Diseases of the autonomic nervous system - detailed and technical article.

Topics covered:

• Essentials
• Introduction
• Individual autonomic disorders
• Further reading

Essentials 

The autonomic nervous system innervates all organs, producing predominantly involuntary and automatic actions that are mediated by two principal efferent pathways, the sympathetic and parasympathetic, which are neurochemically and anatomically distinct. Numerous synaptic relays and neurotransmitters allow the autonomic control of organ function at local and central levels to be integrated with the requirements of the whole body.

The peripheral and central components of the autonomic nervous system are frequently affected by diseases, conditions, or toxins. Autonomic disorders are described as (1) primary—without defined cause, including multiple system atrophy and acute/subacute dysautonomias; or (2) secondary—with specific defects or as a consequence of other conditions, including diabetes mellitus, Riley–Day syndrome, amyloid neuropathy, dopamine β-hydroxylase deficiency, spinal cord injury, and many drugs.

Clinical features

Failure of the autonomic nervous system—manifestations may be (1) sympathetic—adrenergic failure causes postural hypotension and (in men) disturbed ejaculation; cholinergic disturbances interfere with sweating; (2) parasympathetic—causing a fixed heart rate, erectile failure, and disturbed emptying of the urinary bladder and large intestine.

Overactivity of the autonomic nervous system—manifestations may be (1) sympathetic—characterized by hypertension, tachycardia and excessive sweating; (2) parasympathetic—leading to bradycardia. Mixed effects, peripherally and centrally, lead to complex clinical manifestations.

Investigation

Autonomic screening tests include (1) cardiovascular—(a) physiological—e.g. head-up tilt, heart rate responses, (b) biochemical—e.g. plasma noradrenaline, adrenaline, and dopamine levels, (c) pharmacological—e.g. clonidine growth-hormone stimulation; (2) sweating—e.g. thermoregulatory response to increasing core temperature by 1 °C. Autonomic dysfunction may also be suggested by a wide variety of other tests, including those of gastrointestinal, urinary/renal, sexual, respiratory and eye function.

Treatment

Symptomatic—(1) Orthostatic hypotension—management requires an approach combining (a) nonpharmacological measures—e.g. avoidance of sudden standing, high salt intake; and (b) pharmacological measures—e.g. fludrocortisone, sympathomimetics (e.g. ephedrine, midodrine). (2) Other symptoms—combined pharmacological and physical interventions can improve urinary incontinence, gastrointestinal motility disorders, and sexual dysfunction. Care is required to manipulate autonomic activity in patients with parkinsonian manifestations because the autonomic aspects are frequently exacerbated by antiparkinsonian agents.

Specific—some causes of autonomic dysfunction are treatable, e.g. infusions of immunoglobulin and plasmapheresis for immune-mediated neuropathy; hepatic transplantation in familial amyloid polyneuropathy.

Introduction  

The autonomic nervous system has two principal efferent pathways, sympathetic and parasympathetic, that innervate and influence every organ in the body. Autonomic actions are predominantly involuntary and automatic, as indicated by the term ‘autonomic’ first proposed by Langley in 1898. The structure of the autonomic system, with numerous synapses centrally and peripherally, as well as multiple neurotransmitters, provides flexible control of organ function locally and in an integrated manner—as in the maintenance of systemic blood pressure and body temperature. Disease of the autonomic nervous system may cause local or systemic effects.

Basic principles

The autonomic nervous system is primarily a visceromotor system, in which each efferent pathway is influenced in a variety of ways. Feedback and central integration are important and virtually every sensory pathway can influence its activity. For example, in spinal cord lesions, activation of visceral, skin, and muscle receptors below the level of the lesion influences autonomic activity and blood pressure through the spinal pathways, while heart rate responses to classic afferent baroreceptor pathways are retained. Key cerebral autonomic centres are in the hypothalamus, midbrain (Edinger–Westphal nucleus and locus ceruleus), and brain stem (nucleus tractus solitarius and vagal nuclei), and through intracerebral connections. Many other areas affect autonomic activity. Examples are the insular cortex, anterior cingulate gyrus, and amygdala, which are important in processing emotion and autonomic effects. Parasympathetic efferent pathways are craniosacral and sympathetic efferents are thoracolumbar; each has pre- and postganglionic fibres. The sympathetic ganglia are placed further from target organs than the parasympathetic ganglia.

Above: The autonomic nervous system

Autonomic nerve terminals at target organs vary in complexity; they have the capacity to synthesize neurotransmitters and a host of mechanisms affects uptake and interaction with local or blood-borne chemicals (see diagram below).

Above: Schema of some pathways in the formation, release, and metabolism of noradrenaline (norepinephrine) from sympathetic nerve terminals. Tyrosine is converted into dihydroxyphenylalanine (dopa) by tyrosine hydroxylase (TH). Dopa is converted into dopamine (DA) by dopa decarboxylase (DDC). In the vesicles, dopamine is converted into noradrenaline (NA) by dopamine β-hydroxylase. Nerve impulses release both dopamine β-hydroxylase and noradrenaline into the synaptic cleft by exocytosis. Noradrenaline acts predominantly on α1-adrenoceptors but has actions on β-adrenoceptors on the effector cell of target organs. It also has presynaptic adrenoceptor effects. Those acting on α2-adrenoceptors inhibit noradrenaline release and those on β-adrenoceptors stimulate noradrenaline release. Noradrenaline may be taken up by a neuronal process (uptake 1) into the cytosol, where it may inhibit further formation of dopa through the rate-limiting enzyme tyrosine hydroxylase. Noradrenaline may be taken into vesicles or metabolized by monoamine oxidase (MAO) in the mitochondria. Noradrenaline may be taken up by a higher-capacity, but lower-affinity, extraneuronal process (uptake 2) into peripheral tissues, such as vascular and cardiac muscle and certain glands. Noradrenaline is also metabolized by catechol-O-methyl transferase (COMT). Thus, noradrenaline measured in plasma is the overspill not affected by these numerous processes. (b) Outline of the major transmitters at autonomic ganglia and postganglionic sites on target organs supplied by the parasympathetic and sympathetic efferent pathways. The acetylcholine (ACh) receptor at all ganglia is of the nicotinic subtype (ACh-n). Ganglionic blockers such as hexamethonium thus prevent both parasympathetic and sympathetic activation. Atropine, however, acts only on the muscarinic (ACh-m) receptors at postganglionic parasympathetic and sympathetic cholinergic sites. The cotransmitters, along with the primary transmitters, are also indicated. NPY, neuropeptide Y; VIP, vasoactive intestinal peptide.

There are differences between organs, especially the gastrointestinal system, in which the enteric nervous system is considered as a third autonomic division. The multiplicity of neural pathways, transmitters, and modulators results in selective control of responses in specific vascular territories and organs, making it a highly complex but precisely regulated and integrated system.

Classification

Diseases of the autonomic nervous system may result in central or peripheral damage or derangement; these may be primary with no known cause or secondary with specific abnormalities (dopamine β-hydroxylase deficiency), or strong associations with other diseases (Holmes–Adie syndrome or diabetes mellitus) (Table 1). Intermittent autonomic dysfunction may cause cardiovascular or sudomotor abnormalities (neurally mediated syncope or primary hyperhidrosis) (Bullet list 1). Drugs are a common cause of autonomic dysfunction (Bullet list 2).

Classification may be considered in various ways. Dysfunction may be localized (Bullet list 3) or widespread. Diseases may result from lesions that are central (multiple system atrophy), spinal (spinal cord transection), or peripheral (pure autonomic failure), or from a highly specific biochemical deficit (dopamine β-hydroxylase deficiency). Some are age related, with presentation at birth (Riley–Day syndrome), second decade (vasovagal syncope), or adulthood (familial amyloid polyneuropathy). Autonomic failure commonly causes underactivity, but the reverse, overactivity, causes paroxysmal hypertension during autonomic dysreflexia in high spinal cord injuries. In neurally mediated syncope there is a combination of vagal overactivity and sympathetic withdrawal.

Table 1 Classification of disorders resulting in autonomic dysfunction

Primary (aetiology unknown)
Acute/subacute dysautonomias	Pure pandysautonomia
	Pandysautonomia with neurological features
	Pure cholinergic dysautonomia
Chronic autonomic failure syndromes	Pure autonomic failure
	Multiple system atrophy (Shy–Drager syndrome)
	Autonomic failure with Parkinson’s disease
Secondary
Congenital	Nerve growth factor deficiency
Hereditary:
Autosomal dominant trait	Familial amyloid neuropathy
	Porphyria
Autosomal recessive trait	Familial dysautonomia (Riley–Day syndrome)
	Dopamine β-hydroxylase deficiency
	Aromatic L-amino acid decarboxylase deficiency
X-linked recessive	Fabry’s disease
Metabolic diseases	Diabetes mellitus
	Chronic renal failure
	Chronic liver disease
	Vitamin B12 deficiency
	Alcohol induced
Inflammatory	Guillain–Barré syndrome
	Transverse myelitis
Infections:
Bacterial	Tetanus, leprosy
Viral	HIV infection
Parasitic	Chagas’ disease
Prion	Fatal familial insomnia
Neoplasia	Brain tumours—especially of the third ventricle or posterior fossa
	Paraneoplastic, to include adenocarcinomas of lung and pancreas, and Lambert–Eaton syndrome
Connective tissue disorders	Rheumatoid arthritis
	Systemic lupus erythematosus
	Mixed connective tissue disease
Surgery	Regional sympathectomy—upper limbs, splanchnic denervation
	Vagotomy and drainage procedures—‘dumping syndrome’
	Organ transplantation—heart, kidney
Trauma	Spinal cord transection
Miscellaneous	Subarachnoid haemorrhage
	Syringobulbia and syringomyelia
Intermittent autonomic dysfunction	See Bullet list 1
Drugs	See Bullet list 2

(From Mathias CJ (2003)).

Clinical features

Sympathetic adrenergic failure causes orthostatic hypotension and ejaculatory failure in men, while sympathetic cholinergic failure causes anhidrosis. Parasympathetic failure results in a fixed heart rate, a sluggish urinary bladder and large bowel, and, in men, erectile dysfunction. With overactivity there may be hypertension, tachycardia, and hyperhidrosis, although parasympathetic overactivity causes bradycardia. In autonomic disorders there are many clinical manifestations, which may cause diagnostic difficulties, especially when the disorder is generalized.

The presenting complaints often provide clues. Palmar hyperhidrosis or gustatory sweating may indicate a localized disorder, or be a harbinger of widespread autonomic impairment, as the latter may complicate diabetes mellitus. A cardinal feature is orthostatic (postural) hypotension (defined as a decrease in systolic blood pressure of more than 20 mmHg and in diastolic pressure of less than 10 mmHg on standing or head-up tilt); this impairs perfusion of vital organs such as the brain. The symptoms vary from fainting (syncope, loss of consciousness), sometimes with ensuing injury, to fatigue and lethargy. Numerous factors in daily life enhance or reduce hypotension (Bullet list 3). Some patients recognize these, with the self-introduction of corrective measures. Large meals, refined carbohydrate, and alcohol, which enhance postprandial hypotension, are avoided. Many sit down, lie flat, or assume curious postures, such as squatting or stooping, which now are recognized as raising blood pressure. With time, symptoms of orthostatic hypotension wane, for reasons such as improved cerebrovascular autoregulation. In neurally mediated syncope, venepuncture or pain (in vasovagal syncope) or cervical movements and pressure (in carotid sinus hypersensitivity) cause hypotension and bradycardia. A history of impaired sweating and temperature intolerance, urinary disturbances, sexual dysfunction (in men), and gastrointestinal derangement (constipation), especially together with orthostatic hypotension, should suggest a generalized autonomic disorder (Table 2).

In the Riley–Day syndrome (familial dysautonomia) there is a history of consanguinity, usually in the Ashkenazi Jewish population. A family history is often elicited in vasovagal syncope and expected in familial amyloid polyneuropathy. A drug history, including exposure to chemicals, toxins, and poisons, is important.

Bullet list 1 Intermittent autonomic dysfunction

• Autonomic (neurally) mediated syncope
  • Vasovagal syncope
  • Carotid sinus hypersensitivity
• Situational syncope
  • Micturition syncope
  • Swallow syncope
  • With glossopharyngeal neuralgia
  • Defecation syncope
  • Laughter-induced syncope
• Postural tachycardia syndrome
• Primary or essential hyperhidrosis

Bullet list 2 Drugs, chemicals, poisons, and toxins causing autonomic dysfunction

Decreasing sympathetic activity

Centrally acting

• Clonidine
• Methyldopa
• Moxonodine
• Reserpine
• Barbiturates
• Anaesthetics

Peripherally acting

• Sympathetic nerve endings (guanethidine, bethanidine)
• α-Adrenoceptor blockade (phenoxybenzamine)
• β-Adrenoceptor blockade (propranolol) Increasing sympathetic activity
• Amphetamines
• Releasing noradrenaline (tyramine)
• Uptake blockers (imipramine)
• Monoamine oxidase A inhibitors (tranylcypromine)
• β-Adrenoceptor stimulants (isoprenaline)

Decreasing parasympathetic activity

• Antidepressants (imipramine)
• Tranquillizers (phenothiazines)
• Antidysrhythmics (disopyramide)
• Anticholinergics (atropine, probanthine, benzatropine)
• Toxins (botulinum)

Increasing parasympathetic activity

• Cholinomimetics (carbachol, bethanechol, pilocarpine, mushroom poisoning)
• Anticholinesterases
• Reversible carbamate inhibitors (pyridostigmine, neostigmine)
• Organophosphorus inhibitors (parathion, sarin)

Miscellaneous

• Alcohol, thiamine (vitamin B deficiency)
• Vincristine, perhexiline maleate
• Thallium, arsenic, mercury
• Mercury poisoning (‘pink’ disease)
• Ciguatera toxicity
• Jellyfish and marine animal venoms
• First-dose effects of drugs (prazosin, captopril)
• Withdrawal of chronically used drugs (opiates, clonidine, alcohol)

From Mathias CJ (2003).

Bullet list 3 Examples of localized autonomic disorders

• Holmes–Adie pupil
• Horner’s syndrome
• Crocodile tears (Bogorad’s syndrome)
• Gustatory sweating (Frey’s syndrome)
• Reflex sympathetic dystrophy
• Idiopathic palmar/axillary hyperhidrosis
• Chagas’ disease a

Surgical procedures b

• Sympathectomy—regional
• Vagotomy and gastric drainage procedures in ‘dumping syndrome’
• Organ transplantation—heart, lungs

From Mathias CJ (2003). a Listed here because it targets intrinsic cholinergic plexus in the heart and gut. b Surgery may cause some of the disorders listed above such as Frey’s syndrome after parotid surgery.

A detailed clinical examination is necessary. Pupillary and associated ocular abnormalities occur in Horner’s syndrome. To assess orthostatic hypotension, blood pressure should be measured with the patient lying flat, and after standing (or sitting if not possible). A fall in systolic blood pressure of less than 20 mmHg in the presence of appropriate symptoms does not exclude autonomic failure. Indeed, orthostatic hypotension may be unmasked, or enhanced, by factors such as ingestion of food and exercise. Furthermore, in the presence of vascular disease (such as carotid artery stenosis) even a small fall in blood pressure results in cerebral ischaemia. Lack of additional neurological features favours pure autonomic failure (with a good prognosis), while associated parkinsonism or cerebellar dysfunction suggests multiple system atrophy. Several disorders causing a peripheral neuropathy result in autonomic impairment. Basic bedside testing for glycosuria (in diabetes mellitus) or proteinuria (in systemic amyloidosis) provides important information.

Investigations

When an autonomic disorder is suspected, the first step is to determine if autonomic function is normal or abnormal. Autonomic screening tests (Bullet list 5) have their value, but also their limitations. The majority are directed towards cardiovascular assessment and exclusion of autonomic underactivity. Tests of other systems are increasingly being made available. Normal screening results do not necessarily exclude an autonomic disorder, because, on the basis of the history and clinical examination, additional tests such as carotid sinus massage may be needed in patients with syncope. If autonomic tests are abnormal, further evaluation will determine the site and extent of the autonomic lesion, the functional deficit, and whether it results from a primary or secondary disorder, because an accurate diagnosis is essential for prognosis and appropriate management. Thus, a 24-h ambulatory blood pressure profile and the effects of stimuli in daily life (such as food and exercise) help to manage orthostatic hypotension, while plasma catecholamine measurements and the clonidine growth hormone-stimulation test may separate out the different primary autonomic failure syndromes. Investigations may be needed to diagnose underlying diseases, and include neuroimaging studies (MRI or CT), serum amyloid protein (SAP) scans, sural nerve biopsy (with specific staining with monoclonal antibodies), detection of antibodies to specific receptors (such as the nicotinic acetylcholine receptor), and genetic testing. These tests should be combined with non-neurological investigations depending on the suspected diagnosis.

Management

This varies depending on the autonomic disease, the systems affected, and the functional autonomic deficit, and whether the disorder is primary or secondary. Treatment should take the underlying condition into account, e.g. in parkinsonian syndromes, where autonomic features may be worsened by antiparkinsonian therapy. In some diseases simple intervention is effective, such as unblocking a urinary catheter to resolve autonomic dysreflexia in high spinal cord lesions. In some, immunological therapy (intravenous gammaglobulin, plasma exchange) can reverse the autonomic neuropathy. Complex procedures such as liver transplantation are needed to reduce variant transthyretin levels in familial amyloid polyneuropathy. Multidisciplinary expertise may be needed, as in the Riley–Day syndrome and multiple system atrophy, to prevent complications, enhance survival, and improve quality of life. A combined approach is needed to reduce orthostatic hypotension, overcome urinary incontinence, alleviate gastrointestinal disturbances, and treat sexual dysfunction. The management of orthostatic hypotension is outlined in Bullet list 6 and Table 3; in individual disorders, modification is needed.

Individual autonomic disorders 

Primary autonomic failure

The onset is usually slow and insidious in chronic autonomic failure, unlike the acute/subacute dysautonomias.

Chronic autonomic failure

The most common of these disorders is multiple system atrophy where there is additional neurological disease, unlike pure autonomic failure. Patients are usually middle aged at presentation although, with increasing awareness, it is being diagnosed in younger patients.

In pure autonomic failure, diagnosis is usually considered because of orthostatic hypotension. Nocturia (rather than incontinence) is frequent, presumably because fluid shifts from the peripheral to the central compartment elevate blood pressure and improve renal perfusion. Constipation often occurs. In temperate climates, hypohidrosis may not be recognized, unlike tropical areas where heat intolerance and collapse may occur. In men, impotence is common. The clinical and laboratory findings indicate widespread sympathetic failure, usually with parasympathetic deficits. Physiological and biochemical tests, along with limited neuropathological data, indicate a peripheral autonomic lesion. Management is directed predominantly towards reducing orthostatic hypotension. Although recovery does not occur, the overall prognosis in pure autonomic failure is good.

Multiple system atrophy is a nonfamilial and sporadic disorder with autonomic features and additional neurological (parkinsonian, cerebellar, and pyramidal) features (see Bullet list 5) that occur at any stage and in any combination, in an unpredictable manner. Thus, patients may initially consult a range of specialists. It is randomly progressive, which adds to the difficulty of diagnosis. It is synonymous with Shy–Drager syndrome, the former name.

In multiple system atrophy the additional neurological features are predominantly parkinsonian; in a smaller number they are cerebellar and, as the disease advances, there is usually a mixture of features. The neuropathological findings include striatonigral degeneration in multiple system atrophy (parkinsonian) and olivopontocerebellar degeneration in multiple system atrophy (cerebellar), with both changes often seen in either form. There is cell loss in various brain-stem nuclei (including the vagal nuclei), in the intermediolateral cell mass in the thoracic and lumbar spinal cord, and in Onuf’s nucleus in the sacral spinal cord, which accounts for the various autonomic and allied abnormalities. The paravertebral ganglia and visceral (enteric) plexus are spared. A specific feature is the presence of intracytoplasmic, argyrophilic, oligodendrocyte inclusion bodies, within the brain and spinal cord. Most patients with multiple system atrophy have parkinsonian features and distinguishing multiple system atrophy from idiopathic Parkinson’s disease, especially in the early stages, is difficult. Thus, the true prevalence and incidence of multiple system atrophy are not known. At postmortem examination up to a quarter of patients previously considered to have Parkinson’s disease have the characteristic neuropathological features of multiple system atrophy.

Bullet list 4 Factors influencing orthostatic hypotension

• Speed of positional change
• Time of day (worse in the morning)
• Prolonged recumbency
• Warm environment (hot weather, central heating, hot bath)
• Raising intrathoracic pressure: micturition, defecation, or coughing
•  Food and alcohol ingestion
• Water ingestion a
• Physical exertion
• Manoeuvres and positions (bending forward, abdominal compression, leg crossing, squatting, activating calf muscle pump) b
• Drugs with vasoactive properties (including dopaminergic agents)

Adapted from Mathias CJ (2003). a Raises supine blood pressure in chronic autonomic failure. b These manoeuvres usually reduce the postural fall in blood pressure, unlike the others.

Table 2 Some of the clinical manifestations and possible presentations in primary chronic autonomic failure syndromesa

Cardiovascular	Orthostatic hypotension
Sudomotor	Anhidrosis, heat intolerance
Gastrointestinal	Constipation, occasionally diarrhoea, oropharyngeal dysphagia
Renal and urinary bladder	Nocturia, frequency, urgency, incontinence, retention
Sexual	Erectile and ejaculatory failure in men
Ocular	Aniscoria, Horner’s syndrome
Respiratory	Stridor, involuntary inspiratory gasps, apnoeic episodes
Other neurological deficits	Parkinsonian and cerebellar/pyramidal features

a Certain features, such as oropharyngeal dysphagia and respiratory abnormalities (including those resulting from laryngeal fold paresis), occur in multiple system atrophy rather than in pure autonomic failure. From Mathias CJ 1997 and 2003.

In multiple system atrophy (parkinsonian), bradykinesia and rigidity are often bilateral, with minimal or no tremor, unlike Parkinson’s disease; however, this may not be a useful discriminator in an individual. Lack of a motor response to L-dopa is not indicative of multiple system atrophy, because two-thirds respond initially, although refractoriness and side effects eventually reduce the benefit. The presence of autonomic failure (especially orthostatic hypotension) and unexplained genitourinary symptoms with sphincter disturbance should alert one to the possibility of multiple system atrophy in patients with parkinsonian or cerebellar signs. Oropharyngeal dysphagia and respiratory abnormalities favour multiple system atrophy, although these often occur later. The combination of cardiovascular autonomic failure and an abnormal urethral/anal sphincter electromyogram, with characteristic clinical features, are virtually confirmatory of multiple system atrophy. Additional evaluation includes neuroimaging studies using MRI, positron emission tomography, and proton magnetic resonance spectroscopy of the basal ganglia, which are abnormal, at least in established cases. Clonidine growth hormone testing, based on α2-adrenoceptor stimulation of the hypothalamus with release of human growth hormone-releasing factor, distinguishes central from peripheral autonomic failure and separates Parkinson’s disease from multiple system atrophy; whether this is the case in the early stages of parkinsonism and in patients on dopaminergic agents (which are growth hormone secretagogues) remains to be resolved.

The prognosis in multiple system atrophy is poor compared with idiopathic Parkinson’s disease and pure autonomic failure. Akinesia and rigidity often worsen, with increasing refractoriness and side effects (including orthostatic hypotension) from antiparkinsonian therapy. As the disease advances there is often considerable immobility and difficulty in communication. In multiple system atrophy (cerebellar), worsening truncal ataxia causes falls and an inability to stand upright; orthostatic hypotension compounds the disabilities. Incoordination of the upper limbs, speech defects, and nystagmus result in further disabilities.

Respiratory complications include obstructive apnoea (caused by laryngeal abductor cord paresis) and central apnoea may necessitate tracheostomy. Oropharyngeal dysphagia enhances the risk of aspiration, especially when vocal fold paresis is present; a percutaneous feeding gastrostomy may be needed. Urinary bladder dysfunction is distressing, and its management, together with management of constipation and, if appropriate, treatment of sexual dysfunction is important in improving quality of life. There is often a need for specialist therapists, including speech and language therapists, physiotherapists, dietitians, and occupational therapists. As the neurological decline is inexorable, supportive therapy is crucial in management of multiple system atrophy, and should incorporate the family, carers, and community along with the primary care medical practitioner and therapists.

Bullet list 5 Investigations in autonomic failure

Cardiovascular

Physiological

• Head-up tilt, standing; Valsalva’s manoeuvre
• Pressor stimuli: isometric exercise, cutaneous cold, mental arithmetic
• Heart rate responses: deep breathing, hyperventilation, standing, head-up tilt
• Liquid meal challenge
• Exercise testing
• Carotid sinus massage

Biochemical

• Basal plasma noradrenaline, adrenaline, and dopamine levels
• Plasma noradrenaline: supine and standing
• Urinary catecholamines

Pharmacological

• Noradrenaline—α-adrenoceptors, vascular
• Isoprenaline—β-adrenoceptors, vascular and cardiac
• Tyramine—pressor and noradrenaline response
• Edrophonium—noradrenaline response
• Clonidine—growth hormone response
• Atropine—heart rate response

Sweating

• Thermoregulatory: increase core temperature by 1 °C
• Sweat gland response to intradermal acetylcholine
• Sympathetic skin response

Gastrointestinal

Barium studies, videocinefluoroscopy, endoscopy, gastric-emptying studies, anal sphincter electromyography

Renal function and urinary tract

• Day and night urine volumes and sodium/potassium excretion
• Urodynamic studies, intravenous urography, ultrasound examination, urethral sphincter electromyography

Sexual function

• Penile plethysmography
• Intracavernosal papaverine

Respiratory 

• Laryngoscopy
• Sleep studies to assess apnoea/oxygen desaturation

Eye

• Lacrimal function: Schirmer’s test
• Pupillary function: pharmacological and physiological

From Mathias and Bannister (2002).

Orthostatic hypotension and other features of autonomic failure appear more common in Parkinson’s disease than previously thought. A current hypothesis places nonmotor lesions in the olfactory and brain-stem areas, including vagal nuclei, before onset of parkinsonian features. In Parkinson’s disease the autonomic lesions appear peripheral and thus similar to pure autonomic failure. This is based on low basal plasma noradrenaline levels, and radionuclide and positron emission tomography studies, which indicate cardiac postganglionic sympathetic denervation. This is distinct from multiple system atrophy where the lesions are preganglionic. Orthostatic hypotension and autonomic failure may precede the motor and cognitive decline in diffuse Lewy body disease.

Acute/subacute dysautonomias

These disorders are relatively rare and consist of three main varieties: pure pandysautonomia (with features of both sympathetic and parasympathetic failure); pandysautonomia with additional neurological features usually indicative of a peripheral neuropathy; and pure cholinergic dysautonomia. The prognosis in pandysautonomias is variable, with substantial recovery in some. Recovery after immunoglobulin therapy favours an immunological basis, and the possibility of a Guillain–Barré syndrome variant. In pure cholinergic dysautonomia, described mainly in children and young adults, there is widespread parasympathetic failure with blurred vision, dry eyes, xerostomia, dysphagia with middle and lower oesophagus involvement, severe constipation, and urinary retention. Clinical findings include dilated pupils, an elevated heart rate, dry and warm skin, a distended abdomen, and a palpable urinary bladder. Anhidrosis may result in hyperthermia. The term ‘cholinergic’ is used because both parasympathetic and cholinergic sympathetic pathways (to sweat glands) are affected. Sympathetic vasoconstrictor function is preserved and orthostatic hypotension does not occur.

Bullet list 6 Outline of nonpharmacological and pharmacological measures in the management of postural hypotension due to neurogenic failure

Nonpharmacological measures

To be avoided

• Sudden head-up postural change (especially on waking)
• Prolonged recumbency
• Straining during micturition and defecation
• High environmental temperature (including hot baths)
• ‘Severe’ exertion
• Large meals (especially with refined carbohydrate)
• Alcohol
• Drugs with vasodepressor properties

To be introduced

• Head-up tilt during sleep
• Small, frequent meals
• High salt intake
• Judicious exercise (including swimming)
• Body positions and manoeuvres

To be considered

• Water ingestion
• Elastic stockings
• Abdominal binders

Pharmacological measures

• Starter drug—fludrocortisone
• Sympathomimetics—ephedrine or midodrine
• Specific targeting—octreotide, desmopression, or erythropoietin

Adapted from Mathias CJ 2003b.

Table 3 Drugs used in the treatment of orthostatic hypotension

Site of action	Drugs	Predominant action
Plasma volume: expansion	Fludrocortisone	Mineralocorticoid effects—increased plasma volume
		Sensitization of α-adrenoreceptors
Kidney: reducing diuresis	Desmopressin	Vasopressin2-receptors on renal tubules
Vessels: vasoconstriction (adrenoceptor mediated)	Ephedrine	Indirectly acting sympathomimetics
Resistance vessels	Midodrine,a phenylephrine, methylphenidate	Directly acting sympathomimetics
	Tyramine	Release of noradrenaline
	Clonidine	Postsynaptic α2-adrenoceptor agonist
	Yohimibine	Presynaptic α2-adrenoceptor antagonist
	L-Dopa	Prodrug resulting in formation of noradrenaline
Capacitance vessels	Dihydroergotamine	Direct action on α-adrenoceptors
Vessels: vasoconstriction (nonadrenoceptor mediated)	Triglycyl-lysine-vasopressin (glypressin)	Vasopressin1-receptors on blood vessels
Vessels: prevention of vasodilatation	Propranolol	Blockade of β2-adrenoceptors
	Indometacin	Prevents prostaglandin synthesis
	Metoclopramide	Blockade of dopamine receptors
Vessels: prevention of postprandial hypotension
Autonomic ganglia	Caffeine
	Pyridostigmine	Blockade of adenosine receptors
		Acetylcholine esterase inhibition
Heart: stimulation action	Pindolol, xamoterol	Intrinsic sympathomimetic
Red cell mass: increase	Erythropoietin	Stimulates red cell production

a Through its active metabolite. (Adapted from Mathias CJ (2003). Autonomic diseases—management. J Neurol Neurosurg Psychiatry 74, 42–7.)

Recovery is poor, but the prognosis is good if the condition is detected early. Management includes supportive therapy and adequate fluid and nutrient replacement of losses due to gastrointestinal and sudomotor failure. Barium studies should be avoided because contrast medium accumulates in the atonic colon. The differential diagnosis includes exposure to drugs, poisons, and toxins with anticholinergic effects. Similar autonomic features occur in thorn apple (Datura stramonium) seed poisoning; the poisoning is associated with hallucinations, hyperreflexia, and clonic jerking movements, and recovery occurs in a few days. Botulism B affects cholinergic systems but spares motor systems, and substantial recovery is expected within 3 months of exposure.

Secondary disorders

Many disorders are associated with autonomic failure; a few are described here.

Riley–Day syndrome (familial dysautonomia)

This is a recessive genetic defect characterized by absent lingual fungiform papillae, lack of corneal reflexes, absence of overflow emotional tears, decreased deep tendon reflexes, and a diminished response to pain and temperature; the disease occurs typically in children of Ashkenazi Jewish extraction. An abnormal intradermal histamine skin test (absent axon flare) and pupillary hypersensitivity to cholinomimetics provide diagnostic confirmation. Prenatal diagnosis is possible with the genetic markers linked to chromosome 9 (q31). Autonomic underactivity and overactivity include lability of blood pressure (hypertension and orthostatic hypotension), intermittent hyperhidrosis, periodic vomiting, dysphagia, constipation, and diarrhoea. The neurological abnormalities include emotional and behavioural disturbances, and sensory deficits that result in injury to skin and joints. Skeletal problems (scoliosis), and respiratory (aspiration) and renal failure contribute to a poor prognosis. Anticipation of complications and adequate therapy have extended survival into adulthood.

Amyloid neuropathy

Deposition of amyloid into autonomic nerves can occur in reactive systemic (AA) amyloidosis (in chronic inflammatory disorders) or in immunoglobulin light chain (AL) amyloidosis (with lymphomas). In familial amyloid polyneuropathy the sensory, motor, and autonomic abnormalities result from deposition in peripheral nerves of mutated variant transthyretin, produced mainly in the liver. Symptoms of a sensory and motor neuropathy often begin in adulthood in the lower limbs in Portuguese, Japanese, and Swedish forms (familial amyloid polyneuropathy I), and in the upper limbs in Indian/Swiss and German/Maryland forms (familial amyloid polyneuropathy II). These and other forms are now classified by the chemical and molecular nature of abnormal fibrillary protein, immunologically related to transthyretin. The most common is based on the first point mutations in the transthyretin gene associated with familial amyloid polyneuropathy—methionine-30 in the Portuguese form. The cardiovascular, gastrointestinal, and urinary systems are affected at variable stages, with the disease progressing relentlessly. Autonomic symptoms and signs may be dissociated, leading to underrecognition of the autonomic deficit. Liver transplantation reduces variant transthyretin levels and prevents progression of neuropathy. Its ability to reverse neuropathy is unclear, emphasizing the need for intervention before nerve damage occurs.

Dopamine b-hydroxylase deficiency

This rare disorder (with 14 patients reported, 2 of whom are siblings) was recognized in the mid-1980s. Enzymatic deficiency probably occurs at birth but presentation is often in childhood. Orthostatic hypotension has been the clue to recognition. The clinical features indicate sympathetic adrenergic failure, with sparing of sympathetic cholinergic and parasympathetic function; thus sweating is preserved and urinary bladder and bowel functions appear normal. In men, erection is possible but ejaculation difficult to achieve. Basal levels of plasma noradrenaline and adrenaline are undetectable but dopamine is abnormally elevated. Sympathetic nerve terminals, except for the enzymatic and functional defect, are otherwise intact, as demonstrated by electron microscopy, immunohistochemistry, and sympathetic microneurography. Effective treatment is with the prodrug L-dihydroxyphenylserine, which has a structure similar to noradrenaline and is converted by the enzyme dopa-decarboxylase (abundantly present in extraneuronal tissue such as liver and kidneys) to noradrenaline.

Diabetes mellitus

In patients with long-standing diabetes, especially those on insulin, there is a high incidence of peripheral and autonomic neuropathy. Vagal denervation occurs earlier, impairing heart rate variability. Reduced sympathetic activity, e.g. in the feet, may increase blood flow substantially at an early stage before detection of neuropathy. Orthostatic hypotension may be enhanced by insulin. There may be sweating abnormalities (gustatory sweating), delayed stomach emptying (gastroparesis diabeticorum), impaired urinary bladder function (diabetic cystopathy), and impotence. Diarrhoea may be extremely distressing.

Spinal cord injuries

Autonomic dysfunction affecting many systems occurs in spinal injuries, depending on the lesion level and the degree of completeness. Cardiovascular dysfunction may be life threatening, especially in high lesions, in the acute phase in spinal shock, because lack of sympathetic activity with increased vagal tone may cause bradycardia and cardiac arrest. After a few weeks, spinal shock passes and isolated spinal reflex activity returns; in cervical and high thoracic lesions, abnormal spinal activation results in the syndrome of autonomic dysreflexia. This is induced by cutaneous, skeletal muscle, or visceral stimuli below the level of the lesion. Thus, severe muscle spasms, an anal fissure, or a blocked urethral catheter can result in paroxysmal hypertension (due to increased spinal sympathetic nerve activity, independent of normal cerebral pathways) with associated bradycardia (because of preserved baroreceptor afferents and vagal efferent pathways. Patients with lesions below T6 are spared. Patients with high lesions are also prone to orthostatic hypotension, which compounds difficulties in management, especially shortly after injury.

Drugs

Dysfunction may result from an autonomic neuropathy (as induced by alcohol, vincristine, and perhexiline maleate) or through pharmacological effects. The latter may be expected with the sympatholytic agents, or may be a minor unexpected effect in susceptible individuals. An example is the anticholinergic bladder effects of disopyramide, which may cause urinary retention in patients with prostatic hyperplasia. A variety of toxins and poisons, including mushroom toxicity and botulism, as well as nerve gases such as sarin, affect the autonomic nervous system. The first-dose effect of angiotensin-converting enzyme (ACE) inhibitors and prazosin may be mediated by the Jarisch–Bezold reflex. Autonomic overactivity may occur during withdrawal of clonidine, alcohol, and opiates.

Intermittent autonomic dysfunction

There is usually no damage to autonomic nerves and autonomic dysfunction is often short-lived.

Autonomic (neurally) mediated syncope

Syncope (fainting, loss of consciousness) may result from an intermittent and transient abnormality with increased cardiac parasympathetic (causing severe bradycardia, cardioinhibition) and sympathetic withdrawal (causing hypotensive vasodepression). The episodes may be cardioinhibitory, vasodepressor, or mixed. There are three major groups: vasovagal syncope, carotid sinus hypersensitivity, and situational syncope. Between episodes, screening autonomic tests usually reveal no abnormalities. The most common disorder is vasovagal syncope. This is often familial and more likely in females; it may present in the early teenage years and is induced by stimuli such as the sight of blood, pain, needles, and at times even discussion of venepuncture. Hypotension is more likely in the upright position and may occur while standing still, especially in warm weather, and with salt and fluid depletion.

Testing includes head-up tilt, which sometimes may need to be prolonged for about 45 minutes, or with introduction of a provocative stimulus such as venepuncture, ideally during head-up tilt. A variety of physiological (head-up tilt plus lower body negative pressure) or pharmacological (isoprenaline infusions or glyceryl trinitrate) stimuli have been used to unmask an episode, but may result in false-positive results. Cardiac conduction disorders and other causes of syncope (neurological or metabolic) should be excluded. Treatment includes reducing or preventing exposure to precipitating causes and behavioural psychotherapy in patients with phobias. Added salt, fluid repletion, and exercise are often useful. Techniques to increase sympathetic activity and maintain or raise blood pressure (such as sustained hand grip) and to prevent pooling (calf muscle activation) are helpful, especially in patients who have a warning window of symptoms before syncope. Sitting down, or lying flat, with the legs raised should prevent most episodes. Drugs such as fludrocortisone, vasopressor agents (ephedrine and midodrine), and antidepressants such as the serotonin selective reuptake inhibitors (SSRIs) have been used. β-Adrenergic blockers provide no benefit in most cases. The long-term prognosis is favourable.

In older people, carotid sinus hypersensitivity is increasingly recognized, especially in those with falls of otherwise unknown cause. A classic history of syncope induced by head movements or collar tightening may be provided, although in many the precipitating factors are unclear. Carotid sinus massage should be performed in the laboratory with the requisite precautions, ideally using continuous blood pressure and heart rate recordings, with the patient also tilted head up, because hypotension is more likely to occur when sympathetic activation is needed. Treatment, especially of the cardioinhibitory forms, includes a cardiac demand pacemaker; vasodepressor forms may require pressor agents. Surgical denervation of the carotid sinus has been used successfully, especially where unilateral hypersensitivity occurs.

A variety of other stimuli, acting through short-lived autonomic mechanisms, can also cause syncope, considered under situational syncope. This may be together with factors such as heat or drugs that cause vasodilatation or reduce intravascular volume, thus increasing the tendency to hypotension and syncope. Examples include syncope associated with glossopharyngeal neuralgia (caused by swallowing), or induced by micturition, defecation, coughing, laughing, and playing wind instruments.

Postural tachycardia syndrome

This disorder is often observed in people below the age of 50 years, mainly women, with dizziness on postural change or with modest exertion. The symptoms appear to disrupt lives almost disproportionately. There is a substantial rise in heart rate (over 30 beats/min or to 120 beats/min) without orthostatic hypotension, hence the term ‘postural (orthostatic) tachycardia syndrome’, or PoTS. Syncope may occur. Associated disorders include a partial autonomic neuropathy, chronic fatigue syndrome, mitral valve prolapse, and hyperventilation. A noradrenaline transporter deficit, rarely genetically caused, or as a result of drugs, may be causative. A common association is the joint hypermobility syndrome (Ehlers–Danlos syndrome III). The relationship of PoTS to previously considered psychosomatic disorders, such as soldier’s heart or da Costa’s syndrome, is not known. Investigation should include the causes and associated factors, which is an integral part of management. Treatment includes nonpharmacological measures as used in neurally mediated syncope, such as salt and fluid repletion and graded exercise. Similarly drugs to raise blood pressure may be used, except for excluding those that increase heart rate, such as ephedrine. Cardioselective β-adrenergic blockers have a role, but not when the tachycardia is in response to vascular pooling when upright. The selective sinus node blocker, ivabradine, may have a role in reducing tachycardia. Spontaneous recovery may occur in some.

Primary or essential hyperhidrosis

Excessive sweating without an underlying cause (such as hyperthyroidism, infection, etc.) may be familial or sporadic, and it may be localized, involving areas such as the palms, axillae, soles of the feet, or the face. In some there is widespread sweating. It can be distressing and socially destructive. Factors that provoke sweating include stress, heat, and exercise. In primary hyperhidrosis, investigation reveals no underlying pathology or autonomic deficit. Treatment options include percutaneous surgical sympathectomy for upper limb and facial sweating; in some, after surgery a complication is compensatory hyperhidrosis in the innervated areas, which some find worse than the original problem; treatment is with low doses of clonidine and anticholinergics (such as probanthine), iontophoresis for palmar and plantar sweating, and botulinum toxin injections for localized areas. Cognitive–behavioural therapy and anxiolytics, including SSRIs, have a role.

Further reading

Top

Appenzeller O, Oribe E (eds) (1997). The autonomic nervous system, 5th edition. Elsevier Biomedical, Amsterdam.

Low PA (ed.) (1997). Clinical autonomic disorders, 2nd edition. Little Brown & Co., Boston, MA.

Mathias CJ (2003). Autonomic diseases—clinical features and laboratory evaluation. J Neurol Neurosurg Psychiatry, 74, 31–41.

Mathias CJ (2003). Autonomic diseases—management. J Neurol Neurosurg Psychiatry, 74, 42–7.

Mathias CJ, Bannister R (2002). Autonomic failure: a textbook of clinical disorders of the autonomic nervous system, 4th edition. Oxford University Press, Oxford.

Mathias CJ (2009). Autonomic Dysfunction. In Neurology: A Queen Square Textbook. (Eds. Clarke, C., Howard, R., Rossor, M. and Shorvon, S.D). pp 871–982. Oxford: Wiley Blackwell.