Evaluation and Management of Autonomic

Nervous System Disorders

Caroline M. Klein, M.D., Ph.D.1

ABSTRACT

Autonomic nervous system dysfunction may manifest with a variety of symptoms,

with orthostatic intolerance (including orthostatic hypotension or tachycardia) and sweat-
ing abnormalities (increased or decreased sweating) being common problems requiring
medical evaluation and treatment. Determination of the underlying diagnosis for these

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symptoms is critical in terms of classification of the disorder and its prognosis. Recent
advances in evaluation of patients with these conditions and treatment modalities have
enabled physicians to improve overall management of patients with these disorders. These
advances include testing for ganglionic acetylcholine receptor antibody in patients with
suspected autoimmune autonomic neuropathy and use of pyridostigmine for treatment of
patients with orthostatic hypotension or tachycardia.

KEYWORDS: Dysautonomia, orthostatic hypotension, postural tachycardia syndrome

A utonomic nervous system dysfunction may
manifest clinically with a variety of symptoms, including
orthostatic intolerance (due to either orthostatic hypo-
tension or inappropriate tachycardia), change in sweat-
ing, gastrointestinal complaints, pupillary abnormalities,
sexual dysfunction, bladder dysfunction, or secretomotor
changes (dry eyes or dry mouth). Depending on the
clinical setting, these symptoms may represent a limited
autonomic disorder, such as autoimmune autonomic
neuropathy, or indicate the onset of generalized auto-
nomic failure as part of a neurodegenerative process,
such as pure autonomic failure or multiple system
atrophy (Shy-Drager syndrome). One must determine
if there is autonomic dysfunction, its extent and severity,
and what other clinical features help to establish the
overall diagnosis for the patient. Accurate character-
ization of an autonomic disorder and its underlying
pathogenesis is necessary for planning management
strategies and long-term prognosis. Orthostatic intoler-
ance and syncope, for example, may be due to a variety of
underlying causes, including orthostatic hypotension,
orthostatic tachycardia (which may be secondary to
volume depletion, deconditioning, anemia, hyperthyr-
oidism, anxiety, or postural tachycardia syndrome—only
the latter of which is an autonomic disorder), or neuro-
cardiogenic or vasovagal (reflex) syncope. Autonomic
symptoms have a wide variety of causes, some of which
are more common (neurocardiogenic or reflex syncope)
than others (pure autonomic failure, multiple system
atrophy, autoimmune autonomic neuropathy).
CLINICAL FEATURES
Orthostatic Intolerance
Orthostatic intolerance, as a broad definition, includes a
variety of symptoms, which occur when the patient
changes body position, specifically from lying down to

1
Department of Neurology, The University of North Carolina School
of Medicine, Chapel Hill, North Carolina.
Address for correspondence and reprint requests: Caroline M.
Klein, M.D., Ph.D., Assistant Professor, Department of Neurology,
The University of North Carolina School of Medicine, 3114 Bio-
informatics, Campus Box 7025, Chapel Hill, NC 27599-7025 (e-mail:
kleinc@neurology.unc.edu).
Neuromuscular Disorders; Guest Editor, Ted M. Burns, M.D.
Semin Neurol 2008;28:195–204. Copyright # 2008 by Thieme
Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001,
USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2008-1062263. ISSN 0271-8235.
195
196 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
sitting, or most likely, standing upright. Physiologically,
due to gravitational forces, there is an abrupt shift in
blood volume and consequently venous return to the
heart with change in body position, which is compen-
sated for in the normal patient by virtue of intact
baroreflex mechanisms. Patients may develop symptoms
of dizziness, lightheadedness, blurred or tunnel vision,
headache, chest discomfort, nausea, cognitive slowing,
posterior cervical and shoulder pain, and diaphoresis
with change in body position. In elderly patients (age
65 or older), these symptoms may not be immediately
apparent to the patient, but instead occur as a subtle but
consistent change in mental status noted by caregivers
whenever the patient is in an upright posture. In the
most extreme circumstances, syncope or temporary loss
of consciousness may actually occur. These symptoms
may be reported in patients that have orthostatic hypo-
tension or orthostatic tachycardia. In both cases, deter-
mining whether the symptoms are secondary to systemic
causes such as anemia, dehydration, relative decondition-
ing, or hyperthyroidism (with orthostatic tachycardia) is
important. It is also important to determine whether
lightheadedness or vertigo occurs when the patient re-
ports ‘‘dizziness,’’ and whether the dizziness ever occurs in
a supine position or with rapid change in head position,
in which case the symptoms may be due to vestibulop-
athy. How frequently the symptoms occur (daily versus
intermittently) and whether there is any diurnal variation
(worse in the morning, for example, which commonly
occurs in patients with orthostatic hypotension) in the
symptoms are important clinical features.
Sweating Abnormalities
Sudomotor or sweating changes can also be features of
autonomic dysfunction, implying changes in sweating
not related directly to symptoms of orthostatic intoler-
ance or presyncope. Patients may report either in-
creased or excessive sweating, or decreased sweat
output and heat intolerance, either globally, segmen-
tally, or patchy in distribution. Many patients with
distal sweat loss report increased sweat output, which
may occur as a compensatory response in unaffected
areas such as the head and upper torso, but which is
perceived by the patient as excessive sweating. Sudo-
motor dysfunction may be due to abnormalities in
central control mechanisms (as in multiple system
atrophy), or more commonly in patients with auto-
nomic peripheral neuropathy, either as an isolated
abnormality of postganglionic sympathetic nerve fibers
only in hypohidrosis or global anhidrosis, or as part of a
more generalized autonomic neuropathy, either pri-
mary (autoimmune autonomic neuropathy) or secon-
dary (amyloidosis, diabetic peripheral neuropathy, or
small fiber sensory neuropathy due to Sjögren’s syn-
drome) in nature.
Secretomotor Symptoms
Secretomotor symptoms include sicca symptoms of dry
eyes (xerophthalmia) and dry mouth (xerostomia).
Patients do not usually volunteer these symptoms unless
they are severe, but with careful questioning, they may be
elicited. Dysfunction of autonomic innervation may be
seen in autonomic neuropathies or part of generalized
autonomic failure, although more commonly seen in the
former.
Gastrointestinal Symptoms
Gastrointestinal symptoms may include early satiety,
abdominal cramping after meals, frequent diarrhea or
constipation (or alternating bouts of both), nausea and/
or vomiting with meals.
Genitourinary Symptoms
Bladder dysfunction, in relation to autonomic disorders,
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may include urinary incontinence, urinary frequency/
urgency, and symptoms of urinary retention. Male pa-
tients may report symptoms of erectile dysfunction, and
both male and female patients may report decreased
libido and inability to achieve orgasm with autonomic
dysfunction.
Sleep Disorders
A subset of patients may report sleep disturbances as part
of their presentation of autonomic nervous system dys-
function. Specifically, patients with nightmares and
rapid eye movement (REM)-behavioral sleep disturban-
ces may have associated autonomic dysfunction in the
setting of a diagnosis of multiple system atrophy.
PATHOGENESIS
The recent report by Vernino et al1 regarding isolation
of a serum antibody against ganglionic acetylcholine
receptors has led to better understanding and further
characterization of the pathogenesis of autonomic neu-
ropathies, specifically autoimmune autonomic neuropa-
thy, which was previously called idiopathic autonomic
neuropathy. Across a spectrum of patients with auto-
nomic disorders—ranging from idiopathic autonomic
neuropathy to diabetic autonomic neuropathy to postural
orthostatic tachycardia syndrome to pure autonomic fail-
ure to multiple system atrophy—high levels of seroposi-
tivity for this antibody were found. Ganglionic
acetylcholine receptor antibodies were found in
40%
of patients with idiopathic or paraneoplastic autonomic
neuropathy and in a smaller percentage of patients with
postural orthostatic tachycardia syndrome or diabetic
autonomic neuropathy (< 10% for each group). Patients
with other autonomic disorders were seronegative. The
 EVALUATION AND MANAGEMENT OF AUTONOMIC NERVOUS SYSTEM DISORDERS/KLEIN 197

subgroup of patients with idiopathic autonomic neuro-
pathy with seropositivity for ganglionic acetylcholine
receptor antibody were later further characterized by their
clinical features, including sicca complex, pupillary light
abnormalities, upper gastrointestinal symptoms, and neu-
rogenic bladder, in addition to orthostatic hypotension,
suggesting prominent cholinergic nerve fiber dysfunction
in this patient population.2,3 Patients with more limited
forms of autoimmune autonomic neuropathy (diabetic
autonomic neuropathy, isolated gastrointestinal dysmo-
tility, postural tachycardia syndrome) were found to have
lower, but positive, titers of this antibody.4 These anti-
bodies are not found in healthy control subjects,4 so that
their presence appears to have not only diagnostic value
but also to provide information regarding pathogenesis in
these patients, particularly those with very high titers of
antibody. Indeed, further testing with animal models has
provided evidence of pathogenicity.1,5,6
The pathophysiology of postural orthostatic ta-
chycardia syndrome (POTS) remains poorly understood,
tachycardia syndrome, leading to a peripherally gener-
ated hyperadrenergic state.8 Whether other genetic
mutations or polymorphisms are present in the general
population of patients with postural tachycardia syn-
drome remains to be determined.13
An interesting and clinically challenging sub-
group of patients with dysautonomia exhibits chronic
autonomic failure with not only orthostatic hypotension
but also with supine hypertension. This combination
may be seen in patients with multiple system atrophy or
pure autonomic failure or in patients with Parkinson’s
disease and orthostatic hypotension.14 Although the
exact underlying pathophysiology is unknown, specula-
tion is that it may be due to a combination of baroreflex
desensitization and residual serum catecholamines
interacting with hypersensitive peripheral adrenergic
receptors.14 Goldstein et al15 found lower baroreflex-
cardiovagal gain in patients with autonomic failure and
supine hypertension and lower plasma norepinephrine
levels. Whereas patients with pure autonomic failure

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but what has evolved with clinical experience with these
patients is that this is truly a syndrome and not a specific
diagnosis, meaning that the underlying pathogenesis is
variable, and different subgroups of patients who meet
the established diagnostic criteria have different under-
lying causes.7–11 There is a subgroup of these patients
with ‘‘neuropathic POTS,’’ meaning that they appear to
have a limited autonomic neuropathy underlying their
condition—as demonstrated by distal abnormalities on
quantitative sudomotor testing and patchy denervation
of sympathetic nerve fibers to the blood vessels in the
lower extremities and the kidneys—leading to hypovo-
lemia and abnormal vasoconstriction patterns as a cause
for the postural tachycardia.8,11,12 A less common form is
that due to an increase in sympathetic outflow from the
central nervous system, leading to a hyperadrenergic
state and orthostatic hypertension.8–11 Finally, a genetic
mutation in the norepinephrine transporter protein has
been identified in a kindred of patients with postural
have peripheral sympathetic denervation, those with
multiple system atrophy have central sympathetic dener-
vation; but both groups of patients very commonly have
the combination of supine hypertension and orthostatic
hypotension, presumably as a result of baroreflex failure
from differing etiologies.15
CLASSIFICATION
Dysautonomias can be classified into general categories
based on their basic pathology (Table 1). Autonomic
neuropathy may occur as a very limited condition, such
as idiopathic hypo- or hyperhidrosis, limited impaired
gastrointestinal motility, as part of a more generalized
neuropathy such as with diabetic autonomic neuropa-
thy,12,16 or autonomic neuropathy in the setting of
amyloidosis12 or associated with Sjögren’s syndrome,17
or sicca complex.12,16,18 In addition, there are hereditary
autonomic and sensory neuropathies.12,16 Autoimmune

Table 1 Classification of Dysautonomias by Symptomatology

AAN POTS MSA PD þ OH CIA PAF

Orthostatic hypotension þþ  þþ þþ  þþ
Orthostatic tachycardia  þþþ    
Secretomotor symptoms þþþ þ/ þ þ/  þþ
Pupillary abnormalities þþ     þ/
Gastrointestinal symptoms þþþ þ þ þ  þ/
Genitourinary symptoms þþ þ/ þþ þþ  þ/
Sleep disorder   þþþ þ  
CNS involvement  þ/ þþþ þþþ  
PNS involvement þ  þ/   
Sudomotor abnormality þþ þ þþ þ þþþ þþ
AAN, autoimmune autonomic neuropathy; POTS, postural orthostatic tachycardia syndrome; MSA, multiple system atrophy; PD þ OH,
Parkinson’s disease with orthostatic hypotension; CIA, chronic idiopathic anhidrosis; PAF, pure autonomic failure; CNS, central nervous
system; PNS, peripheral nervous system.
198 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
autonomic neuropathy, as recently highlighted, typically
has an acute or subacute (less than 3 months) onset and
may be limited or generalized.2,3,12 Paraneoplastic auto-
nomic neuropathy associated with occult malignancy
may also occur, although rarely.12,16 Lambert-Eaton
myasthenic syndrome is associated with autonomic dys-
function as well, presumably on the basis of a paraneo-
plastic syndrome or neurological autoimmunity
secondary to calcium channel antibodies.1,4,19
Chronic autonomic disorders leading to general-
ized autonomic failure may be due to central neuro-
degenerative conditions, such as Parkinson’s disease with
orthostatic hypotension or multiple system atrophy.
These conditions are progressive in their course, with a
relatively shorter prognosis for patients with multiple
system atrophy. Studies evaluating sympathetic innerva-
tion to the heart with radioisotope neuroimaging tech-
niques demonstrate preserved innervation in patients
with multiple system atrophy in contrast to Parkinson’s
disease, where there is absence of sympathetic innerva-
tion to the heart.7,20,21 So, although these two neuro-
logical conditions may share some clinical features,
including autonomic failure, the underlying pathogene-
sis may be different, with preganglionic lesions in the
case of multiple system atrophy and lesions in postgan-
glionic sympathetic nerve fibers in Parkinson’s disease
with autonomic failure.7,20,22 Pure autonomic failure, in
contrast, is a very slowly progressive dysautonomia with-
out symptoms or signs of central nervous system involve-
ment. In this condition, sympathetic innervation to the
heart is reduced20–22 and patients have low supine or
resting plasma norepinephrine concentrations.20,22,23 Of
these three causes for generalized autonomic failure,
pure autonomic failure has, overall, the best progno-
sis.9,23 Mabuchi et al23 recently compared retrospectively
a small group of patients with pure autonomic failure
and compared them to patients with multiple system
atrophy. They found that patients with pure autonomic
failure presented initially with orthostatic intolerance or
sudomotor abnormalities followed by constipation and
syncope, with urinary complaints occurring much later in
their course, and respiratory involvement not being
affected. In contrast, patients with multiple system
atrophy had early urinary tract dysfunction, followed
by sudomotor abnormalities and orthostatic hypoten-
sion, with respiratory problems occurring late in the
clinical course.
Postural orthostatic tachycardia syndrome leads
to orthostatic intolerance and may be due to peripheral
or central pathological mechanisms, as noted previously.
In general, it is a condition that predominantly affects
female patients between the ages of 15 and 50 years of
age, and in most patients it is a self-limited or mono-
phasic illness.10–12 It may manifest with more general-
ized autonomic dysfunction, including orthostatic
hypotension, in younger patients.10 It may occur after
a prodromal illness, surgery, or trauma, lending to
speculation that some forms of this syndrome may
have an autoimmune basis. A retrospective review of
152 patients evaluated over 10 years at the Mayo Clinic
found that 15% of 42 patients of the group tested had
positive ganglionic acetylcholine receptor antibodies.11
Neurocardiogenic or reflex syncope may occur in patients
with postural orthostatic tachycardia syndrome or in
patients without other symptoms or signs of autonomic
dysfunction. Reflex syncope and carotid sinus hyper-
sensitivity are more common causes of syncope and are
generally self-limited conditions.9,24
DIAGNOSTIC APPROACH
Patients with symptoms suggestive of autonomic dys-
function require a thorough evaluation, starting with a
history and physical examination, including neurological
examination. In all patients, performance of bedside
orthostatic blood pressure and heart rate monitoring is
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important. Supine parameters should be obtained after
the patient has rested quietly for a few minutes, followed
by standing upright, if possible, with obtaining and
recording blood pressure immediately upon standing,
then repeating the process for the next 2 to 3 minutes
with a pulse rate obtained at the end of the standing
period. It is best to use a manual blood pressure cuff to
obtain these measurements, as it is more accurate than
most automated devices. In addition, bedside assessment
of heart rate response to deep breathing can be easily
judged by having the patient breathe in and out at a rate
of six breaths per minute (5 seconds for inspiration,
5 seconds for expiration) while palpating the patient’s
pulse rate. Part of the physical examination should
include notation of dry oral mucous membranes, dry
skin, skin temperature, vasomotor changes (i.e., acrocya-
nosis or livedo reticularis), and peripheral edema of the
extremities.
Further autonomic testing is valuable in obtaining
objective and reproducible assessment of autonomic
impairment.25 This testing may include heart rate re-
sponse to deep breathing and peripheral skin potentials,
which can be performed on many standard electromyog-
raphy (EMG) machines. However, peripheral skin po-
tential responses are sometimes difficult to elicit and are
the end result of a centrally stimulated autonomic
response to startle. Standardized autonomic testing of
cardiovascular reflex pathways (beat-to-beat monitoring
of heart rate response to deep breathing and Valsalva
maneuver, and to head-up tilt table testing), in addition
to direct iontophoretic stimulation of postganglionic
sympathetic nerve fibers to measure sudomotor function,
is also available and accomplished with minimal dis-
comfort to the patient in an autonomic laboratory with
testing expertise. A minimum of 5 minutes of head-up
tilt table testing is able to capture abnormalities in the
 EVALUATION AND MANAGEMENT OF AUTONOMIC NERVOUS SYSTEM DISORDERS/KLEIN
majority of patients with orthostatic hypotension,26
although some investigators propose that an additional
population of patients with ‘‘delayed orthostatic hypo-
tension’’ may be missed on standard tilt table testing
unless the duration of the tilt is extended beyond
10 minutes.27 Autonomic function testing is particularly
useful in patients with suspected subclinical autonomic
involvement, as in patients with diabetes who present
with complaints of orthostatic intolerance but who may
have more generalized autonomic failure with testing.
Likewise, in patients with postural orthostatic tachycar-
dia syndrome, autonomic function testing may not only
confirm the diagnosis on head-up tilt table testing, but
also provide evidence of a hyperadrenergic state and a
limited autonomic neuropathy with sudomotor testing.
Additional testing may also be directed in areas of
clinically symptomatic autonomic dysfunction, including
urodynamic studies for bladder complaints and gastro-
intestinal motility studies for patients.
Additional screening laboratory tests should in-
clude complete blood count for anemia, serum protein
electrophoresis with immunofixation and free light
chain analysis for patients with peripheral neuropathy
and possible primary systemic amyloidosis, testing for
Sjögren’s antibodies, and testing for ganglionic acetylcho-
line receptor antibodies in patients with possible auto-
immune autonomic neuropathy. Obtaining supine and
standing plasma catecholamine levels is not critical for
diagnosis but may be helpful in distinguishing patients
with multiple system atrophy versus pure autonomic fail-
ure, as the former has normal levels of norepinephrine,
whereas in pure autonomic failure the patient’s plasma
norepinephrine levels are reduced.20 A baseline electro-
cardiogram (ECG) and possibly additional cardiac eval-
uation, such as Holter monitoring or echocardiogram,
may be indicated in patients with orthostatic intolerance
or syncope. Testing for sicca complex symptoms (Schirm-
er’s testing for xerophthalmia, minor salivary gland lip
biopsy for xerostomia) may be indicated in patients with
suspected Sjögren’s syndrome, particularly if the serolog-
ical testing for anti-SSA and anti-SSB antibodies is
negative. A 24-hour urine sodium excretion test is useful
in patients with orthostatic intolerance to determine if
their daily salt and fluid intake is adequate to maintain
euvolemia. The target sodium excretion is 170 mmol/L
per 24 hours, with a target urine output volume between
2000 and 2500 mL per 24 hours.12 For patients with
suspected supine hypertension in addition to orthostatic
hypotension, a 24-hour ambulatory blood pressure mon-
itor may be useful to document this abnormality, as its
presence may alter management decisions.
TREATMENT
One of the most important aspects of treatment of
patients with dysautonomia is careful education of pa-
199
tients and their family members or caregivers about the
nature of their condition and the approach to treatment.
Symptoms of dysautonomia, especially blood pressure
and heart rate, tend to fluctuate and are impacted by a
variety of other influences. Therefore, patients and their
families need to be aware of interventions that should be
done routinely to help stabilize the patient, and those
which may be adjusted depending on the circumstances.9
For example, patients with orthostatic intolerance, from
either tachycardia or hypotension, should always main-
tain adequate salt and fluid intake daily, elevate the head
of their bed 4 to 6 inches, and avoid situations that may
precipitate or worsen their symptoms.16,28 On the other
hand, dosing of medications to treat these conditions in
some cases may work optimally by day-to-day adjust-
ments, with higher dosages being given on certain days
or certain times of the day, depending on the medication
and the patient’s diagnosis. Other medications need to
be taken regularly as prescribed for optimal benefit. With
appropriate education and understanding of these issues
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on the part of the patient and their caregivers, the quality
of life in patients with dysautonomia can be substantially
improved, in most cases.
Nonpharmacological Treatment
A variety of approaches can be instituted for patients
with dysautonomia, particularly those with orthostatic
intolerance (Table 2). Encouraging patients to main-
tain adequate daily salt and fluid intake is critical,10,16,29
and can be easily monitored by checking 24-hour
urinary sodium excretion. In patients who are main-
taining adequate salt and fluid intake, the 24-hour
urinary sodium excretion should be greater than
150 and ideally greater than 170 mmol or mEq per
24 hours,12 with a total 24-hour urinary output volume
Table 2 Nonpharmacological Management of
Dysautonomias
Orthostatic intolerance
 Adequate daily salt and fluid intake
 Head of bed elevated 4–6 inches
 Lower body resistance isometric training exercises
 Compression stockings or abdominal binder
 Eat smaller, more frequent meals
 Plan daily activities to occur later in the day
 Arise to standing upright slowly
Secretomotor symptoms
 Artificial tears
 Over-the-counter oral mucous membrane moisturizers
 Punctal plugging or cauterization
Sudomotor symptoms
 External cooling devices
 Avoidance of warm/hot environments if heat intolerance
 Use of antiperspirants (Drysol) for excessive sweating
200 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
of between 2000 and 2500 mL. This requires patients
to consume between 5 and 10 g of salt per day and to
drink between 2 and 3 L of fluid per day. Patients
should be encouraged to read food packaging labels and
to use drinking containers of known volumes to esti-
mate what amounts of salt and fluid they are consuming
daily. The 24-hour urinary sodium measurement
should ideally be done when the patient’s salt and fluid
intake are at steady state in terms of their day-to-day
consumption pattern, and can be easily checked during
times when the patient’s symptoms may be worsening
and it needs to be determined if the patient is main-
taining the target consumption levels. Patients should
limit caffeine-containing beverages because of their
diuretic effect and try to use various commercially
available fitness waters or beverages containing sodium
to reach their daily goal. Recent studies have shown
that simply drinking 300 to 500 mL of water has an
acute effect on blood pressure, even beyond simple
volume expansion.16,30–32
Mechanical elevation of the head of the patient’s
bed is important to diminish natriuresis, which occurs
particularly in patients with orthostatic hypotension
overnight, leading to increased urinary output and wor-
sening the drop in blood pressure when the patient gets
up the following morning.9,12,14,33 This should be done
with cinder blocks under the head of the bed frame to
maintain a constant elevation of at least 4 inches above
the horizontal when the patient is lying in bed.
Use of compression stockings is also important in
patients with orthostatic intolerance.9,10,12,14,16,33,34
These stockings are available in a variety of forms, and
it has generally been found that stockings that extend
from toes to mid-thigh provide the best benefit,
although some patients find putting on such stockings
daily cumbersome, and this reduces compliance. Patients
should be strongly encouraged to wear these stockings as
much as possible, especially on days when they are more
symptomatic, as that is when they will add the most
benefit. A moderate degree of compression, between 30
and 40 mm Hg, for the stockings is ideal,10 although
again any degree of compression is better than the
patient not wearing anything. In elderly patients with
arthritis or other medical issues that may reduce grip
strength and their ability to pull on compression stock-
ings, a milder degree of compression, 15 to 20 mm Hg,
can be considered. Abdominal binders to reduce blood
pooling in the splanchnic vascular beds can also be used
successfully in selected patients.12,14,33
An exercise program for patients, including aero-
bic and isometric exercises, is important for maximizing
lower body muscle tone, which improves venous return
in the upright posture.9,10,33 Depending on the patient,
simple exercises such as repetitively standing on tiptoes
to contract calf muscles or performing repetitive deep
knee bends. These movements can be translated into
physical counter-maneuvers the patient can use—when
he or she experiences presyncopal symptoms and cannot
immediately sit down—to try and abort an impending
syncope.33 In other patients, a more formal exercise
program using an exercise bench can be done with
even better results. In some cases, institution of an
exercise program can be implemented under the guid-
ance of a physical therapist.
Pharmacological Treatment
Pharmacological treatment for dysautonomia has been
primarily focused on treatment of patients with ortho-
static intolerance (Table 3). Medication should only be
prescribed to treat patients who are symptomatic (or for
patients whose standing systolic blood pressure is 80 mm
Hg or lower who may not be symptomatic but who are at
increased risk of syncope) and who have adequately
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Table 3 Pharmacological Treatment of Dysautonomias
Orthostatic intolerance—orthostatic hypotension
 Pyridostigmine, 15–60 mg TID or SR 180 mg daily
 Midodrine 2.5–15 mg TID
 Fludrocortisone 0.1–0.2 mg daily or every other day
 DDAVP (Desmopressin) 0.2–0.4 mg daily at bedtime
 Erythropoietin 2000–10,000 units subcutaneously, weekly,
titrated for hematocrit of 50%
Orthostatic intolerance—orthostatic tachycardia
 Pyridostigmine, 15–60 mg TID or SR 180 mg daily
 b blocker (metoprolol, nadolol, propranolol)
 Midodrine 2.5–15 mg TID
 Fludrocortisone 0.1–0.2 mg daily or every other day
 Selective serotonin reuptake inhibitors (SSRIs)
 Erythropoietin 2000–10,000 units subcutaneously,
weekly, titrated to hematocrit of 50%
 Phenobarbital 15–60 mg qhs
Autoimmune autonomic neuropathy
 Plasmapheresis
 Intravenous immunoglobulin, repeated courses if necessary
 Oral prednisone or other immunosuppressants for
chronic recurrence
Sudomotor abnormalities
 Hypo/anhidrosis
o Intravenous methylprednisolone or oral prednisone if skin
biopsy demonstrates inflammatory response
associated with sweat glands
 Hyperhidrosis
o Botulinum toxin A subcutaneous injections, if localized to
palmar or axillary regions
o Oral anticholinergic agents, including amitriptyline
10–50 mg at bedtime, glycopyrrolate 1–2 mg TID orally or
0.5–4% compounded cream TID, scopolamine patch;
hyoscyamine 0.125–0.25 mg every 4 hours; belladonna
tincture
TID, three times a day; SR, sustained release; qhs, at bedtime.
 EVALUATION AND MANAGEMENT OF AUTONOMIC NERVOUS SYSTEM DISORDERS/KLEIN
implemented nonpharmacological measures. For patients
with orthostatic hypotension, there are two U.S. Food
and Drug Administration (FDA)-approved medications
available: fludrocortisone, a synthetic mineralocorticoid,
and midodrine, which is an a-adrenergic receptor ago-
nist.9,14,33,35
Fludrocortisone works to increase salt and thereby
water retention, thus increasing plasma volume. It is
dosed once or twice daily and, due to its long half-life,
may also be dosed on alternate days. Common side
effects include hypokalemia, peripheral edema, and in-
creasing intraocular pressure; therefore, it should be used
with caution in patients with congestive heart failure or
glaucoma.33 It may also worsen supine hypertension in
patients with a combination of supine hypertension and
orthostatic hypotension as part of their dysautonomia.
Fludrocortisone is not a first-line agent and should be
reserved for patients who are unable to maintain adequate
daily salt and fluid intake on their own, or for patients
with refractory orthostatic hypotension on maximal
therapy.12 The therapeutic dosing range is narrow, with
effective doses being between 0.1 and 0.2 mg daily.12
Midodrine is a peripherally acting a-adrenergic
receptor agonist that has a short duration of action, only
4 hours, and is beneficial in patients who can be educated
on how the medication affects their blood pressure and
when to use it properly to manage their symptoms.
Midodrine can be useful in patients with either ortho-
static hypotension or tachycardia. It is typically used at
much lower doses in patients with postural orthostatic
tachycardia, as it has some action on veins and can reduce
venous pooling in the lower extremities in these patients,
thereby improving their orthostatic symptoms. Side
effects of the medication are due to its mechanism of
action and include scalp paresthesias and ‘‘goose bumps’’
due to piloerection at the skin surface, supine hyper-
tension, and urinary retention.33,35 Patients should be
advised not to take the medication within 4 hours of
lying supine, as it may lead to supine hypertension.
Typically this medication is given in higher doses in
the morning, when patients with orthostatic hypoten-
sion commonly have more severe symptoms, with lower
doses in the afternoon, when orthostatic hypotension is
usually less severe, and no doses given within 4 hours of
the patient’s bedtime.12,33 Generally, patients may have
some control of their doses so that on days when they
are more symptomatic and their orthostatic blood pres-
sure drop is more severe, they may take a higher dose of
the medication. For patients with severe orthostatic
hypotension, taking a dose 30 to 45 minutes before
they attempt to get out of bed in the morning can be
very helpful, although they must be sure to get up by that
time frame or risk worsening supine hypertension once
the medication takes effect.33 Typically, doses of this
medication range from 2.5 to 15 mg up to three times a
day, with the average dose being 5 to 10 mg three times a
201
day. For the initial dose of the medication, because of the
risk of denervation hypersensitivity of the peripheral
adrenoreceptors, the patient should take a dose of
2.5 mg while being medically supervised with the patient’s
blood pressure recorded 2 hours after taking the dose.
Pyridostigmine is a medication that has not been
FDA-approved for treatment of orthostatic intolerance,
but has recently been found to be useful in patients not
only with orthostatic hypotension but also patients with
orthostatic tachycardia.36–38 Pyridostigmine (Mestinon)
is an acetylcholinesterase inhibitor that is thought
to benefit patients with orthostatic hypotension by in-
creasing acetylcholine neurotransmission at peripheral
autonomic ganglia, thereby increasing peripheral vaso-
constriction via sympathetic nerve fiber transmission.
Patients with orthostatic tachycardia benefit from the
drug’s effect of increasing vagal cardiac input.36–39 Not
only is the medication well-tolerated by most patients,39
but it also does not worsen supine hypertension.36–38 Its
duration of action is 4 hours, similar to midodrine, so
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that patients can take up to three doses during the day to
help to alleviate symptoms occurring when they are
upright. The most common side effects are increased
salivation, sweating, and increased gastrointestinal mo-
tility,37,39 all of which are usually beneficial in patients
with dysautonomia.39,40 Rarely patients may experience
muscle fasciculations, which are benign and are due to
increased neuromuscular junction transmission. The
usual dose of the medication is 60 mg up to three times
a day, although I usually start patients at a lower dose,
such as 15 mg three times a day, titrating to the target
dose as needed.
Additional medications that have been used in
patients with orthostatic hypotension include desmo-
pressin, or DDAVP, which can be administered at night
to reduce nocturnal diuresis and, subsequently, ortho-
static hypotension in selected patients by its antidiuretic
hormonal effect.28,33,41 However, serum sodium levels
and osmolarity must be closely monitored when using
this therapy.33 Erythropoietin subcutaneous injections,
given weekly, have also been used successfully and are
thought to improve orthostatic intolerance not only by
increasing blood volume by increasing red blood cell
counts, but also by a direct vasoactive effect on peripheral
vasculature.9,10,16,28,42
For patients with orthostatic hypotension and
supine hypertension, striking a balance between these
two states is particularly challenging to the clinician and
does require vigilance on the part of the patients and
their caregivers. Obviously, during the day if the patient
has an elevated blood pressure while seated or reclining,
then sitting or standing up will bring the blood pressure
down again. However, if the blood pressure drops too
much and/or the patient becomes symptomatic, then use
of medications to increase the patient’s blood pressure is
required. In contrast, at night, the patient is in a reclined
202 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008
position (head of bed elevated 4 inches) but may have
unacceptably high blood pressure even in this position.
These patients should record their blood pressure in
the resting position in bed before they go to sleep or
in the morning before they get out of bed; if their
blood pressure is consistently or frequently greater than
180/100 mm Hg, then an antihypertensive medication,
ideally one with a short duration of action, might be
taken at bedtime so that their orthostatic hypotension is
not worsened the following morning. The reason to treat
supine hypertension is to reduce adverse long-term
effects on the brain and heart caused by 6 to 8 hours of
hypertension daily. Commonly used medications include
oral hydralazine (10 to 50 mg), clonidine (0.1 mg), and
nifedipine (10 to 30 mg) given at bedtime if needed,
depending on the patient’s blood pressure.43,44 Nitro-
glycerin paste (1/2 to 1 inch) may also be used for some
patients.14,43,44 None of these medications are ideal,43,44
and it is very important to counsel patients that if they
use an antihypertensive agent at night, they cannot get
up out of bed to urinate due to the increased risk of
worsened orthostatic hypotension secondary to the
effects of the antihypertensive medication. A urinal at
the bedside for male patients and a bedside commode or
a bedpan for female patients are the alternatives.
For treatment of orthostatic tachycardia, use of
b-blocker medications in low dosages—to avoid an
excessive drop in blood pressure and worsening exercise
intolerance—is generally effective,10,11 particularly for
patients with a more hyperadrenergic state. Many differ-
ent b blockers can be used with success, but metoprolol is
recommended as it can be administered in either a short-
or immediate-acting form or a long-acting form, and
both tablet formulations can be divided. Start with a low
dosage, such as 12.5 mg once or twice a day, and titrate
as tolerated to a target dose of 50 mg of the long-acting
formulation once or twice a day. Patients should be
monitored closely for orthostatic changes in blood pres-
sure, particularly if their orthostatic intolerance symp-
toms actually worsen. Caution should be used in patients
with a history of asthma. If the patient has a history
of severe asthma requiring hospitalization, this type of
medication is relatively contraindicated. Low doses of
midodrine may also be helpful in selected patients,10,11
with administration of the medication usually being
most effective earlier in the day. Additional choices
include low doses of selective serotonin reuptake inhib-
itors (SSRIs),9 fludrocortisone10 and phenobarbital.11
Pyridostigmine has been recently shown to be of benefit
in this population of patients, not only to reduce the
patient’s orthostatic tachycardia, but also to improve
symptoms.10,36,45
For patients with autoimmune autonomic neu-
ropathy, who commonly have orthostatic hypotension
as part of their symptomatology, use of the above
therapies is of benefit for symptomatic treatment. In
addition, there have been case reports of improvement
in patients with immunomodulatory therapy, including
plasmapheresis,46 infusion of intravenous immunoglo-
bulin (IVIg),47–51 and use of oral immunosuppressive
medications for long-term therapy.49 Interestingly, this
approach to therapy has been shown to be of benefit not
only in the acute setting, but also in patients who have
had symptoms for months or even years.46,49 A similar
approach may also be considered in patients with
autonomic neuropathy associated with Sjögren’s syn-
drome, as presumably the neuropathic features of this
condition are on an autoimmune basis and may respond
to immunomodulatory therapy. Clearly, additional re-
search into the benefit of this type of therapy in this
population of patients with dysautonomia is needed
to determine the best approach and to determine for
which patients immunomodulatory therapy may be
most successful.
Other symptoms of dysautonomia that are ame-
nable to treatment include sudomotor and secretomotor
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abnormalities. Patients with hypohidrosis should be
strongly cautioned about the risks of heat intolerance
and the need to avoid hot environmental temperatures.
Patients with acute idiopathic anhidrosis or hypohidrosis,
which may be a form of limited autonomic neuropathy,
should have a skin biopsy performed within the affected
region to be examined pathologically for lymphocytic
infiltration around sweat glands and their ducts. If
positive, then consideration should be given to possible
short-term treatment with oral prednisone or intravenous
methylprednisolone, based on case reports that this may
be effective.52 Hyperhidrosis, if localized, may respond to
treatment with subcutaneous injections of botulinum
toxin to denervate sweat glands.16 Patients with more
generalized hyperhidrosis may benefit from oral medica-
tions that have a strong anticholinergic side effect, such as
amitriptyline or glycopyrrolate. Topical treatments for
excessive sweating include aluminum chloride (the active
ingredient in antiperspirants) and topical compounded
cream formulations of glycopyrrolate. Treatment for
secretomotor abnormalities includes punctal plugging
for xerophthalmia and use of artificial tears and cyclo-
sporine eye drops locally, and administration of fish oil
supplements systemically. Chronic, severe dry eye has a
risk of development of corneal abnormalities and should
be treated aggressively. Xerostomia may be treated with
over-the-counter agents to control symptoms of dry
mouth; pyridostigmine may also increase salivation as a
side effect, as mentioned previously.
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