This Article is an encyclopedia of sweating – its anatomy, physiology and pathology. There is extensive information on conditions associated with excessive or decreased sweating. Excessive sweating in particular can be very disabling. As excessive sweat in the hands may make it impossible to play a musical instrument or pursue careers requiring contact with paper or electrical devices even army and military service s have stringent rules for sweaty palms. Axillary hyperhidrosis damages clothes and plantar hyperhidrosis damages shoes. An overview of the treatments available for these and other conditions is given.
The Neuroanatomy of Sweating
The peripheral nerve innervation of sweat glands is through sympathetic C fibers releasing acetylcholine which particularly binds to the M3 muscarinic receptor to trigger sweat production. The number of glands depends on an intact peripheral sympathetic innervation, together with average experienced environmental temperature and humidity, particularly during childhood.
Emotional sweating arises from signals emanating from the amygdala, prefrontal cortex, insula and cingulum, then passing along the same routes as for hypothalamic autonomic sweat innervation. In contrast to temperature-related sweating, it leads to vasoconstriction of blood vessels in the dermis, unlike raised temperature which leads to sweating and vasodilation (hence the cold sweat with emotion). However, the distinction between temperature and emotional sweating is not absolute, with each influencing the other.
Thermoregulatory Sweating Control
The control of thermoregulatory sweating is primarily under sympathetic nervous system regulation coordinated by the hypothalamus. If central temperature drops below 37 degrees, muscle tremor (shivering) and cutaneous vasoconstriction resulting in cooler periphery, as well as behavioral adaptation (i.e. putting on clothes). If the temperature is above 37°C, sweating and cutaneous vasodilation occur.
The factors influencing the amount of sweating include emotional state, plasma osmolality, oxygen tension and hormonal state. For example, progesterone tends to lead to higher body temperature and lower rate of sweating, estrogen the opposite. As would perhaps be predicted, a decrease in blood volume or increase in concentration of plasma proteins (i.e., hypovolemia or increased plasma osmolality) lowers the rate of sweating.
The Thermoregulatory Sweat Test (TST)
This tests for reflex sweating by elevating general body temperature. Signals then pass to the hypothalamus and travel via the intermediolateral cell column, sympathetic chain and postganglionic sudomotor nerves to the sweat glands. A material which changes colour when mixed with sweat, such as alizarin red, corn starch or sodium carbonate is applied to the skin of the unclothed subject who is then placed in a cabinet or room with heaters which raise the air temperature to 44 to 50°C with a constant humidity.
Normally, when the temperature rises by 1°C above baseline (temperature to above 38°C), uniform sweating is seen over the entire body, with characteristic areas of the body displaying either increased or decreased amounts of sweat production. This can then be quantified by photographing the body areas and digitizing the change in colour or appearance of the test powder.
Filter Paper Method
Axillary perspiration may be easily quantified by inserting filter paper into the axilla for a defined period and then weighing it pre and post application. Axillary hyperhidrosis has been defined as greater than 50 mg per minute of sweat. Palmar hyperhidrosis is regarded as pathological if greater than 20 mg per minute are produced.
Sympathetic Skin Testing
Typically, a pair of electrodes 1 cm apart is applied to the thighs, hand, or foot. A stimulus is then applied such as a loud noise, electric shock, or cough, this then typically leading to a brief change in sweating and therefore electrical conductivity. In conditions with marked loss of sweating the response may be lost, but beyond this the method is not very useful because of the extreme variability in the response, both between patients and when testing the individual on repeated occasions. It is thus not useful for quantification of degree of perspiration.
Hyperhidrosis or excessive sweating may occur from abnormalities anywhere along the pathway involved with sweat control, namely brain, spinal cord, peripheral nerves or the glands themselves. Furthermore, any process which raises body temperature, increases body metabolism, or acts on the hypothalamus thermoregulatory sensor may lead to increase in perspiration.
The most common such condition is hyperthyroidism/thyrotoxicosis, with another important condition to exclude being a phaeochromocytoma. Nocturnal sweats are also a classic symptom of lymphomas and PUOs (pyrexia of unknown origin) being a much-loved detective hunt of infectious diseases specialists, although chronic inflammatory conditions and other cancers are also responsible for a significant number of PUOs, as well as the exotic infections. Classic infections as a cause of excessive sweating include tuberculosis, characteristically causing night sweats.
When nerves become more sensitive, such as through changes in the extracellular milieu (for example, raised potassium levels), mechanostimulation, or other nerve damage, one may experience increased perspiration.
Quite often during a peripheral neuropathy, particularly if the cause is an underlying toxin such as thallium, arsenic, or acrylamide poisoning, as well as certain metabolic conditions, in particular diabetes, the condition may manifest with increased sweating in the extremities along with dysesthesias (most typically burning pains) and the feeling of coldness. Similarly, a nerve root or plexus irritative lesion may lead to hyperhidrosis in the area supplied by the nerve, with progression of the lesion then leading to decreased sweating in this area with surrounding compensatory excessive sweating.
Hyperhidrosis can be divided into generalized and focal hyperhidrosis depending on whether the entire body or just one particular region is affected.
Generalized hyperhidrosis may be caused by:
- Endocrine abnormalities – hyperthyroidism, diabetes, pheochromocytoma, menopause and pregnancy, carcinoid syndrome, acromegaly.
- Neurological disorders, particularly those involving the autonomic system such as Parkinson’s.
- Drug withdrawal.
The most common age for focal hyperhidrosis to develop is in puberty, typically in otherwise healthy people. Approximately 50% have a positive family history. The axillae are the most commonly affected site, followed by feet, hands and the face. The sweat glands themselves are normal in hyperhidrosis, but the autonomic nervous system is overactive.
Focal hyperhidrosis characteristically does not occur during sleep, in contrast to generalized hyperhidrosis which is usually present during both wake and sleep.
Step one with palmar and plantar hyperhidrosis is prescription strength antiperspirant. If botulinum toxin is used, euhidrosis may last as long as a year.
Secondary focal hyperhidrosis may result from either peripheral or central nervous system dysfunction. For example, during the early stages of acquired polyneuropathy affecting small fibers, sweating may be increased, later becoming decreased as nerve damage progresses. In complex regional pain syndrome (CRPS) hyperhidrosis may be found in the affected area.
With destructive central nervous system lesions, such as infarcts (strokes) or haemorrhages, decreased cortical inhibition results in contralateral increased perspiration. In contrast, with spinal lesions sweating is decreased ipsilaterally. Compensatory hyperhidrosis may then develop in other body parts.
Venlafaxine, an SNRI, whilst actually utilized at a low dose for menopausal flushing (37.5mg od or bd), has also been reported as causing excessive sweating in some.
Gustatory sweating is when facial sweating occurs whenever the salivary glands are stimulated. Thus, the aroma or thought of food or the act of eating not only leads to saliva production, but also facial sweating. This occurs when the tiny nerve that mainly innervates the sweat glands of the face is damaged.
There is an attempt at regrowth and re-innervation of the facial sweat glands. Sprouting from the neighboring nerve which supplies the saliva glands may occur, this nerve then ultimately innervating both the saliva glands and the facial sweat glands. Thus, whenever this nerve is stimulated to produce saliva, it also stimulates sweat production. This is mostly commonly seen after Bell’s palsy or in diabetes.
Essential or Primary Hyperhidrosis
Essential or primary hyperhidrosis is excessive sweating particularly in hands and axillae (armpits and feet). It typically begins in the teens and may ease off in the fourth or fifth decade. As much as 30 ml per hour of sweat may be produced. Although symptoms are most noticeable in the aforementioned areas, increased perspiration actually occurs throughout the entire body. Patients with this condition may have excessive sympathetic drive and hypertrophic sweat glands. There is a positive family history in 25% to 50% of patients and it has been suggested that it may be inherited in an autosomal dominant fashion with incomplete penetrance.
Rare Cause of Excessive Sweating
1. Shapiro’s Syndrome
This is a very rare syndrome consisting of episodic temperature dysregulation with hyperhidrosis and hypothermia, associated with agenesis of the corpus callosum. It may be associated with lethargy, confusion and weight loss during the abnormal episodes. The exact mechanism is not known, although hypotheses include a resetting of the hypothalamic thermostat to a lower level secondary to neurochemical dysregulation, inflammation, neurodegeneration or autoimmunity. Clonidine has been helpful in some reported cases. Appropriate fluid resuscitation is also needed if there is dehydration.
2. Frey’s Syndrome
Frey’s syndrome is focal gustatory sweating, i.e., sweating of the face during eating or drinking. This occurs after damage to the facial nerve, such as following an operation or Bell’s palsy with aberrant reinnervation occurring such that the nerve fibres which would normally innervate the facial sweat glands through the parasympathetic chorda tympani nerve fibers being incorrectly replaced by fibers which should be innervating the salivary glands. Thus, when salivation is stimulated, so is perspiration.
Botulinum is very effective for Frey’s syndrome. Alternatives include topical antiperspirants or topical anticholinergics such as glycopyrrolate.
3. Harlequin’s Syndrome
In Harlequin’s syndrome, erythema and hyperhidrosis develop unilaterally. Typically, there is a compensatory reaction to decreased perspiration because of damage to the sympathetic system on the opposite side of the body. It may result from either central or peripheral sympathetic pathway damage.
4. Spinal Cord Lesions
Autonomic dysreflexia may occur with lesions of the spinal cord above T6, manifested by exaggerated autonomic responses to otherwise innocuous stimuli. This may be a presenting feature of a syrinx or intramedullary tumour.
5. Serotonin Syndrome
This is an important syndrome to be aware of as it is commonly overlooked and very variable in degree. It classically manifests with mental status changes, neuromuscular hyperactivity, and autonomic instability, in particular sweating and hyperthermia, but only a component may be present. Patients taking more than one agent acting on the serotonin system are particularly prone, for example an SSRI plus a tricylic.
Other agents to have on the alert list when thinking about this diagnosis include monoamine oxidase inhibitors (MAOIs), trazodone (Desyrel), lithium, opioids, and amphetamine/stimulants, including methylphenidate (Ritalin), 3,4 methylenedioxymethamphetamine (MDMA, Ecstasy), SNRIs (e.g. Venlafaxine (Effexor) and duloxetine (Cymbalta)), cocaine, herbal supplements (St. John’s Wort, ginseng), alpha-2 adrenergic heteroreceptor blocking agents (e.g. mirtazapine (Remeron)) that act by increasing noradrenaline and serotonin release and block serotonin receptors, Trazodone (Desyrel) and certain opioids. Less frequently, serotonin syndrome may be seen with the use of a single agent.
6. Stroke Related Sweating
Sweating associated with stroke may be mild or profuse, usually occurring early, either with the onset of stroke or a few days later, typically lasting two days to a couple of months. Delayed onset six to eight months following a stroke as well as prolonged persistence of perspiration has also been described. The sweating may be spontaneous or precipitated by exercise or minor infection. It involves one entire side of the body, although face and arm are more prominently affected. Other associated autonomic features are not usually present. The hemi-hyperhidrosis is contralateral.
Anxiety and Sweating
It has been said that excessive sweating is just a reflection of the affected individuals being very anxiety-prone. However, studies looking at general anxiety personality profiles have not found this to be so and indeed in patients with primary hyperhidrosis treated by sympathectomy, anxiety levels decreased post treatment suggesting that the excessive sweating is a contributor to anxiety rather than necessarily the other way around.
Although emotion (and heat) will make focal hyperhidrosis worse with increased forehead, axilla, or palmar and plantar sweating, this does not mean that it is primarily an emotional condition, as evidenced by the fact that it may occasionally begin in infancy.
By far the most common clinical disorders related to sweating arise from decreased sweating. This may be from abnormalities of the glands themselves, or more typically the nerve pathways which innervate the glands.
When the decrease in perspiration is primarily in the hands and feet (distal anhidrosis), the cause is most likely to be a peripheral neuropathy such as diabetes. Amyloid is another common cause. In more advanced cases of amyloid and diabetic neuropathies, the anhidrosis may also have a preganglionic component.
When the loss of sweating is generalized, the causes may either be central (eg. MSA or multiple system atrophy or idiopathic orthostatic hypotension) or peripheral (eg. acute panautonomic neuropathy).
When the loss of sweating is throughout the body but with relative sparing of hands and feet, a central cause is most likely, such as MSA or primary autonomic failure.
A peripheral nerve abnormality may lead to abnormal perspiration in the distribution of that peripheral nerve. Thus, trauma or inflammation of an isolated root, trunk, or nerve may lead to a patch of altered sweating.
The nerve pathways from the hypothalamus to the periphery travel on one side of the nervous system and therefore a lesion within this pathway will lead to hemi-anhidrosis, i.e., loss of sweating on one side of the body only. The individual nerves within this pathway do not form a tight well-defined bundle and therefore the decrease in sweating is typically patchy.
Local skin pathology may also lead to altered sweating through direct destruction of glands or blocking of their ducts. In these cases or in focal nerve lesions, there may be a compensatory increase in perspiration from neighboring normal sweat glands.
Conditions associated with decreased sweating:
- Diabetic Neuropath
- Sjogren’s Eyndrome
- Lambert-Eaton Myasthenic Syndrome
- Atopic Dermatitis
- Small Fiber Neuropathies
- Parkinsons’s Disease
- Other Parkinsonian Syndromes
- Chronic Idiopathic Anhidrosis
- Other Autonomic Neuropathies
Talc, starch and other powders may be applied to absorb excessive sweat.
Topical antiperspirants will normally have already been tried. The most effective of these which may have not been tried are the aluminium-containing compounds. Aluminium salts are present in many over-the-counter antiperspirants, typically at concentrations of 1% to 2%. However prescribed medications may contain aluminum chloride at a much higher concentration of up to 15% to 25%.
It is not fully understood how they work, but it is assumed that the aluminum ions in some way block the sweat gland ducts and then after a time lead to atrophy of the secretory cells. Thus, if application is repeated on a regular basis, the effect is markedly enhanced. Therefore more severe cases of axillary or acral hyperhidrosis can be treated with Drysol (20% aluminium chloride hexahydrate dissolved in anhydrous ethyl alcohol), applied to dry skin every night and washed off in the morning, decreasing frequency of application to once per week once if sweating is brought under control.
With aluminum compounds effectiveness may be improved by covering the treated area with for example a shower cap (for scalp application), plastic wrap, and gloves or socks for hands or feet or T-shirt for axilla.
Problems include skin irritation and burning pain. To minimize irritation, it is best to wash off the aluminium preparations if used at high strength. They may help some people with palmar hyperhidrosis, but the effect usually wears off within 48 hours.
The skin should be dry before application of aluminum preparations to prevent irritating hydrochloric acid formation if moisture is present. Washing should therefore be avoided before application. Applying just before bedtime is optimum because of the relative inactivity of sweat glands through the night. Hydrocortisone creams may be applied to help with any minor irritation that may develop.
Astringent substances such as formaldehyde, tannic acid or glyceraldehyde are occasionally used to try and dry the skin, but skin irritation and allergic reactions are common and they may stain and sensitise the skin.
For axillary symptoms, botulinum injections are very effective. The treatment can last six to nine months before it needs repeating.
Typically, 50 to 200 units of botulinum toxin type A are injected, beginning with 50 units per axilla through a 30-gauge needle in a grid-like pattern in spacing of 1 to 2 cm. There does not appear to be a great deal of difference whether injections are done intradermally or subcutaneously; intradermal may be more painful but are probably more effective. Thus most give intradermally at 10 to 20 sites
How much botulinum is needed for axillary hyperhidrosis? It is worth noting that in a randomized study of botulinum injection for hyperhidrosis, when the sweating gradually returned, patients described it as “close to as it has been before treatment” even though objectively it was below baseline. Several have found that 100 and 200 unit doses of Dysport were equally effective.
The average duration of effective botulinum is seven months for axillary treatment.
Botulinum toxin injection is overall the most effective nonsurgical therapy for focal hyperhidrosis. Therapeutic failure from antibody formation is theoretically possible, but unlike the circumstance of its use for dystonia where large amounts are administered, this appears to be very rare with hyperhidrosis.
An easy way of identifying areas of sweat is a simple facial tissue and a gentian violet, starch or iodine marker. Hot spots producing greater amounts of sweat can then be identified and higher doses are applied there. The typical area of treatment corresponds to the hairy area. Generally, all that is needed for analgesia is an ice pack applied to the axillae prior to injection.
The neurotransmitter and receptor between the peripheral autonomic nerve fiber and sweat gland is acetylcholine and muscarinic receptor respectively, so antimuscarinic agents may be useful. These may be given orally, such as propantheline bromide 15 mg t.d.s., or topically. Oral administration is convenient, but one may also get blockade of muscarinic receptors throughout the body with consequent side effects including dry mouth, constipation and a tendency to retention of urine.
An alternative is topical administration, although the issue here is finding an appropriate preparation of the drug such that it is not uncomfortable to apply, does not break down and manages to get across the outer keratin layer of the skin so it can reach the base of the sweat gland, but does not just pass completely systemically, in which case one might as well have just taken it orally in the first place.
Some patients use scopolamine patches, although this results in the drug scopolamine permeating throughout the entire body including the brain with important side effects. Non-blood-brain barrier penetrant anticholinergics are preferable such as propantheline, although again have important systemic side effects. Ergoloid mesylates, mecamylamine, atropine, propoxyphenel, dibenamine, piperoxan, phentolamine and methantheline bromide have all been described. A low dose of a beta-blocker such as atenolol or propanolol may also be useful given that a hyperadrenergic state (overactive sympathetic system) will exacerbate sweating.
Some people have a more active sympathetic system than others and going along with this is a quite frequent tendency to anxiety. Having said that, it may actually be that it is the end-organ response of the hyperadrenergic state (aging, palpitations, sweating) that feeds back to the brain and increases the level of anxiety.
This may be treated through cognitive behavioral therapy or alternatively in more severe cases medications directed towards anxiety such as pregabalin, SSRIs or SNRIs.Alpha-2 agonists such as clonidine, beta-blockers, and calcium channel antagonists have been described as having a slight effect in single case reports. Clonidine in particular is thought to be more effective for menopause-related hyperhidrosis or hyperhidrosis secondary to antidepressants. Fludrocortisone 0.3 mg daily has been used to control sweating in quadriplegics with orthostatic hypotension.
Palmar and Plantar Hyperhidrosis
One particular kind of procedure is the treatment of excessive sweating in the hands and feet-palmar and plantar hyperhidrosis. Two units per site were injected with a total dose of 100 units for each palm for palmar hyperhidrosis, but because of the pain, high-intensity vibration devices, cool packs, liquid nitrogen or regional anesthesia nerve blocks may be required. Application of EMLA does not prevent the pain of a needle penetrating the skin with its extremely dense sensory invasion.
Given that the majority of the pain occurs during the piercing of the skin itself, the smaller the hole created, the less the pain is likely to be. Cryo-analgesia, i.e., numbing of the tissue by cooling, is an alternative technique for palmar hyperhidrosis. Jet injectors have also been used. With this technique the botulinum is directed through a hole four times smaller than that of a 30 comfortable G needle (Med-Jet).
An ice cube held in gauze applied just prior to each individual injection of toxin may be a very effective form of anesthesia. Alternatively, topical lidocaine under occlusion for an hour followed by ice packs may be used, or a Bier’s block.
Dealing with psychological issues is always going to help if this could be contributory, through methods such as CBT.
The most persistent cases may occasionally be treated by cutting the sympathetic nerve supply. Unfortunately, it is quite common to get unpleasant compensatory excessive sweating in other areas of the body distant to the area innervated by the sympathetic nerves which have been cut.
Surgical approaches involve cutting the sympathetic nerve supply below the level of T1 (first thoracic root). Approaches include bilateral upper dorsal sympathectomy via the supraclavicular approach, percutaneous radiofrequency upper thoracic sympathectomy and thoracoscopic sympathicolysis. As well as direct surgical complications, compensatory and gustatory sweating are the most commonly reported problems with this.
In a thoracic sympathectomy where the T2/T3 sympathetic ganglia are removed, success rates of approximately 80% have been reported. Plantar sweating may also be reduced, even though the nerve supply interrupted does not innervate the feet, presumably because of a secondary effect through decreased emotional feedback from decreased palmar hyperhidrosis. The principal problems with surgical treatment are compensatory hyperhidrosis in other areas, as well as the surgery-related complications such as pneumothorax, Horner’s syndrome, damage to the phrenic nerve or thoracic duct.
Removal of axillary sweat glands through curettage or liposuction is also being used with success rates of approximately 90%, although this figure is debated and the operation is quite major with complications including scar formation, skin necrosis, discoloration and wound infection.
Image Credits: Pexels
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