradenitis

Lesions are most often painful, pruritic, erythematous plaques or papules developing on the limbs, trunk, neck, face, and ears. Most commonly reported is chemotherapy-associated neutrophilic eccrine hidradenitis (NEH), typically occurring within 2 weeks of initiation of multiagent antineoplastic therapy. Fever and neutropenia may occur and the disorder is usually self-limited (lasting several weeks). Necrosis of eccrine secretory coils and associated epithelium with surrounding dense neutrophilic neutrophilic infiltrate that characterizes NEH is seen histologically (see eFig. 84-4.3). A direct toxic effect of the drug on eccrine glands is suspected and recurrences with repeated chemotherapy may occur. Treatment with colchicine and dapsone has been beneficial. Another category of NEH appears due to bacterial infection. Biopsied lesions have grown Serratia, Staphylococcus, Enterococcus, Pseudomonas, and Nocardia.117 Community outbreaks due to swimming pool water contamination with P. aeruginosa have been described. Spontaneous resolution in weeks is common, although some patients receive antibiotics. It is not known whether susceptible individuals have deficient innate dermcidin antimicrobial peptide secretion in sweat (see Section “Disorders Affecting the Sweat Duct”) or if changes in sweat duct structural proteins produce reduced barrier protection against infection.

A recent case of NEH due to Streptococci showed the presence of human β-defensin 2, an epithelial antimicrobial peptide, in lesional epidermis and the eccrine duct; however, levels of dermcidin, a recently discovered antimicrobial peptide constitutively expressed in human eccrine sweat glands and secreted into sweat, were not determined. Dermcidin levels have been reported to be reduced in atopic dermatitis and have recently been shown to activate normal human keratinocytes.118

Recurrent, palmoplantar NEH has been increasingly reported in otherwise healthy children between 1 and 15 years of age. Vigorous exercise with heavy sweating and damp, occlusive footwear are possible risk factors.119 Spontaneous resolution in 3–4 weeks is common, but repeated bouts with subsequent exercise occur. Treatment with cool compresses and topical steroids and rest has provided symptomatic relief. NEH has been described in association with Behçet disease120 and human immunodeficiency virus infection. A possible treatment for NEH-Behçet is an anti-TNF-α agent, such as infliximab, which has been effective for other manifestations of Behçet disease121,122 (see eTable 84-1.1 for summary of NEH).

Sjögren Syndrome and Scleroderma

Variable degrees of anhidrosis can occur in Sjögren syndrome (see Chapter 161). Most often patchy areas of anhidrosis occur on proximal and/or distal limbs, compatible with a small-fiber neuropathy. Case reports of widespread anhidrosis and heat intolerance associated with dry eyes and dry mouth, positive extractable nuclear antigen panel, and lymphocytic infiltrates of minor salivary glands exist.123,124 Skin biopsies have shown perieccrine infiltrates in some patients, but not in others. The failure of the anhidrotic skin on TST to respond to ACh/pilocarpine iontophoresis in one report suggests that autoantibodies to the muscarinic (type 3, M3) cholinergic receptor interfere with eccrine gland function.125–128 M3 cholinergic receptors predominate on salivary glands and sweat glands, which further supports an association. The stage of the immune-mediated response may determine whether lymphocytic infiltration is present or not.129

The aquaporin 5 (AQP5) water channel has been identified in the apical plasma membrane of sweat gland cells,130 and mobilization of these channels may influence sweat production.131 The effects of drugs or disease on these channels at this time are speculative with regard to sweat gland disorders. Preliminary evidence of autoantibody-mediated alterations in M3 cholinergic receptor activation and AQP5 expression in salivary gland cells of Sjögren's syndrome patients raises the possibility that some patients with disturbances of sweating may turn out to have AQP5 channelopathies.21

Atrophic sweat glands and focal anhidrosis have been noted in patients with linear scleroderma. The forehead is most commonly affected.132

Incontinentia Pigmenti

Hypohidrosis has also been noted in the hypopigmented streaks and patches on the legs, arms, and scalp of ten women with incontinentia pigmenti.133 Skin biopsies reveal a lack of eccrine sweat glands and hair follicles at these sites. Hypohidrosis has also been described in segmental vitiligo, but not the generalized or acrofacial types.134,135 Anhidrosis of the face and neck has also been reported in members of a family with “follicular atrophoderma, basal cell carcinoma, and hypotrichosis,” a rare X-linked, dominantly inherited syndrome (Bazex–Dupre–Christol syndrome). Milia and sweat duct occlusions may occur, but are inconstant features of the disease.136

Disorders Affecting the Sweat Duct

Miliaria

Miliaria results from disruption of sweat ductal integrity137 with consequent sweat secretion into layers of the epidermis. Ultraviolet light exposure, resident organisms on skin, and repeated sweating episodes are facilitating factors. Focal anhidrosis can occur and persist for several weeks, much longer than the miliaria in affected skin regions. Based on clinical and histopathology findings, miliaria is subdivided into four groups: (1) miliaria crystallina; (2) miliaria rubra; (3) miliaria pustulosa; and (4) miliaria profunda.

Miliaria crystallina (sudamina) consists of superficial, subcorneal, noninflammatory vesicles that easily rupture when rubbed with a finger (Fig. 84-5). They are common in infants in warmed environments, including in intensive care units where medications employed (cholinergic and adrenergic agents) may be stimulating sweating and aggravating the problem.138,139

Miliaria rubra (prickly heat) results when obstructed sweat migrates into the epidermis as well as the upper dermis, causing pruritic inflammatory papules around the sweat pores (see eFig. 84-5.1). This disorder is common in infants, but also occurs in children and adults after repeated episodes of sweating in a hot, humid environment. The eruption usually subsides within a day after the patient moves to a cool environment. However, anhidrosis associated with miliaria takes 2 weeks (the time needed to repair the affected epidermal sweat duct unit by epidermal turnover) to recover completely. Some of the eruptions of miliaria rubra become pustular, resulting in miliaria pustulosa. Miliaria profunda results when the sweat leaks into the deeper dermis. During exposure to intense heat or after local injection of cholinergic agents, the affected skin can be uniformly covered with multiple discrete, flesh-colored papules that resemble gooseflesh. Ductal blockade at various levels is the immediate cause of miliaria. However, investigators do not agree on why the sweat escapes the duct at different levels (causing different subgroups of miliaria) nor on what causes the ductal blockade and/or ductal leakage at different levels.

It is puzzling that the morphologic evidence of ductal blockade, such as keratin rings, PAS-positive proteins, or clusters of microorganisms, is rarely seen by light microscopic observation of miliarial lesions. Thus, Holzle and Kligman speculated that the keratin rings and PAS-positive proteins are the consequence but not the cause of ductal damage. The role of resident organisms especially Staphylococcus epidermidis has been proposed as a leading predisposing factor in miliaria.140,141 Indeed, there was a linear correlation between the severity of miliaria rubra and the number of cocci in experimental miliaria under a plastic film. The development of experimental miliaria could be markedly suppressed by pretreatment of the skin with hexachlorophene or pyrithione.140

Other Disorders Affecting the Sweat Ducts

Abnormalities of the epidermal portion of the spiraling sweat duct (acrosyringium) with altered sweat delivery to the skin surface are present in several disorders with immunohistologic evidence of neurogenic inflammation of skin. The presence of vanilloid receptors and neuropeptide fibers containing substance P and calcitonin-gene related protein in the acrosyringium may explain the presence of mast cell and other mediators of inflammation with subsequent impairment of sweating.142–144

Disorders with Altered Composition of Sweat

Atopic Dermatitis

Dermcidin is a recently discovered antimicrobial peptide with a broad spectrum of activity. It is constitutively expressed in human eccrine sweat glands and secreted into sweat. Recent evidence suggests deficient amounts of sweat-derived antimicrobial peptides may play a role in skin inflammatory disorders characterized by increased bacterial colonization of the skin, such as atopic dermatitis.143,145 Dermcidin and other antimicrobial proteins and peptides may have a therapeutical potential as topical anti-infectives in several skin diseases because of their broad spectrum of antimicrobial activity, the low incidence of bacterial resistance and their function as immunomodulatory agents.118,146,147

Cystic Fibrosis

Sweat chloride ion concentration can determine the integrity of the CFTR Cl− channel and provide diagnostic information for cystic fibrosis.15 This in vivo assay may prove useful in studying the effectiveness of CF gene therapy. In vitro studies of the CFTR Cl− activity from sweat glands obtained via skin biopsy are presently under evaluation as markers of the efficiency of CF-gene delivery and expression in sweat gland epithelial cells.148 The saltier sweat may be responsible for the frequent observation of the aquagenic wrinkling of the palms (AWP) syndrome in CF patients.149,150

Aquagenic Wrinkling of Palms (AWP) Syndrome

AWP is an uncommon disease characterized by the rapid and transient formation of edematous whitish plaques on the palms on exposure to water.151 Although the exact cause of this condition is unknown, hyperplastic glandular epithelium and aberrant AQP5 staining in the patient's sweat glands suggest that AWP stems from dysregulation of sweating.