REVIEWS

The clinical approach to autonomic failure

in neurological disorders
Eduardo E. Benarroch
Abstract | Central or peripheral neurological disorders can manifest with autonomic failure or autonomic
hyperactivity, which may affect the sympathetic, parasympathetic and/or enteric nervous systems. Disorders
causing autonomic failure can be classified according to the presence or absence of associated neurological
manifestations, such as peripheral neuropathy or parkinsonism, and their temporal profile (acute or subacute,
chronic progressive, static, or episodic). A systematic approach allows focused evaluation to detect treatable,
potentially disabling or life-threatening conditions. Subacute isolated autonomic failure affecting sympathetic,
parasympathetic and enteric nervous system function, in various combinations, occurs in autoimmune
autonomic ganglionopathy, which might be the first manifestation of an underlying neoplasm. Autonomic
failure can be an important feature of several types of peripheral neuropathy, including sensorimotor peripheral
neuropathies, sensory ganglionopathy, and distal painful peripheral neuropathies. Progressive autonomic
failure occurs in neurodegenerative synucleinopathies such as multiple system atrophy and Lewy body
disorders. Autonomic failure may also occur in hereditary leukoencephalopathies or prion disorders. This
Review outlines the clinical approach to patients with generalized autonomic failure, focusing predominantly
on classification and diagnosis, but also touching briefly on treatment and management.

Benarroch, E. E. Nat. Rev. Neurol. advance online publication 27 May 2014; doi:10.1038/nrneurol.2014.88

Introduction Clinical approach to autonomic failure

Autonomic disorders manifest with autonomic failure
or hyperactivity, which may be generalized or focal.
Autonomic failure can affect the sympathetic, para­sympa­
thetic or enteric nervous systems, either in isolation or in
various combinations, and can result from lesions at any
level of the CNS or PNS. Sympathetic failure manifests
primarily with orthostatic hypotension and anhidrosis
(absence of sweating), cranial parasympathetic failure
with intolerance to light, dry eyes (xerophthalmia) and
dry mouth (xerostomia), sacral parasympathetic failure
with urinary retention and erectile dysfunction, and
enteric nervous system (ENS) failure with gastroparesis
and constipation. In some cases, postural tachycardia
syndrome is a manifestation of an underlying autonomic
neuropathy. Many symptoms attributed to ‘dysautonomia’
in otherwise healthy young patients, such as gastroparesis
or urinary retention, are rarely associated with objective
evidence of autonomic failure.
This Review will focus on the clinical approach to
patients with generalized autonomic failure. The degen­
erative synucleinopathies, autonomic ganglionopathies
and autonomic neuropathies have been reviewed in
detail elsewhere.1–5 Rather than providing an exhaustive
discussion of the wide spectrum of disorders associated
with autonomic failure, this article will focus on specific
Department of examples to emphasize clinical cues and outline recent
Neurology, Mayo Clinic,
200 First Street SW, concepts of the underlying pathobiology.
Rochester, MN 55905,
USA.
benarroch.eduardo@ Competing interests
mayo.edu The author declares no competing interests.
Disorders associated with autonomic failure can be clas­
sified according to the type and severity of autonomic
manifestations, associated neurological symptoms, and
temporal profile (Box 1). The temporal profile of onset
and progression has important implications for diag­
nosis, and for guidance of further laboratory evalua­
tion (Figure 1). Isolated autonomic failure of acute or
subacute onset suggests an immune cause such as auto­
immune autonomic ganglionopathy (AAG), including
paraneoplastic autonomic neuropathy, or a toxic cause
such as effects of medications. Pure autonomic failure
(PAF) refers to the slow development of general­ized
auto­nomic failure in the absence of motor or sensory
symp­toms. Manifestations associated with chronic and
pro­gressive generalized autonomic failure, such as ataxia
or parkinsonism, suggest a degenerative cause, typi­
cally a synuclein­opathy such as multiple system atrophy
(MSA), or a Lewy body disorder such as Parkinson
disease (PD) or dementia with Lewy bodies (DLB). Auto­
nomic failure can also be a salient feature of various types
of peripheral neuropathy, including distal sensori­motor
peripheral neuropathy, painful or ataxic forms of sensory
ganglionopathy, distal painful small fibre ­neuropathy
(SFN), and acute motor polyradiculopathy.
Manifestations and pathophysiology
Orthostatic hypotension
Orthostatic hypotension is defined as a sustained reduc­
tion in systolic blood pressure of at least 20 mmHg or
diastolic blood pressure of 10 mmHg within 3 min of

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Key points Box 1 | Neurological causes of autonomic failure

■■ Autonomic failure can occur in isolation, in association with peripheral A. Isolated autonomic failure
neuropathy, or as a manifestation of a neurodegenerative disorder 1. Acute or subacute
■■ Disorders associated with autonomic failure can be classified according to (a) Autoimmune autonomic ganglionopathy
the type and severity of autonomic manifestations, associated neurological (b) Paraneoplastic autonomic neuropathy
symptoms, and temporal profile 2. Progressive
■■ Acute or subacute autonomic failure suggests an autoimmune autonomic (a) Pure autonomic failure
ganglionopathy, which may be paraneoplastic
B. Progressive autonomic failure associated with
■■ In patients with parkinsonism and autonomic failure, early onset and
parkinsonism, ataxia or dementia
progression of orthostatic hypotension or urogenital dysfunction, urinary
1. Multiple system atrophy
incontinence, generalized anhidrosis, and/or laryngeal stridor are highly
2. Lewy body disorders
suggestive of multiple system atrophy
(a) Parkinson disease
■■ Autonomic failure can occur with any type of diabetic or amyloid neuropathy
(b) Dementia with Lewy bodies
■■ Important causes of painful neuropathy associated with autonomic failure
3. Others
include Sjögren syndrome, HIV infections, Fabry disease, and sodium
(a) Familial leukoencephalopathies
channelopathies
(b) Prion disorders
C. Autonomic failure associated with peripheral
neuropathy
standing or head-up tilt.6 Some patients with neuro­ 1. Chronic sensorimotor neuropathies
genic orthostatic hypotension have postprandial hypo­ (a) Diabetes
tension. 7 Manifestations of orthostatic hypotension (b) Amyloidosis
include lightheadedness, blurred vision and neck pain (c) Other metabolic disorders (vitamin B12 deficiency,
(coat hanger distribution) among others; the symptoms uraemia)
(d) Toxic neuropathies
are worse in the morning, after meals, or on exposure
2. Sensory ganglionopathies
to heat.8,9 (a) Sjögren syndrome
Neurogenic orthostatic hypotension is the mani­ (b) Paraneoplastic
festation of impaired sympathetically mediated vaso­ 3. Distal painful neuropathies
constriction of skeletal muscle and mesenteric vessels in (a) Diabetes
response to baroreceptor unloading due to orthostatic (b) Amyloidosis
stress. Neurogenic orthostatic hypotension may occur (c) Idiopathic (sodium channelopathies)
(d) Infectious (HIV)
as a consequence of disorders affecting the barosensi­
(e) Hereditary
tive sympathoexcitatory neurons in the rostral ventro­ (i) Hereditary sensory and autonomic neuropathy
lateral medulla (for example, MSA); spinal preganglionic (ii) Fabry disease
sympathetic neurons (for example, MSA or PD); auto­ (iii) Sodium channelopathies
nomic ganglia (for example, AAG or PAF); unmyelin­ 4. Acute or subacute motor polyradiculopathy or
ated axons (SFN); noradrenaline availability (for neuropathy
example, dopamine β‑hydroxylase deficiency); or vas­ (a) Guillain–Barré syndrome
cular α1-adrenergic receptors (typically as a side effect (b) Porphyria
5. Acute autonomic and sensory neuropathy
of drugs).10
6. Ross syndrome (segmental anhidrosis, Adie pupils
and areflexia).
Anhidrosis
Sweating is an important thermoregulatory activity
mediated by the sympathetic nervous system through supraspinal reflex coordinated by the pontine mictur­
cholinergic activation of muscarinic M 3 receptors in ition centre, which activates the sacral pre­gangli­onic
the eccrine sweat glands. Depending on its distribu­ para­sympa­thetic output to the bladder detrusor while
tion and severity, anhidrosis might be asymptomatic ­simultaneously inhibiting the Onuf nucleus.13
or might manifest with compensatory hyperhidrosis Neurogenic bladder can manifest with detrusor over­
(in unaffected areas) or heat intolerance. Anhidrosis activity or underactivity.14 Detrusor overactivity pro­
in autonomic failure may reflect impairment of central duces urinary urgency with or without incontinence,
thermoregulatory pathways, spinal preganglionic urinary frequency, and nocturia. Reduced detrusor
sudomotor units, cholinergic sympathetic ganglion activity leads to incomplete bladder emptying, increased
neurons, peripheral unmyelinated axons, or M3 ­receptors post-void residual, low peak urinary flow rate and, even­
at the sudomotor unit.11 tually, urinary retention and overflow incontinence.
Impaired micturition can result from lesions affecting
Neurogenic bladder and sexual dysfunction the bladder afferents, sacral parasympathetic neurons or
Normal bladder function includes a urine storage their axons, or cholinergic muscarinic neurotransmis­
phase and a micturition phase, which are controlled sion. Neurogenic bladder is commonly associated with
at all levels of the neuraxis.12 Urine storage depends on erectile and ejaculatory dysfunction in men and poor
spinal reflexes mediated by the lumbosacral sympathetic vaginal lubrication in women. Erectile dysfunction
noradrenergic and sacral cholinergic motor neurons of reflects impaired sacral parasympathetic output and
the Onuf nucleus. Normal micturition depends on a nitric oxide release in the erectile tissue.

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Autonomic failure

Associated
manifestations None (‘pure’ autonomic failure) Parkinsonism, ataxia Peripheral neuropathy

Acute or subacute Chronic, progressive Subacute Distal Distal painful

sensory sensorimotor
Onset/ or any other
subtype type

Autoimmune ‘Pure’ Lewy body Multiple Sjögren Diabetes Vasculitis

autonomic autonomic disorders system syndrome Amyloidosis HIV
Main or ganglionopathy failure ■ PD atrophy
typical causes Paraneoplastic Idiopathic
Paraneoplastic ■ DLB Fabry disease
autonomic Hereditary
ganglionopathy Autoantibodies
(SSA/SSB, paraneoplastic)
Salivary gland biopsy

Autonomic studies Autonomic studies, neuroimaging (MRI), Autonomic studies, electromyography/nerve

Specific conduction studies, FBG, SPEP, UPEP,
evaluation* Autoantibodies polysomnogram, urodynamic studies,
(gnAChR, abdominal fat aspirate, ANCA, HIV,
paraneoplastic) neuropsychometrics α-galactosidase, punch skin biopsy

Figure 1 | Evaluating the main causes of autonomic failure. All patients with autonomic failure should undergo
determination of serum glucose (or in some cases haemoglobin A1c), thyroid stimulating hormone and vitamin B 12 levels.
Autonomic laboratory testing is helpful to detect and assess severity of autonomic failure. Patients with acute isolated
autonomic failure should also be tested for gnAChR and paraneoplastic antibodies, and SSA and SSB autoantibodies in
cases with prominent sensory symptoms. Patients with chronic progressive autonomic failure, including multiple system
atrophy, PD or DLB, should also undergo MRI (if possible), polysomnography, urodynamic studies and, in some cases,
neuropsychometric testing. Evaluation of patients with autonomic failure associated with peripheral neuropathy includes
electromyography and nerve conduction studies, SPEP and UPEP with immunofixation, abdominal fat aspirate
and/or sural nerve biopsy for detection of amyloidosis and, in some cases, determination of ANCA, HIV serology or
α‑galactosidase. Punch skin biopsy can also be helpful to detect small fibre neuropathy. *Include thermoregulatory sweat
test, sudomotor axon reflex tests, heart rate response to deep breathing and Valsalva manoeuvre, beat-to-beat blood
pressure profile during the Valsalva manoeuvre, and blood pressure and heart rate responses to head-up tilt.
Abbreviations: ANCA, antineutrophil cytoplasmic antibodies; DLB, dementia with Lewy bodies; FBG, fasting blood glucose;
gnAChR, ganglionic nicotinic acetylcholine receptor; PD, Parkinson disease; SPEP, serum protein electrophoresis; UPEP,
urine protein electrophoresis.

Gastrointestinal dysmotility after standing; and examination of the skin to identify

Control of gastrointestinal motility depends on intrin­
sic reflexes mediated by the ENS, and their modulation
by vagal and paravertebral sympathetic inputs. Upper
gastro­intestinal motility is primarily controlled by the
vagal reflexes involving the nucleus of the solitary tract
and dorsal motor nucleus of the vagus in the medulla;15
peristalsis in the lower gastrointestinal tract depends
primarily on local ENS reflexes;16 and paravertebral
­sympathetic reflexes inhibit gastrointestinal motility.
Symptoms of delayed oesophageal transit include
dysphagia and regurgitation. Delayed gastric emptying
produces early satiety, anorexia, nausea, bloating, belch­
ing, postprandial vomiting, and pain. Lower gastro­
intestinal dysmotility manifests with constipation and,
­occasionally, diarrhoea.
Evaluation
Clinical
In addition to a careful history and general physical and
neurological examination, clinical evaluation of patients
with suspected autonomic failure includes assessment of
pupil size, symmetry and reactivity with both bright and
dim light; measurement of blood pressure and heart rate
after 2 min in the supine position and at 1 min and 2 min
areas of localized or generalized absence of or excessive
sweating, and changes in skin temperature or colour in
the hands and feet.
Laboratory tests
General laboratory tests that should be performed in
patients with autonomic failure include determination
of serum glucose (or in some cases haemoglobin A1c),
thyroid-stimulating hormone and vitamin B12 levels.
Serum and urine protein electrophoresis with immuno­
fixation, including light-chain quantitation, are indi­
cated to detect amyloid light-chain (AL) amyloidosis.17
SSA and SSB antibody testing for Sjögren syndrome may
be helpful in some cases. Determination of ganglionic
nicotinic acetylcholine receptor (gnAChR) anti­bodies,18
as well as paraneoplastic antibodies (particularly anti-
Hu, P/Q and N‑type voltage-gated calcium channel
and voltage-gated potassium complex anti­b odies), is
indicated in all patients with subacute onset of symp­
toms.18,19 Determination of forearm venous catecho­
lamines, including noradrenaline, dopamine and
adrenaline, in the supine position and after 5–10 min
of standing may be helpful in some cases; the results
require careful interpretation, however, as they can be

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affected by concomitant use of drugs or impaired pre­
synaptic noradrenaline reuptake.20 Low or undetectable
noradrenaline and adrenaline levels associated with
increased dopamine levels indicate a deficit of dopamine
β‑hydroxylase as the cause of orthostatic hypotension.21
Autonomic function tests
Autonomic laboratory evaluation is indicated to deter­
mine the extent and severity of autonomic failure; to
detect autonomic failure in patients with parkinsonism
or ataxia; to assess small fibre function in patients with
peripheral neuropathy or ganglionopathy; to evalu­
ate patients with symptoms of orthostatic intolerance;
and to obtain objective evidence of disease progression
or response to medications.22,23 The most commonly
used tests assess sudomotor, cardiovagal and adren­
ergic vasomotor functions. Sudomotor function tests
include the thermoregulatory sweat test (TST), which
assesses the integrity of central and peripheral sudo­
motor pathways,22 and sudomotor axon reflex tests such
as the quanti­tative sudomotor axon reflex test (QSART)23
and the quanti­tative direct and indirect test of sudo­
motor function (QDIRT),24 which assess the peripheral
sympa­thetic cholinergic innervation of the sweat glands.
Tests that assess vagal control of the sinus node (cardio­
vagal function) include the heart rate response to deep
breathing,25 and the heart rate response to the Valsalva
manoeuvre, or Valsalva ratio.26 Tests that indirectly assess
sympathetic vasomotor function include the beat-to-beat
blood pressure profile during the Valsalva manoeuvre27
and the blood pressure response to head-up tilt.28 The
physiological basis, methods, normal and abnormal
responses, and pitfalls of these and other autonomic
­function tests have been the subject of several reviews.29–31
Other tests
Electromyography is indicated for patients with periph­
eral neuropathy or ganglionopathy, and MRI may be
helpful in evaluation of central autonomic disorders.
Gastrointestinal motility and urodynamic studies might
be indicated in some cases. Polysomnography to detect
sleep-related respiratory dysfunction is indicated in all
patients with suspected MSA.
Tissue biopsy
Skin biopsy with assessment of intraepidermal nerve
fibre density (IENFD) can be useful in the evaluation
of SFN;32,33 immunocytochemical markers allow quanti­
fication of the density of innervation of sweat gland34
and pilomotor 35 nerves. Abdominal fat aspirate or sural
nerve biopsy are indicated to evaluate for amyloidosis.36,37
Immunostaining and laser microdissection, along with
mass spectrometry-based proteomic analysis of amyloid
deposition, allow identification of the specific subtype of
amyloid protein.38
Neurodegenerative synucleinopathies
Autonomic failure is an important manifestation of
neuro­degenerative disorders characterized by the pres­
ence of intracellular inclusions containing α‑synuclein.
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These conditions include MSA, 1,39–41 and Lewy body
­disorders such as PD, DLB or PAF.42,43
Multiple system atrophy
MSA was initially defined as a sporadic neurodegenera­
tive disease characterized by any combination of auto­
nomic failure, parkinsonism, cerebellar ataxia and/or
pyramidal signs.44 The prevalence of MSA has been esti­
mated at 4–8 cases per 100,000 people, and its incidence
varies from 0.6 cases per 100,000 person-years in the
general population to 3 cases per 100,000 person-years
in people above 50 years of age.1,40
The neuropathological hallmark of MSA is the accumu­
lation of α‑synuclein-immunoreactive glial cytoplasmic
inclusions in oligodendrocytes, and neuronal loss in the
striatum, substantia nigra pars compacta, pontine nuclei,
inferior olivary nuclei, cerebellum, and premotor auto­
nomic nuclei.45 According to current criteria, probable
MSA is defined as a sporadic, progressive, adult-onset
(over 30 years of age) disease characterized by autonomic
failure, with urinary incontinence and erectile dysfunc­
tion (in males) or orthostatic hypotension (blood pres­
sure decrease ≥30 mmHg systolic or ≥15 mmHg diastolic
within 3 min of standing), as well as parkinsonism poorly
responsive to levodopa (MSA‑P), or cerebellar syndrome
(MSA‑C).39 A large European study including 437 patients
with probable (72%) or possible (28%) MSA showed that
symptomatic autonomic failure was present in almost all
cases; the most frequent manifestations were urinary dys­
function (83%) and orthostatic hypotension (75%).41 In a
study on 29 autopsy-confirmed cases, a pattern consist­
ing of severe and progressive adrenergic and sudomotor
failure was highly predictive of MSA.46
Although MSA is still generally regarded as a sporadic
disease, several studies have identified familial cases.1
A recent study identified mutations of the coenzyme Q2
(COQ2) gene in Japanese families with MSA, and COQ2
variants were also associated with an increased risk of
sporadic MSA.47
Median survival from symptom onset in MSA is
8–10 years, but the spectrum ranges from 4–15 years.
Natural history studies indicate that presence of the
parkinsonian variant, early onset of autonomic failure,
incomplete bladder emptying, and shorter duration
of symptoms at baseline are all factors that predict
shorter survival.48–50
In MSA, orthostatic hypotension occurs at earlier
stages and is more severe than in PD. 51 Orthostatic
hypotension in MSA reflects involvement of pre­gangli­
onic sympathetic neurons52 and sympathoexcitatory
neurons of the rostral ventrolateral medulla.53 Urogenital
manifestations may herald the onset of MSA.51 Bladder
dysfunction in MSA is characterized by urinary urgency,
followed by incontinence and incomplete bladder empty­
ing. These manifestations result from a combination of
detrusor hyperreflexia and urethral sphincter weakness
followed by detrusor contraction failure,54 and they
reflect involvement of the pontine micturition centre,55
sacral preganglionic neurons 56 and Onuf nucleus. 57
Erectile dysfunction is almost always present in male
www.nature.com/nrneurol

patients with MSA.58 Upper gastrointestinal symptoms,
constipation and faecal incontinence occur frequently;
anal sphincter electromyography shows large motor
unit potentials indicating denervation due to loss of
Onuf nucleus motor neurons.59 Anhidrosis occurs in the
majority of patients with MSA, and the percentage of
the body affected by anhidrosis may help to differentiate
MSA from PD.60,61
An important manifestation of disrupted brainstem
homeostatic mechanisms in MSA is sleep-related dis­
ordered breathing, including sleep apnoea and laryn­
geal stridor, which occur in up to 70% of patients with
MSA.62–64 Whereas the development of central hypo­
ventilation and laryngeal stridor is closely related to the
severity of autonomic failure, respiratory manifestations
can occur early in the course of MSA.65 Laryngeal dys­
tonia with inspiratory adduction of the vocal cords might
underlie laryngeal stridor in at least some individuals with
MSA.66 Impaired automatic ventilation reflects involve­
ment of the brainstem respiratory network, including
the pre-Bötzinger complex 67 and the medullary raphe,68
which may predispose patients to sudden death.69
Lewy body disorders
Accumulation of Lewy neurites and Lewy bodies in
the ENS, autonomic ganglia, peripheral autonomic
nerve terminals, and intermediolateral cell column
can be detected at autopsy of cases of incidental Lewy
body disease (ILBD), PAF, early-stage PD, and DLB.70–73
α‑Synuclein inclusions can be also detected in cutan­eous
nerves of patients with PAF 74 or PD.75 These findings
indicate that Lewy body disorders constitute a contin­
uum of progressive involvement of areas of the periph­
eral autonomic nervous system, and subsequently the
CNS, by α‑synuclein neuropathology, which may range
clinically from asymptomatic cases (ILBD) to pure auto­
nomic failure (PAF), and might eventually manifest with
­parkinsonism (PD), dementia (DLB) or both.
Pure autonomic failure
PAF was first described by Bradbury and Eggleston in
1925, and was initially termed idiopathic orthostatic
hypotension. PAF is a rare, sporadic, adult-onset dis­
order characterized by symptomatic orthostatic hypo­
tension and variable gastrointestinal, bladder and sexual
dysfunction, in the absence of somatic motor deficits.
Onset is typically between 50 and 70 years of age.42
The symptoms of PAF are insidious in onset, and are
less progressive and disabling than those in other neuro­
degenerative autonomic disorders. Some patients may
have bladder symptoms, erectile or ejaculatory dysfunc­
tion, or impaired sweating, before developing ortho­
static hypotension. Constipation is common, but other
symptoms of gastrointestinal dysmotility are rare.76 The
diagnosis of PAF is always tentative; after a few years,
many patients with presumed PAF may develop cerebel­
lar, extrapyramidal or cognitive deficits indicating MSA,
PD or DLB. Thus, the diagnosis of PAF requires at least a
5 year history of isolated autonomic dysfunction without
other neurological manifestations. PAF is a clinical
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syndrome reflecting involvement of the autonomic gan­
glion cells and their postganglionic axons. This disorder
can have a variety of different pathobiological substrates.
Patients with PAF have been shown to have accumula­
tion of α‑synuclein-containing Lewy bodies and neurites
in sympathetic ganglia peripheral tissues, including skin
sympathetic nerves.74,75 However, some cases of PAF are
associated with low-titre gnAChR antibodies, suggesting
that this condition can reflect a chronic form of AAG in
some instances.77
Parkinson disease
Autonomic dysfunction—particularly gastrointestinal
dysmotility—is a prominent nonmotor manifestation
of PD.43 Gastrointestinal dysmotility in PD can affect
any level of the gastrointestinal tract.78 Gastrointestinal
symptoms can occur at an early stage of the disease;79 for
example, constipation may precede the development of
motor symptoms by several years.80,81 Excessive drooling
in PD must reflect oropharyngeal dysphagia, as salivary
secretion is reduced even at an early stage of disease;82,83
this finding is consistent with the presence of α‑synuclein
pathology in the salivary gland.84 Oesophageal dysmotility
and delayed gastric emptying are frequent manifestations
in PD,85,86 and are likely to reflect early involvement of
the dorsal motor nucleus of the vagus.70 The prevalence
of constipation ranges from 20–89%,79 and is primarily
attributable to slow colonic transit, reflecting the early
involvement of the ENS.87 However, defecatory dysfunc­
tion due to paradoxical contraction of the ­puborectalis
muscle is also an important contributory factor.85,88
Orthostatic hypotension is estimated to occur in
16–58% of patients with PD.89 In general, orthostatic
hypotension in PD is asymptomatic and tends to occur
at later stages of disease than in MSA, but in a subgroup
of patients it may be early and prominent, manifesting
even before the initiation of dopaminergic therapy.89
Urinary symptoms occur in 38–71% of patients with
PD.77,90,91 The most prominent symptom is nocturia, fol­
lowed by urgency and frequency, and the most common
urodynamic finding is detrusor overactivity.92 Nocturia is
the only urinary symptom that improves after deep brain
stimulation of the subthalamic nucleus.
Differential diagnosis
The differential diagnosis between MSA‑P and PD with
autonomic failure can be difficult. A prospective study
showed that autonomic indices, particularly the percent­
age of the body affected by anhidrosis, were significantly
and persistently more abnormal in MSA than in PD with
autonomic failure.61 Urodynamic findings such as large
post-micturitional residual volume (>100 ml), detrusor
external sphincter dyssynergia, and open bladder neck
at the start of filling are highly suggestive of MSA. 54
Anal sphincter denervation due to loss of Onuf nucleus
motor neurons may help to distinguish MSA from PD
within the first few years of onset of motor symptoms,
but this finding is not specific for MSA, and can occur
in progressive supranuclear palsy or in PD patients with
chronic constipation.93
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Structural brain imaging, including diffusion-
weighted and diffusion tensor MRI, and functional
imaging, including PET and single-photon emis­
sion CT (SPECT), might aid the differential diagnosis
between MSA and PD.1 The presence of atrophy in the
putamen, middle cerebellar peduncle and pons on MRI
serve as supporting features for the diagnosis of pos­
sible MSA.39 Signal changes on T2-weighted images,
including the slit-like void signal (hypointensity of
the posterior putamen surrounded by hyperintense
lateral putaminal rim) and the hot cross bun sign (due
to myelin loss in the basis pontis) are more charac­
teristic of MSA but are not specific for this condition.
Diffusion-weighted imaging shows elevated apparent
diffusion coefficient in the putamen, pons and middle
cerebellar peduncle in MSA.94 In MSA‑P, but not in PD,
brain perfusion SPECT shows striatal hypoperfusion,95
and 18F-fluorodeoxyglucose PET shows striatal hypo­
metabolism.96 By contrast, dopamine transporter SPECT
using 123I-FP-CIT demonstrates reduced striatal binding
in both disorders.97
Myocardial scintigraphy using 123I-metaiodo­benzyl­
guanidine (MIBG) 98 or 6‑18F-fluorodopamine PET 99
assesses postganglionic sympathetic innervation of the
heart; these modalities are potential tools to differenti­
ate between MSA and Lewy body disorders. However,
although initial studies suggested that loss of cardiac
sympathetic innervation in PD or PAF could help in
distinguishing Lewy body disorders from MSA,99,100
decreased cardiac MIBG uptake has also been found in
up to 30% of patients with MSA,101 possibly reflecting
coexistent Lewy body pathology.
Dementia with Lewy bodies
Severe autonomic dysfunction, as well as repeated falls
and syncope, are features supporting the diagnosis of
DLB. 102 Orthostatic hypotension, urinary frequency
and urge incontinence can be disabling symptoms in
DLB,103,104 and symptomatic orthostatic hypotension
may occur in 30–50% of cases. On the basis of auto­
nomic laboratory evaluation, the severity of autonomic
failure in DLB is intermediate between that seen in MSA
and PD.105
Other neurodegenerative disorders
Other central neurodegenerative disorders can manifest
with autonomic failure that reflects peripheral autonomic
involvement. These conditions, which may clinically
mimic MSA or Lewy body disorders, include fragile X
tremor–ataxia syndrome, in which bladder symptoms
might be prominent;106 adult-onset autosomal dominant
leukodystrophy, which is associated with pure sympa­
thetic failure;107 and a novel prion disorder character­
ized by diarrhoea and length-dependent, predominantly
sensory and autonomic axonal neuropathy, followed by
cognitive decline.108
Autoimmune autonomic disorders
Autoimmune autonomic disorders are characterized
by acute or subacute onset of generalized or restricted
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autonomic failure, including gastrointestinal enteropathy.
Early recognition of these disorders is important because
they are disabling and might be the initial manifestation
of an underlying neoplasm. In addition, patients with
autoimmune autonomic disorders may show substantial
improvement with i­ mmunomodulatory therapy.4,109
Autoimmune autonomic ganglionopathy
AAG (formerly known as acute pandysautonomia or
idiopathic subacute autonomic neuropathy 18,110) is
characterized by severe autonomic failure that develops
over the course of days or weeks in a previously healthy
person. The onset of symptoms may follow a viral infec­
tion, minor surgical procedure, or vaccination. The
most common manifestation is generalized sympathetic,
parasympathetic and ENS failure, but the spectrum is
broad; symptoms might be confined to pure choliner­
gic neuropathy manifested by sicca syndrome, isolated
adrenergic neuropathy, or isolated gastrointestinal dys­
motility. Patients may recover spontaneously, but only
one-third experience substantial functional ­improvement
without treatment.
Approximately 50% of cases of subacute AAG are
associ­ated with gnAChR antibodies18 that block trans­
mission at the autonomic ganglia. Antibody titres
correlate with the severity of autonomic failure.19,111
gnAChR antibodies can also be associated with chronic
or restricted forms of autonomic dysfunction,77 and with
neurological or paraneoplastic disorders unrelated to
the autonomic nervous system.19 In one series, 30% of
gnAChR-seropositive patients had other paraneoplastic
antibodies in the setting of occult cancer, most com­
monly adenocarcinoma.19 In some cases, AAG coexists
with other autoimmune disorders, such as myasthenia
gravis, in patients with occult cancer.112,113
Several observational studies report that patients
with gnAChR-seropositive AAG benefit from intra­
venous immunoglobulin, plasma exchange, prednisone,
mycophenolate, azathioprine and rituximab, either
individually or in combination. 19,114–116 A substantial
percentage of patients with AAG are seronegative for
gnAChR and other autoantibodies;117 some of these
patients may also show symptomatic improvement with
­immunomodulatory therapy.116
Paraneoplastic autonomic neuropathy
A type of subacute autonomic neuropathy that is clinically
indistinguishable from idiopathic AAG might occur as
a manifestation of an occult neoplasm, most commonly
small-cell lung carcinoma associated with anti-Hu
antibodies or, less frequently, thymoma or other neo­
plasms.118,119 Like AAG, paraneoplastic autonomic neuro­
pathy may manifest with generalized autonomic failure,
or with isolated enteric ganglionopathy leading to the
intestinal pseudo-obstruction syndrome.120,121
Acute autonomic and sensory neuropathy
Acute autonomic and sensory neuropathy is a rare dis­
order that differs from AAG in that profound autonomic
failure is associated with various degrees of sensory
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impairment, including loss of pain and temperature
sensation, followed by sensory ataxia due to impair­
ment of proprioception.109,122,123 The mean age of onset
is in the late second decade, but can vary from child­
hood to the elderly. A triggering event, such as respira­
tory or gastrointestinal tract infections, is reported in
two-thirds of patients. Gastrointestinal dysmotility is
the most prominent autonomic symptom; the sensory
loss affects the proximal regions of the limbs, face, scalp
and trunk, and tends to be asymmetrical and segmen­
tal. Pain in the involved region is a common and serious
symptom. Other features of this disorder are reduction of
sensory nerve action potentials and increased T2 signal
in the posterior columns of the cervical spinal cord. 123
Autopsy studies have shown severe neuronal cell loss in
the thoracic sympathetic and dorsal root ganglia, and
in Auerbach’s plexus.123
Sjögren syndrome
Primary Sjögren syndrome manifests with a wide variety
of peripheral neuropathies or ganglionopathies.124 Dorsal
root ganglionopathy may manifest with neuropathic pain
or ataxic neuropathy; autonomic neuropathy might be
prominent in some cases, but is the least frequent form
of neuropathy overall.124
Autoantibodies against muscarinic M3 receptors have
been identified in a subset of patients with Sjögren syn­
drome.125 These antibodies are particularly prevalent in
juvenile cases126 and have cholinergic blocking actions
in vitro.127 Some patients with Sjögren syndrome and
chronic progressive autonomic failure have gnAChR
antibodies, which may predict a positive response to
immunomodulatory therapy.128
Peripheral neuropathies
Peripheral neuropathies associated with autonomic
failure present with various phenotypes, including typical
distal symmetric sensorimotor neuropathy; dorsal root
ganglionopathy manifesting with neuropathic pain or
sensory ataxia; demyelinating, predominantly motor
polyradiculopathy; or distal painful neuropathy. The
spectrum of severity of autonomic failure is highly vari­
able in these disorders, ranging from being a major cause
of disability, as can occur in neuropathies associated
with diabetes or amyloidosis, to restricted distal vaso­
motor and sudomotor impairment in the lower limbs,
as observed in painful SFN.
Diabetic autonomic neuropathy
Diabetic neuropathies are heterogeneous: they include
typical diabetic sensorimotor polyneuropathy, painful
diabetic neuropathy, and diabetic autonomic neuro­
pathy.129 Estimates of the prevalence of diabetic auto­
nomic neuropathy vary depending of the source of
information (community, clinic or tertiary referral centre)
and the type of tests performed to assess autonomic func­
tion.129 Using strict criteria based on autonomic testing
abnormalities, the prevalence in one study was 16.8% for
patients with type 1 and 34.3% for patients with type 2
diabetes mellitus.130
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© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Diabetic autonomic neuropathy can affect cardio­
vascular, gastrointestinal, urogenital and sudomotor
functions to various degrees. In most of the typical cases,
a combination of cardiovascular tests and sudomotor
tests allows its detection in otherwise asympto­matic
patients. An impaired heart rate response to deep
breathing­—an indicator of cardiovagal failure—has the
greatest specificity (~80%).131,132 Characteristic mani­
festations of diabetic cardiovascular autonomic neuro­
pathy include resting tachycardia, exercise intolerance,
orthostatic hypotension, intraoperative cardiovascular
instability, and silent myocardial infarction–silent ischae­
mia syndrome. Cardiovascular autonomic neuropathy
has been associated with increased morbidity and mor­
tality,133 so screening for this condition should be per­
formed at the time of diagnosis of type 2 diabetes and
5 years after the diagnosis of type 1 diabetes, particularly
in high-risk patients.129
Upper gastrointestinal dysmotility, which is present
in 40–50% of longstanding cases of diabetes, may
affect postprandial blood glucose levels and glycaemic
control. Constipation is the most frequent gastrointesti­
nal symptom in diabetes, and was reported by 60% of
patients in one study.134 Profuse, watery and predomi­
nantly nocturnal diarrhoea135 and faecal incontinence136
may be disabling in some patients. Bladder symptoms
occur in up to 50% of patients; 43–87% of type 1 and 25%
of type 2 diabetic patients have abnormal urodynamic
findings.137,138 Erectile dysfunction has a reported preva­
lence of 35–90% in patients with diabetes.139,140 Length-
dependent loss of thermoregulatory sweating is common,
and is occasionally associated with compensatory hyper­
hidrosis.22 Gustatory sweating can result from aberrant
innervation of sweat glands by parasympathetic fibres.141
Some patients with diabetes develop an acute painful
neuropathy associated with autonomic failure within a
short time of commencing tight glucose control.142 The
symptoms may be associated with abnormal autonomic
test results and reduced IENFD on punch skin biopsy,
and can all improve over time.142
Amyloid neuropathy
Amyloidoses manifesting with autonomic neuro­
pathy include the AL type (which may be associated
with myeloma or macroglobulinaemia), and familial
amyloid polyneuropathy (FAP), which is most com­
monly linked to mutations in the transthyretin (TTR)
gene. The types of amyloid neuropathy associated with
autonomic failure are highly heterogeneous. 143,144 In a
retrospective study on 65 cases of AL amyloidosis or
FAP, generalized autonomic failure was associated with
painful (62%) or nonpainful (17%) sensorimotor poly­
neuropathy or distal SFN (5%); autonomic failure also
occurred without neuropathy (11%), but polyneuro­
pathy without generalized autonomic failure was infre­
quent (6%).143 In AL amyloidosis, peripheral neuropathy
may be the presenting feature or an incidental finding
of the disease, and can occur in up to 20% of cases. 145
The median survival of patients with AL amyloidosis
who have peripheral neuropathy has improved with the
REVIEWS
Table 1 | General management of autonomic failure
Symptom Approach
Orthostatic Patient education: recognize atypical symptoms of
hypotension orthostatic hypotension; get up slowly from bed; urinate
in the sitting position; avoid hot, humid environments;
exercise regularly; avoid straining; keep a blood
pressure diary; discontinue aggravating drugs
Sleep with the head elevated 4 in (reverse
Trendelenburg position)
Postural countermanouevres (for example, leg crossing,
squatting)
Support garments (waist-high support stockings,
abdominal binder)
Volume expansion (daily intake of 8–10 g sodium,
fluid intake of at least 2.0–2.5 l)
Rapid ingestion of 500 ml tap water
Dietary changes; avoid alcohol; eat small, frequent
meals (carbohydrate is best ingested with the last
meal of the day)
Florinef (0.1–0.4 mg daily)
Midodrine (10–40 mg daily)
Pyridostigmine (60–240 mg daily)
Droxidopa (100–600 mg TID)
Erythropoietin (25–75 U/kg SQ)
Desmopressin nasal spray (5–40 μg)
Octreotide (25–200 μg SQ)
Neurogenic Anticholinergics (for example, oxybutynin, tolterodine);
bladder clean intermittent self-catheterization
Drooling Anticholinergics; botulinum toxin
Gastroparesis Metoclopramide (5–20 mg QID); domperidone
(10–30 mg QID); erythromycin (50–250 mg QID);
pyridostigmine (30–60 mg TID); bethanechol (25 mg
QID); nutritional support (low-fat, low-fibre oral
supplementation; infusion of formula via a jejunal
feeding tube)
Constipation Fibre supplementation (15 g per day); bulk agents
(for example, psyllium [1 tsp up to three times daily],
methylcellulose); osmotic laxatives (for example, milk
of magnesia [two tablets up to four times daily],
polyethylene glycol [17 g in 25 ml once or twice daily],
lactulose [15–30 ml TID]); docusate (stool softener,
100 mg BID); lubiprostone (24 μg BID); pyridostigmine
(up to 180–540 mg); bisacodyl (10 mg up to three times
a week); antibiotics to prevent bacterial overgrowth;
surgery for intractable colonic inertia
Erectile Oral phosphodiesterase type 5 inhibitors (for example,
dysfunction sildenafil 25–100 mg)
Intracavernous drugs (for example, alprostadil,
papaverine)
Abbreviations: BID, twice a day; QID, four times a day; SQ, subcutaneous; TID, three times a day.
8  |  ADVANCE ONLINE PUBLICATION
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Comments
The most important aspect of management
Avoids supine hypertension and nocturnal polyuria
Increases orthostatic tolerance
Reduces venous pooling
Initial step before pharmacological management
Rapidly increases blood pressure independently
of volume expansion
Prevents splanchnic vasodilation
Adverse effects include supine hypertension, ankle
oedema, hypokalaemia, hypomagnesaemia, headache,
and reduced effects of warfarin
Adverse effects include scalp tingling or itching,
goose bumps, supine hypertension, and urinary urgency
or retention
Adverse effects include nausea, abdominal cramps,
diarrhoea, increased salivation, urinary urgency and
bradycardia
Main potential adverse effect is supine hypertension
Iron supplementation is usually required; supine
hypertension may occur
Risk of water intoxication and hyponatraemia
Adverse effects include nausea and abdominal cramps,
hypertension, risk of gallstones and postprandial
hyperglycaemia
Adverse effects include constipation, dry mouth, risk
of glaucoma, and worsening of cognitive function
Anticholinergics may worsen confusion; botulinum toxin
may worsen dysphagia
Gastroparesis may impair absorption of levodopa;
metoclopramide is contraindicated in parkinsonian
disorders; domperidone may cause QT prolongation,
and is not available in the USA
Donepezil and other cholinesterase inhibitors may
cause diarrhoea
Adverse effects include headache, flushing, nasal
congestion, blue vision, and non-arteritic ischaemic
optic neuropathy; these drugs may worsen orthostatic
hypotension
Adverse effects include penile pain, oedema and
haematoma, palpable nodules or plaques, and priapism
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 REVIEWS

combination of melphalan, prednisone and autologous
stem cell transplantation.146
The clinical and pathological features of FAP have
been reviewed in detail elsewhere.147,148 Over 100 muta­
tions in the TTR gene have been identified, the most
common (~50% of cases of FAP worldwide) of which
causes a Val30Met substitution. Different TTR variants
contribute to variable age at diagnosis, degree of cardiac
involvement, and survival.149 The first-line specific treat­
ment of choice for Val30Met TTR-FAP is liver transplan­
tation.150 In addition, tafamidis, a stabilizer of tetrameric
transthyretin, has shown short-term effectiveness in
slowing the progression of peripheral neuropathy at very
early stages of Val30Met TTR-FAP.151
Painful small fibre neuropathies
Selective involvement of postganglionic as well as noci­
cep­tive fibres in painful SFN typically manifests with
distal anhidrosis (or sometimes hyperhidrosis) and
vasomotor dysfunction (generally erythema, but some­
times vasoconstriction and coldness) in the lower limbs.
In some cases, SFN can result in more-generalized
autonomic failure that may be symptomatic or detect­
able with autonomic testing. Important examples of
painful SFN are those associated with HIV infections152
and Fabry disease,153 in addition to the types related to
dia­betes and amyloidosis, as highlighted above. Distal
sympathetic sudomotor and vasomotor failure in con­
junction with neuropathic pain also occur in sodium
channelopathies associated with gain-of-function
SCNA9 mutations, both in familial syndromes154 and in
a substantial proportion of idiopathic SFN cases.155 The
SCNA9 gene encodes the Nav1.7 voltage-gated sodium
channel, which is expressed in nociceptive dorsal root
ganglion and sympathetic neurons. These gain-of-­
function mutations cause increased excitability of the
nociceptor and hypoexcitability of sympathetic ganglion
neurons,156,157 which might explain the coexistence of
neuropathic pain and postganglionic sympathetic failure.
Management issues
A detailed discussion of the management of autonomic
failure is beyond the scope of this Review, but the general
approach is summarized in this section and in Table 1.
The principles of management include discontinua­
tion of potentially causative drugs; immunomodula­
tory therapy for autoimmune disorders; management
of diabetes, amyloidosis or other potentially treatable
cause of autonomic neuropathy; patient education; non-­
pharmacological approaches; and pathophysiologically
based drug therapy. Patient education is a fundamen­
tal aspect of management. For example, patients with
orthostatic hypotension should be instructed to recog­
nize atypical symptoms and avoid precipitating factors.
Appropriate fluid and sodium intake, dietary adjust­
ments and regular exercise are beneficial in most cases
of autonomic failure.
Conclusions
The wide spectrum of clinical manifestations and dis­
orders associated with autonomic failure requires a
systematic clinical and laboratory approach to establish
the diagnosis, particularly in cases where autonomic
failure is disabling or life-threatening. A careful history
and examination is the mainstay of diagnosis, and lab­
oratory and other ancillary tests must be prioritized to
search for potentially treatable causes. Patient education,
avoidance of precipitating factors, non-pharmacological
approaches, and pathophysiologically based drug therapy
form the basis of current treatment of these disorders.
Further elucidation of the pathobiological mechanisms
that lead to immune, metabolic or degenerative damage
or dysfunction of central and peripheral autonomic
neurons will provide more-specific therapeutic targets.
Review criteria
A PubMed search from 1st January 1975 to 15th December
2013 was performed using the following terms (individually
and in various combinations): “autonomic failure”,
“autonomic neuropathy”, “orthostatic hypotension”,
“multiple system atrophy”, “Parkinson disease”, “Lewy
body disease”, “dementia with Lewy bodies”, “autoimmune
autonomic ganglionopathy”, “paraneoplastic”, “diabetic
neuropathy”, “amyloid neuropathy”, “Sjögren syndrome”,
“leukoencephalopathy”, “fragile X” and “prion”. The
search was limited to full articles published in English.
Other articles were identified from bibliographies of the
retrieved articles.

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