Sweating disorders

Introduction

The autonomic nervous system maintains internal body temperature with a strict margin around 37°C (98.6°F). Eccrine sweating is the chief mechanism of evaporative heat loss to maintain thermoregulation in humans.  Elevation in the core temperature triggers warm-sensitive neurons in the hypothalamus to activate sweating pathways that descend to the thoracic spinal cord to synapse on preganglionic sympathetic neurons in the intermediolateral cell columns of the spinal cord and from there to exit in segmental pathways. Postganglionic unmyelinated C fibers pass through the gray ramus, combine with peripheral nerves, and travel to the skin, where they innervate predominantly cholinergic sweat glands.  Any lesion along this pathway, from central to peripheral, may manifest as abnormal sweating.

Disorders of sweating are categorized into hyperhidrosis and hypohidrosis/anhidrosis. 

Hyperhidrosis may interfere with the quality of life, whereas compensatory hyperhidrosis may occur in areas adjacent to hypohidrosis or anhidrosis.  Disorders causing anhidrosis are often manifestations of autonomic failure or neuropathy and can lead to hyperthermia with heat intolerance or, in circumstances of heat stress, potentially leading to heatstroke, which can fatal.

Anatomical Considerations

Sweating from eccrine glands is the principal mechanism of evaporative heat loss in humans to maintain thermoregulation. To maintain a narrow core body temperature margin around 37°C (98.6°F), the autonomic nervous system balances heat loss and heat production.  Core and skin thermoreceptors sense both temperature and nonthermal factors.  Cutaneous, visceral, and spinal cord thermoreceptors ascend in the spinothalamic tract with multisynaptic fibers reaching the reticular formation of the brainstem, thalamus, and hypothalamus.

The medial preoptic area of the hypothalamus is the primary thermosensitive area of the central nervous system. Warm-sensing neurons in the medial preoptic area respond to subtle changes in core temperature.  With an elevation in core temperature, the sympathetic nervous system response involves generalized sweating, vasodilation, and hyperpnea to trigger radiant and evaporative heat loss and restore thermal homeostasis.  From the preoptic area, warm-sensing neurons trigger evaporative sweat loss through inputs to neurons in the rostral ventromedial medulla, which project ipsilaterally through the medial portion of the lateral funiculus to synapse on preganglionic neurons in the intermediolateral column of the spinal cord.  Spinal innervation of sweating is segmental: T1 through T4 segments innervate the face, T2 through T8 segments innervate the upper limbs, T4 through T12 segments innervate the trunk, and T10 through L2 segments innervate the lower limbs.  After exiting the spinal cord, sympathetic vasomotor fibers pass through white rami communicantes to join the paravertebral sympathetic chain.  

Sweat glands are innervated by unmyelinated C fibers, which are mainly cholinergic. However, evidence shows that human sympathetic sudomotor neurons can also coexpress markers of noradrenergic neurons.  Results from animal studies suggest that a postnatal switch from adrenergic to cholinergic innervation of sweat glands occurs.  While sweat glands may maintain some dual innervation, activation of eccrine sweat glands is mediated primarily by acetylcholine acting via M3-type receptors.  Activation of the cholinergic M3-type receptors triggers an increase of intracellular calcium concentration, which increases the permeability of potassium and chloride channels and initiates the release of an isotonic precursor fluid from the secretory cells.  Other cotransmitters, such as vasoactive intestinal polypeptide, elicit vasodilation, which promotes sweating.  

Sympathetic fibers innervate 2 million to 4 million eccrine sweat glands distributed over the body surface.  The greatest density of eccrine sweat glands associated with thermoregulation is on the forehead, followed by the upper limbs and then the trunk and lower limbs.  The palms and the soles have a high density of sweat glands (600 glands/cm2 to 700 glands/cm2); however, these are not chiefly involved in thermoregulation but mediate emotional sweating.

Hyperhidrosis

Hyperhidrosis is defined as excessive sweating beyond what is needed to maintain core temperature in response to a thermal stimulus.  Hyperhidrosis is considered more socially bothersome than medically worrisome, but it can interfere with some occupations, whereas heavy generalized sweating may lead to hypovolemia and depletion of electrolytes. 

Disorders Associated With Hyperhidrosis

Generalized

• Essential generalized hyperhidrosis

• Secondary to central nervous system disorders

  • Shapiro syndrome (episodic hypothermia with hyperhidrosis)

  • Posttraumatic or posthemorrhagic

  • Fatal familial insomnia

  • Parkinson disease

• Secondary to central and peripheral nervous system disorders

  • Familial dysautonomia

  • Morvan fibrillary chorea

• Secondary to systemic illness

  • Infection

  • Neoplasm

    • Pheochromocytoma, lymphoma, leukemia, carcinoid, renal cell cancer, Castleman disease

  • Metabolic

    • Thyrotoxicosis, diabetes mellitus, hypopituitarism, menopause

  • Drug withdrawal

    • Opiates, alcohol

• Nocturnal diaphoresis

  • Tuberculosis

  • Lymphoma

  • Endocarditis

  • Diabetes mellitus

  • Acromegaly

  • Menopause

  • Obstructive sleep apnea

  • Prinzmetal angina

• Medication related

  • Neuroleptic malignant syndrome, serotonin syndrome

• Focal

  • Essential focal hyperhidrosis

    • Palmoplantar, axillary, craniofacial

  • Secondary to central nervous system disorders

    • Cerebral infarction

    • Spinal cord injury

      • Autonomic dysreflexia, posttraumatic syringomyelia

      • Cold-induced sweating syndrome

      • Olfactory hyperhidrosis

      • Chiari type I malformation

  • Associated with peripheral nervous system disorders

    • Autonomic neuropathy

    • Dermatomal due to nerve trunk irritation

  • Craniofacial disorders

    • Gustatory sweating

    • Lacrimal sweating

    • Harlequin syndrome

  • Associated with dermatologic disorders

    • Pretibial myxedema

    • POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes)

Selected Medications Causing Hyperhidrosis

• Antidepressants: SNRIs, SSRIs.

• Anticholinesterases: Pyridostigmine

• Muscarinic Receptor Agonists: Pilocarpine, Bethanechol

• Opioids

• Proton Pump Inhibitors

Generalized Hyperhidrosis

Essential (or primary generalized) hyperhidrosis involves the entire body but is typically most pronounced in areas of the highest sweat gland density, with excessive sweating often noted over the face, neck, and upper trunk. Sweating may occur at a lower temperature or exercise threshold than in people without hyperhidrosis.

Secondary causes of generalized hyperhidrosis are often associated with a systemic process or illness.  For example, nocturnal diaphoresis may be a manifestation of a neoplasm, infection, diabetes mellitus, or coronary vasospasm, with improvement of the hyperhidrosis requiring treatment of the underlying cause.  Medications may also cause hyperhidrosis.

Common offenders include opioids, antidepressants (selective serotonin reuptake inhibitors [SSRIs]), and prostaglandin inhibitors. Hyperhidrosis is noted in both acute and chronic opioid administration, likely related to histamine release, yet may also be seen in opioid and alcohol withdrawal. Both serotonin syndrome and neuroleptic malignant syndrome may manifest hyperthermia with hyperhidrosis in addition to labile blood pressure, rigidity, agitation, and confusion.  Medication effects in the setting of CNS disorders may also contribute to hyperhidrosis as seen in Parkinson disease. 

Shapiro Syndrome:  

CNS dysfunction may lead to generalized hyperhidrosis, such as in Shapiro syndrome, which is characterized by episodic hypothermia and hyperhidrosis.  Radiographically, this syndrome is associated with abnormalities of midline structures, such as agenesis of the corpus callosum.  Episodes in Shapiro syndrome may respond to treatment with clonidine, glycopyrrolate, or antiepileptic medications.

Paroxysmal Sympathetic Hyperactivity:  

Paroxysmal sympathetic hyperactivity after acquired brain injury is the consensus term for the syndrome characterized by paroxysmal sympathetic overreactivity leading to diaphoresis, fever, flushing, shivering, hypertension, tachypnea, tachycardia, and, in some cases, motor involvement such as dystonic posturing. The original case described by Penfield as “diencephalic epilepsy” was due to a tumor at the foramen of Monro; however, numerous causes of acquired CNS damage leading to this syndrome have been described, including trauma, hemorrhage, tumors, and hydrocephalus. Treatment is aimed at reducing sympathetic nervous system activity by maintaining adequate hydration, and mimicking conditions should be excluded. 

Pharmacologic treatment includes morphine, nonselective beta-blockers, or gabapentin.  While thermoregulatory sweating is often accentuated in disorders with generalized hyperhidrosis, focal hyperhidrosis may be independent of thermoregulatory processes, with localized sweating occurring spontaneously or precipitated by emotional stimuli.

Primary focal hyperhidrosis:

Essential (or primary focal) hyperhidrosis is likely the most common cause of sweating dysfunction, with an estimated prevalence of 2.8% in the United States.  Primary focal hyperhidrosis affects the palms, soles, axillae, and sometimes the craniofacial region.  The hyperhidrosis is independent of thermoregulatory needs, and sweating may be constant; however, anxiety-inducing stimuli, elevated ambient temperature, or physical exertion often exacerbates the hyperhidrosis.  Sweating from the palms may influence academic pursuits, as it may cause difficulty writing with pen and paper; it may also impair fine motor tasks and present a potential risk of minor electrical shock if the fingers come into contact with poorly insulated wires or switches of electrical appliances. Sweating from the soles can render certain footwear such as sandals slippery, and frequent exposure to sweat can cause shoes to wear out more quickly.  When severe, focal hyperhidrosis may interfere with the patient’s quality of social and professional life because of the embarrassing appearance of sweat and avoidance of shaking hands in greeting and may lead to social anxiety.

Treatment of focal primary hyperhidrosis is based on the severity of symptoms and the patient’s goals. Topical treatments are recommended for initial treatment, with topical antiperspirants containing 6% to 25% aluminum chloride in alcohol applied nightly over affected areas.  When topical treatments fail, tap water iontophoresis is a safe and useful treatment. The patient immerses the affected area in an electrolyte solution while a low-intensity current of 15 mA to 30 mA is applied by a battery-powered unit. The suspected mechanism is mechanical plugging of sweat pores at the stratum corneum. Since the effect is temporary, patients repeat the procedure on a nightly basis or, after the desired effect is achieved, every few days thereafter for continued benefit. Adding crushed glycopyrrolate to the solution may enhance the results.

Systemic medications may also be tried. Anticholinergic medications such as glycopyrrolate often lead to intolerable side effects, especially dry mouth, in the doses necessary to ameliorate focal sweating. When anxiety or psychosocial stressors trigger severe hyperhidrosis, anxiolytics may be useful.  After topical and medication treatments, intradermal botulinum toxin injections may be useful.  Botulinum toxin inhibits release of acetylcholine at the sympathetic nerve junction with the sweat gland.  Multiple injections are necessary as the anhidrotic effect is localized to a square centimeter of the injection site. However, the effect may last as long as 6 months.  When injecting for palmar hyperhidrosis, patients must be made aware of the risk of intrinsic hand weakness.

Long-term success for palmar hyperhidrosis is often achieved with endoscopic transthoracic sympathotomy or sympathectomy. Surgical approaches involve interruption of sympathetic outflow to the hands via resection, ablation, or clip placement to the sympathetic thoracic chain, with various success rates and complications. Surgical sympathectomy involves removal of the stellate ganglion, which may lead to Horner syndrome with associated pupillary and eyelid dysfunction. Sympathotomy, which refers to cautery of the sympathetic chain at the level of the second thoracic ganglion, leads to a high success rate of more than 95% for controlled palmar sweating with low risk of compensatory hyperhidrosis. Surgical options for axillary hyperhidrosis are reserved for severe cases and include axillary gland liposuction or resection.

Gustatory and Olfactory Sweating:

Sweating may normally be triggered by eating hot and spicy foods and localized to the perioral area, forehead, scalp, and nose.  When pathologic, gustatory hyperhidrosis is asymmetric and intense and may even include patches over the trunk and extremities. The etiology in pathologic cases is aberrant regeneration of damaged nerves from facial parasympathetic fibers originally destined for salivary glands that instead innervate facial sweat glands that have been sympathetically denervated. One cause is Frey syndrome, with sweating occurring over the distribution of the auriculotemporal nerve after injury such as abscess or surgery of the parotid region. Cases have also been reported due to diabetic neuropathy, cluster headache, and injury to the sympathetic trunk.

Treatment may include subcutaneous botulinum toxin injection in the symptomatic area.  Olfactory hyperhidrosis syndrome is characterized by profuse facial sweating precipitated by perfume smells but not by gustatory or emotional stimuli; it has been treated with oral amitriptyline.

Cold-Induced Sweating Syndrome:

Cold-induced sweating syndrome is a genetic disorder associated with missense mutations in the CRLF1 or CLCF1 gene; these genes are part of a cytokine signaling pathway involved in normal development of the nervous system.  In cold temperatures, patients demonstrate profuse truncal sweating, but, paradoxically, they do not sweat in the heat. The syndrome may also include a limited autonomic neuropathy with thermal and pain insensitivity and characteristic facial features and joint abnormalities.

Compensatory Hyperhidrosis:

Secondary hyperhidrosis commonly occurs either adjacent or distant to areas of anhidrosis or hypohidrosis as the body compensates for the area of reduced sweating.  Often, the areas of excessive sweating are what lead patients to seek medical attention, while the region of hypohidrosis or anhidrosis is related to the pathologic cause.  Both central and peripheral causes of anhidrosis may have accompanying hyperhidrosis

CNS disorders:  Strokes, particularly those affecting the insular and opercular cortex, can lead to hemi-hyperhidrosis affecting the side contralateral to the stroke, with the face and arm often more affected.  Strokes involving the hypothalamus, paramedian thalamus, pons, and medulla may also lead to acute and transient hyperhidrosis.  The putative mechanism involves interruption of inhibitory pathways controlling contralateral sweating.

In multiple sclerosis, involvement of the hypothalamus may lead to unilateral sweating.  Spinal cord involvement is more likely to cause abnormal sweating, often with areas of anhidrosis related to myelopathy leading to compensatory hyperhidrosis above the lesion.

Autonomic dysreflexia:  Patients with spinal cord injury may experience segmental hyperhidrosis above the lesion, with episodes of profuse sweating occurring in the acute stage as well as months to years after injury.  When the lowest segment of cord injury is above T6, autonomic dysreflexia is very common.  Autonomic dysreflexia is characterized by an elevation in blood pressure with accompanying bradycardia, facial flushing, and profuse sweating above the level of the lesion and pale cold skin and piloerection below the level of the lesion. Patients may report severe headaches with risk for hypertensive complications with frequent or prolonged elevations in blood pressure.  The mechanism is related to stimulation of sympathetic afferents below the lesion that leads to exaggerated sympathetic discharges due to disconnection from supraspinal regulation.  As blood pressure rises, vagal responses triggered by the baroreflex lead to bradycardia, but baroreflex-mediated sympathoinhibition is disrupted due to interruption of descending inputs to the spinal cord.

Vasoconstriction occurs below the level of the lesion and vasodilation above the lesion. Treatment involves urgent identification of the stimulus, such as bladder or bowel distension or skin or visceral irritation, while fast-acting antihypertensives are used to control blood pressure.  

Hyperhidrosis in Cervical Sympathetic Chain Lesions:  Injury of the cervical sympathetic chain ganglia or postganglionic sympathetic fibers leading to reduced or exaggerated activity may lead to sweating symptoms in the face, neck, and upper thorax before causing other symptoms.  Encroachment by neoplasms is commonly seen with Pancoast tumors, commonly due to pulmonary adenocarcinoma, mesothelioma, and lymphoma; occasionally a cervical rib may also compress the sympathetic chain.  Symptoms may include hemifacial flushing and typically include Horner syndrome with unilateral ptosis, miosis, and facial anhidrosis.  Pancoast syndrome refers to additional involvement of the brachial plexus with associated upper extremity weakness and sensory loss.

Idiopathic unilateral circumscribed hyperhidrosis may be related to hyperfunction of the localized sympathetic chain ganglia.  Patients with this disorder present with profuse sweating in a defined area on the face and upper extremities that is precipitated by heat and lasts between 15 and 60 minutes.

Treatment may include application of topical aluminum chloride or a topical anticholinergic, botulinum toxin injection, or oral anticholinergic or clonidine.

Harlequin Syndrome:  Harlequin syndrome denotes contralateral hemifacial flushing and hyperhidrosis that is due to unilateral sympathetic denervation leading to ipsilateral anhidrosis.  Harlequin syndrome has a number of different presentations and causes, which may include spinal cord involvement, ganglionopathy, or iatrogenic causes. When oculosympathetic fibers are involved, Horner syndrome accompanies the anhidrotic side. Sudomotor fibers destined for the head exit the spinal cord at T2 to T3 and join oculopupillary fibers exiting between C8 and T2 to pass through the stellate ganglion and ascend in the cervical sympathetic trunk to synapse on postganglionic neurons in the superior cervical ganglion.  Sudomotor fibers innervating the face follow the external carotid artery, whereas oculosympathetic fibers and sudomotor fibers innervating the medial supraorbital area continue with the internal carotid plexus through the carotid canal and cavernous sinus to reach orbital structures. The presence of Horner syndrome with anhidrosis helps to localize the site of the lesion.

Ross Syndrome:  Ross syndrome consists of the triad of segmental anhidrosis, areflexia, and tonic (Adie) pupil.  Often, the most problematic feature is compensatory hyperhidrosis.  The areas of anhidrosis may be asymmetric and progressive.  Autonomic testing typically demonstrates a postganglionic lesion, with skin biopsies showing absent or reduced cutaneous and autonomic innervation underlying anhidrosis and loss of cutaneous blood flow regulation.

Clinical Vignette: Hyperhidrosis in Parkinson Disease

A 72-year-oldmanwith a 6-year history of Parkinson disease treated with carbidopa/levodopa presented with generalized sweating episodes.  The episodes characteristically began with sweating over the forehead and proceeded to involve his entire body, often necessitating a change in clothing.  The episodes occurred daily, leading to social isolation, and followed a typical pattern: after taking carbidopa/levodopa, he experienced mild dyskinesia when in the on state, but as dyskinesia began to wane, sweating would begin.  Sweating occurred roughly 30 minutes before his next scheduled dose of carbidopa/levodopa and continued for about 20 minutes after taking the dose.  This patient demonstrated off state hyperhidrosis episodes that were significantly limiting his quality of life. 

Comments: Sweating abnormalities in Parkinson disease were noted by Gowers but became more evident after the introduction of levodopa.  Hyperhidrosis episodes are more often reported in the off period in Parkinson disease and may have a significant negative impact on quality of life.

Clinical Vignette: Palmoplantar hyperhidrosis

A 21-year-old woman presented with hyperhidrosis of the palms and soles.  Even as a toddler, the patient had been noted to leave damp handprints and footprints. The symptoms became problematic for the patient around puberty and influenced her ability to write with paper and pen, shake hands without embarrassment, and put on gloves during nursing classes. Examination showed sweat beading from the palms and soles. A thermoregulatory sweat test confirmed resting sweat activity with otherwise normal sweat recruitment and distribution (FIGURE 7-2). The patient had tried topical therapies, which led to cracking of the palms, and tap water iontophoresis and systemic therapies of glycopyrrolate, which offered only marginal benefit and led to intolerable side effects 

Comments:  This case illustrates the typical features of essential palmoplantar hyperhidrosis. The patient had tried multiple topical and systemic therapies for hyperhidrosis with only marginal benefit. Since her hyperhidrosis had failed to respond to multiple topical and systemic therapies, she was referred to a neurosurgeon for endoscopic transthoracic sympathotomy, which achieved lasting anhidrosis of the palms 

Harlequin syndrome

A 60-year-old man was referred for evaluation of excessive facial sweating.  His history was notable for a double aortic arch, for which he underwent repair 2 years before presentation.  Following the procedure, he noted increasing sweating over the right half of his face, which was sometimes accompanied by marked right hemifacial flushing.  Episodes were triggered by exertion and mild increases in ambient heat.  On examination, his pupils were symmetric and reactive to light.  A thermoregulatory sweat test showed anhidrosis of the left face and neck, with well-demarcated sweating occurring over the right half of the face.

In this patient, harlequin syndrome was likely due to injury to the preganglionic sympathetic fibers or ganglia during thoracotomy. Oculopupillary fibers, which depart primarily at T1, were preserved, while vasomotor fibers, which exit primarily at T2 to T3, were impaired. Both join the paravertebral sympathetic chain and pass through the stellate ganglion. 

Hypohidrosis and anhidrosis

Anhidrosis is the absence of sweating, whereas hypohidrosis refers to reduced sweating that is inadequate to dissipate body heat for thermoregulation.  Central and peripheral etiologies may contribute to anhidrosis.  Medication effects may influence sweating at central or peripheral levels.  Anticholinergic medications are the most common drug-related cause of anhidrosis due to muscarinic receptor antagonism at the junction between the sympathetic nerve terminal and the eccrine sweat gland.  Multiple classes of medication cause an anticholinergic effect, although other mechanisms may also reduce sweating.

Disorders Associated With Anhidrosis

Central Nervous System Disease

• Multiple system atrophy

• Dementia with Lewy bodies

• Parkinson disease

• Stroke

• Multiple sclerosis

• Spinal cord disease

Peripheral Nervous System Disease

• Pure autonomic failure

• Autoimmune autonomic ganglionopathy

• Autonomic neuropathy

  • Diabetic neuropathy

  • Paraneoplastic neuropathy

  • Inherited neuropathy

  • Amyloid neuropathy

  • Lepromatous neuropathy

• Sjögren syndrome

• Ross syndrome

• Harlequin syndrome

• Fabry disease

Chronic Idiopathic Anhidrosis

Dermatologic Disorders

• Local skin injury

• Systemic sclerosis

• Congenital absence of sweat glands

Selected Medications Causing Anhidrosis

Mechanism [] Class Selected []  Examples

• Anticholinergic effect via M3 receptor antagonists:  Glycopyrrolate, doxepin, atropine, cyproheptadine, hyoscyamine

• Tricyclic antidepressants: Amitriptyline.

• Antihistamines: Diphenhydramine

• Bladder antispasmodicsL Oxybutynin, tolterodine 

• Antipsychotics and antiemetics:  Chlorpromazine, clozapine, quetiapine. 

• Carbonic anhydrase inhibition: Antiepileptics: Topiramate, zonisamide

• Central adrenergic effect:  Antihypertensives: Clonidine

• Hypothalamic μ-opioid receptor agonism: Opioids Fentanyl, morphine, hydrocodone, oxycodone

• Inhibiting presynaptic acetylcholine release:  Neuromuscular paralytics: Botulinum toxins

Synucleinopathies

Disorders due to abnormal intracellular accumulation of misfolded α-synuclein have characteristic patterns of thermoregulatory dysfunction that range in degree and distribution of anhidrosis and preganglionic or postganglionic site of the thermoregulatory lesion

Multiple System Atrophy (MSA): 

Multiple system atrophy is a neurodegenerative disorder characterized by autonomic failure with parkinsonism or cerebellar ataxia, or both. Neuropathologically, it is characterized by abnormal α-synuclein accumulation as glial cytoplasmic inclusions in brainstem autonomic centers involved in blood pressure control and thermoregulation, including the rostral ventrolateral medulla and medullary raphe.  As a manifestation of autonomic failure, patients with multiple system atrophy often have extensive anhidrosis on the thermoregulatory sweat test.  The site of the lesion is predominantly central/preganglionic, although evidence exists of increasing peripheral involvement with disease duration, suggesting involvement of postganglionic fibers or sweat glands later in the disease course. Skin biopsies from patients with multiple system atrophy may also show a reduction in sweat gland innervation. Some patients may have preserved sweating over the hands, which may be explained by preserved acral sympathetic innervation similar to the cold hand sign in this disorder.

Pure Autonomic Failure:  

Previously known as Bradbury-Eggleston syndrome, pure autonomic failure is a progressive degenerative disorder of the autonomic nervous system characterized by orthostatic hypotension, often with widespread autonomic dysfunction involving genitourinary, bowel, and thermoregulatory functions.  Pathophysiologically, pure autonomic failure is characterized by α-synuclein deposition peripherally in autonomic ganglia and nerves. While, by definition, no evidence of CNS dysfunction is seen in pure autonomic failure, these patients may progress to other synucleinopathies, such as multiple system atrophy, Parkinson disease, or dementia with Lewy bodies.  Classically, thermoregulatory dysfunction in pure autonomic failure is peripheral in origin and may have striking degrees of anhidrosis, sometimes with compensatory hyperhidrosis. However, one sign that patients may later progress to CNS disease may be a central pattern of sweat loss showing anhidrosis on thermoregulatory sweat testing in the presence of preserved QSART volumes.

Lewy Body Disorders

Patients with Parkinson disease may manifest symptoms of thermoregulatory dysfunction such as heat or cold intolerance, and may have episodes of hyperhidrosis, which are often medication-related.  Classically, patients with Parkinson disease have evidence of mild distal anhidrosis that is peripheral in origin.  Patients with dementia with Lewy bodies tend to have a similar pattern of postganglionic sudomotor failure, with a greater degree of anhidrosis compared to patients with Parkinson disease.

Peripheral Disorders

Thermoregulatory sweat output declines with normal aging. This decline may be because of factors related to peripheral neural and eccrine glands as well as physical conditioning levels and genetic predisposition.  Any disruption of the autonomic ganglia or peripheral sudomotor nerves leads to characteristic patterns of peripheral hypohidrosis or anhidrosis.

Autoimmune autonomic ganglionopathy

Autoimmune autonomic ganglionopathy is a subacute or insidiously progressive disorder affecting autonomic ganglia and their nerves and is commonly due to autoantibodies to the neuronal ganglionic nicotinic acetylcholine receptor. Patients may manifest severe autonomic dysfunction, including gastrointestinal dysmotility, urinary retention, dilated pupils, reduced heart rate variability, and orthostatic hypotension.  The degree of autonomic failure may correlate with the antibody titer.  The percentage of anhidrosis in patients with autoimmune autonomic ganglionopathy may be severe and tends to increase distally

Autonomic neuropathies

 A distal pattern of anhidrosis is a frequent manifestation of length-dependent neuropathies.  Patients are often unaware of reduced distal sweating, which underscores the importance of testing sudomotor function to determine small fiber involvement in neuropathies.  Hereditary sensory and autonomic neuropathies (HSAN) with small fiber involvement (such as HSAN I, HSAN II, HSAN IV [congenital insensitivity to pain], and HSAN V) have varying degrees of anhidrosis.  HSAN II is characterized by anhidrosis with distal acropathy.  Familial dysautonomia (HSAN III, or Riley-Day syndrome) is characterized by episodic orthostatic hypotension and hypertension with profuse sweating, skin blotching, absence of emotional tears, gastrointestinal dysmotility, and insensitivity to pain.  On skin biopsy, significantly reduced epidermal nerve fiber density and reduced innervation of sweat glands are seen. Testing suggests that central sudomotor pathways and remaining peripheral sudomotor axons are hyperexcitable in patients with familial dysautonomia. HSAN IV is a congenital or infantile onset of fevers with widespread anhidrosis and insensitivity to pain, with lack of epidermal and sweat gland innervation on skin biopsy.

Acquired neuropathic disorders may also manifest anhidrosis.  Lepromatous neuropathy due to infection with Mycobacterium leprae leads to tender enlargement of peripheral nerves with a predilection for cooler (often distal) body parts.  Testing may show sensory loss over affected regions, with multifocal, well-circumscribed areas of anhidrosis.  Small fiber involvement manifesting as anhidrosis is often present in neuropathies, such as in amyloid neuropathies. Tangier disease, vasculitis, alcoholism, and Fabry disease.

Diabetic autonomic neuropathy. 

Diabetes mellitus is the most common cause of autonomic neuropathy, with neuropathy found in approximately half of all patients with type 1 diabetes mellitus and nearly three-fourths of those with type 2 diabetes mellitus.  The most frequent pattern of sweat loss is length-dependent, often in a stocking-glove distribution.  In addition to distal sweat loss, thoracic nerve roots may be involved, leading to asymmetric sweat loss over affected areas; when severe, patients may manifest global anhidrosis.

Sjogren disease

Sjögren disease is an autoimmune exocrinopathy that causes sicca symptoms of xerostomia (dry mouth) and xerophthalmia (dry eyes).  With lymphocytic infiltration of the eccrine glands, patients with Sjögren disease may have accompanying hypohidrosis.

Chronic idiopathic anhidrosis

The syndrome of chronic idiopathic anhidrosis was described in 1985 in patients with heat intolerance and widespread anhidrosis without accompanying features of autonomic failure.  Clinically, patients present with flushing, dyspnea, dizziness, and weakness when exposed to elevated ambient temperatures.  The pattern of the lesion varies and may be preganglionic or postganglionic, and the prognosis is favorable.  An autoimmune etiology may account for some cases, as skin biopsies may demonstrate perieccrine lymphocytic infiltrates over areas of anhidrotic skin.

Idiopathic pure sudomotor failure

Autoimmune mechanisms may also underlie anhidrosis as seen in idiopathic pure sudomotor failure, which clinically presents with the sudden onset of generalized anhidrosis with concomitant sharp pain or cholinergic urticaria.  No other features of autonomic dysfunction are seen, and skin biopsy may not show morphologic abnormalities; however, serum IgE levels are elevated, and patients respond well to steroids.

Dermatologic disorders

Primary dermatologic disorders in which disruption of sweat gland integrity occurs, such as psoriasis, exfoliative dermatitis, lichen sclerosus, ichthyosis, or miliaria, may lead to hypohidrosis. Hypohidrosis may also develop after dermatologic injury, such as damage to sweat glands (burns, radiation, inflammation, scarring) or secondary to sweat gland necrosis following blistering from medication overdoses.

Clinical Vignette: anhidrosis/hypohidrosis

 A 46-year-old man presented for evaluation of orthostatic hypotension.  He had a 4-year history of erectile dysfunction with urinary frequency and urgency.  During the few months before presentation, he endorsed sloppier handwriting and gait imbalance.

Neurologic examination showed evidence of cerebellar ataxia.  On autonomic reflex screen, the patient had autonomic failure with preserved quantitative sudomotor axon reflex test (QSART) volumes.

Thermoregulatory sweat test showed global anhidrosis with preserved sweating over the hands 

This patient fulfills criteria for multiple system atrophy with predominant cerebellar ataxia, with autonomic failure manifesting as orthostatic hypotension with genitourinary dysfunction. The thermoregulatory sweat test and QSART results interpreted together indicate a central/preganglionic pattern of sweat loss.

Clinical Vignette: Autoimmune autonomic ganglionopathy

A 49-year-old man presented 2 months after developing nausea followed by diarrhea, urinary retention, erectile dysfunction, orthostatic hypotension, and sicca symptoms (dry eyes and dry mouth).  Neurologic examination was normal other than slow pupillary responses to light.  

Autonomic testing showed reduced or absent quantitative sudomotor axon reflex test (QSART) volumes with blunted heart rate responses to deep breathing and Valsalva maneuver.  Beat-to-beat blood pressure recording during Valsalva showed absent late phase II recovery and phase IV overshoot with prolonged blood pressure recovery time, while orthostatic hypotension was immediately detected on head-up tilt.  The thermoregulatory sweat test showed global anhidrosis with preserved islands of sweating.  Laboratory testing for ganglionic nicotinic acetylcholine receptor antibodies was positive at 0.22 nmol/L (normal less than 0.02 nmol/L).

This case demonstrates severe autonomic failure and the characteristic sweating pattern in a patient with autoimmune autonomic ganglionopathy.  The patient was treated with a course of IV immunoglobulin (IVIg) with improvement of all symptoms other than mild residual orthostatic intolerance.

Trends

Historically, skin biopsies were performed in patients with metabolic diseases such as lysosomal disorders. With the discovery of protein gene product 9.5 as a component of axons, leading to the detection of unmyelinated nerve fibers in the epidermis, it is now possible to perform qualitative and quantitative studies of cutaneous nerve fiber density and morphology.  The use of skin biopsy has been expanded to peripheral autonomic disorders, and skin biopsy is commonly used to quantify autonomic innervation in diabetic neuropathy.  

The use of skin biopsies has also been extended to synucleinopathies with decreased sudomotor and pilomotor innervation demonstrated in Parkinson disease and pure autonomic failure.  In multiple system atrophy, autonomic innervation is relatively preserved, which leads to the intriguing possibility that skin biopsy may become a potential tool to differentiate the various synucleinopathies. However, the current methodologies are variable, and consensus does not yet exist for optimal reporting of α-synuclein quantification.

Additionally, histologic evaluation does not differentiate the etiology of the disease and rarely changes clinical management.

Conclusion: Any lesion along the thermoregulatory pathway, from central involvement to peripheral structures, including autonomic nerves and eccrine sweat glands, may manifest as abnormal sweating.  Hyperhidrosis may interfere with quality of life, whereas compensatory hyperhidrosis may be a red flag for hypohidrosis or anhidrosis. Disorders with anhidrosis are often due to autonomic failure or neuropathy, portending a more severe neurologic disorder.

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