Contemporary Reviews in Cardiovascular Medicine

Neurogenic Orthostatic Hypotension

A Pathophysiological Approach
David S. Goldstein, MD, PhD; Yehonatan Sharabi, MD

O rthostatic hypotension (OH) is defined as a persistent,

consistent, orthostatic fall in systolic blood pressure of
ⱖ20 mm Hg or diastolic pressure of ⱖ10 mm Hg by 3
minutes of standing up.1 Acute, unexpected, episodic falls in
blood pressure while standing, as in neurocardiogenic syn-
cope, do not satisfy criteria for OH.
Medical records for ⬇0.4% of all hospitalizations in the
United States include OH as a diagnosis, and of these ⬇17%
have OH as the primary diagnosis.2 OH is associated with
increased mortality in middle-aged adults3 and occurs espe-
cially commonly in the elderly, with a prevalence in the
United States of ⬇12%.4 The rate of hospitalization for
nonacute OH increases exponentially with age.2 Therefore, as
the US population ages, the prevalence of OH and the
incidence of OH-related morbidity are likely to increase.
OH can be an asymptomatic sign or manifest as symptoms
that range from lightheadedness to loss of consciousness. In
our experience, patients with OH do not typically present
with recurrent syncope because they come to recognize and
respond to premonitory symptoms such as generalized weak-
Downloaded from http://ahajournals.org by on April 5, 2022
identifiable causes of OH. Probably the most common are
medications, hypovolemia, dehydration, cardiac pump fail-
ure, and diseases—mostly irreversible—that are associated
with autonomic neuropathies (eg, diabetes mellitus, chronic
renal failure, and amyloidosis).
Even after extensive evaluation, approximately one third of
patients with persistent, consistent OH have no identified
cause.6 For these, the term idiopathic OH has been used. In
virtually all such cases, OH is associated with an abnormality
of reflexive regulation of the circulation by the sympathetic
noradrenergic system—that is, idiopathic OH is neurogenic.
Failure of the sympathetic nervous system always results in a
failure to tolerate upright posture because of OH. Conversely,
OH is a cardinal manifestation of sympathetic failure. Indeed,
absence of OH excludes generalized sympathetic failure.
Therefore, the third step is to confirm that OH is neurogenic—
neurogenic OH (NOH).
Clinical Laboratory Tests to Identify NOH
A variety of means are available to identify failure of

ness, dizziness, fading vision, or lightheadedness that are

relieved by lying down. Instead, OH patients often present
with orthostatic intolerance and recurrent falls, an important
risk factor for hip fracture and head trauma.
Moreover, OH often occurs concurrently with supine
hypertension, which can be severe.5 The combination of OH
and supine hypertension poses a challenging clinical dilemma
because the clinician must balance the risk of chronic high
blood pressure versus the immediate risk of falls and conse-
quent morbid events.
Causes of OH
Many causes of OH have been identified. The listing in Table
1 stratifies these in terms of drugs, secondary nonneurogenic
causes, secondary neurogenic causes, and primary neurogenic
causes. Accordingly, the clinical approach to a patient with
OH (Figure 1) is, first, to determine that the patient has a
persistent, consistent orthostatic fall in blood pressure. Com-
mon reversible causes of orthostatic decreases in pressure,
such as gastrointestinal hemorrhage and nitroglycerin treat-
ment, should be excluded. Second, one should look for
reflexive sympathetically mediated cardiovascular responses
(sympathetic neurocirculatory failure) as the cause of OH in
individual patients. Different medical centers have different
tests available.
Such failure produces characteristic abnormalities of beat-
to-beat blood pressure associated with the Valsalva maneuver
(Figure 2). In patients with NOH, systolic blood pressure
decreases progressively during the maneuver; after release of
the maneuver, systolic pressure increases slowly toward the
baseline value, and no pressure overshoot occurs.7,8 Beat-to-
beat blood pressure can now be measured noninvasively with
any of a variety of commercially available devices.
Measurements of forearm or total peripheral resistance
responses provide other indirect physiological measures. In
sympathetic neurocirculatory failure, these resistances fail to
increase during orthostasis or other stimuli that decrease
venous return to the heart.9
A neurochemical index to detect NOH is the plasma
norepinephrine response to orthostasis. Normally, plasma
norepinephrine levels approximately double within 5 minutes

From the Clinical Neurocardiology Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological
Disorders and Stroke, National Institutes of Health, Bethesda, Md (D.S.G., Y.S.); and Hypertension Unit, Sheba Medical Center, Tel-HaShomer, and
Sackler Faculty of Medicine, Tel Aviv, Israel (Y.S.).
Correspondence to Dr David S. Goldstein, Bldg 10, Room 6N252, 10 Center Dr, MSC-1620, Bethesda, Md 20892-1620. E-mail
goldsteind@ninds.nih.gov
(Circulation. 2009;119:139-146.)
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.108.805887

139
 140 Circulation January 6/13, 2009

Table 1. Some Causes of Orthostatic Hypotension Table 1. Continued

Drugs Brain stem lesions/syringobulbia
Vasodilators Cerebrovascular accidents
Nitrates Multiple sclerosis
Adrenoceptor blockers (especially ␣-adrenoceptor blockers) Primary neurogenic causes
Dopamine receptor agonists Sympathetic noradrenergic denervation
Sympatholytics PD
Drugs for erectile dysfunction (eg, sildenafil) PAF
Chemotherapeutic agents (eg, vincristine) Lewy body dementia
Phenothiazines Familial dysautonomia (incomplete development of sympathetic
Diuretics noradrenergic innervation)

Monoamine oxidase inhibitors Intact sympathetic noradrenergic innervation

Narcotics/tranquilizers/sedatives MSA, in most cases

Tricyclic antidepressants Dopamine ␤-hydroxylase deficiency (intact innervation but

norepinephrine deficiency)
Secondary nonneurogenic causes
Autoimmune ganglionopathy (rare; probably intact sympathetic
Hypovolemia noradrenergic innervation)
Dehydration
Chronic blood loss (eg, colon cancer)
Adrenal insufficiency
of standing. In NOH, plasma norepinephrine usually in-
Diabetes insipidus
creases by ⬍60% or by ⬍⬇1 nmol/L (⬇150 pg/mL).10
Diarrhea Patients with NOH typically also have baroreflex-
Salt-losing nephropathy cardiovagal failure. This explains why heart rate responses to
Chronic vomiting the Valsalva maneuver or deep breathing usually are subnor-
Cardiac pump failure mal in NOH (Figure 2). It should be noted, however, that these
Bradycardia or heart block responses are mediated mainly by the parasympathetic cholin-
Aortic stenosis ergic system, not the sympathetic noradrenergic system.
Downloaded from http://ahajournals.org by on April 5, 2022

Tachyarrhythmia NOH is a major manifestation of several diseases that are

Myocardial infarction associated with chronic autonomic failure. Approximately
Myocarditis/pericarditis
40% of patients with Parkinson disease (PD) have OH,11 and
according to our experience, in all such patients the OH is
Venous pooling
neurogenic. Multiple system atrophy (MSA), pure autonomic
Prolonged recumbency or standing
failure (PAF), autoimmune autonomic ganglionopathy
Postprandial dilation of splanchnic vessel beds
(AAG 12 ), familial dysautonomia, and dopamine- ␤ -
Fever hydroxylase deficiency also cause NOH.
Heat exposure Studying diseases in which the sympathetic nervous sys-
Severe varicosities tem fails can shed light on the pathophysiology of NOH and
Secondary neurogenic causes allow better understanding of this clinically challenging
Peripheral neuropathies condition. Appraisal of published data by our group and
Diabetes mellitus others has induced us to view primary NOH syndromes with
Alcoholic polyneuropathy a somewhat new perspective that puts more emphasis on the
Amyloidosis pathophysiological findings than on the specific diagnosis,
Guillain-Barré syndrome
which can require postmortem pathologic confirmation and
therefore may not ever be established with surety in individual
HIV/AIDS
patients. The following section focuses on these data and the
Paraneoplastic
insights that can be drawn from them about NOH in general.
Renal failure/posthemodialysis
Vitamin B12 or folate deficiency
Spinal cord problems Stratification of NOH in Terms of
Spinal cord injury Sympathetic Noradrenergic Denervation
Syringomyelia
Analysis of our data, summarized below, indicates that NOH
patients can be classified pathophysiologically in terms of the
Transverse myelitis
presence or absence of sympathetic noradrenergic denerva-
Tumors
tion. Moreover, this categorization applies to NOH with or
Tabes dorsalis
without central neurodegeneration and regardless of whether
(Continued) the neurological clinical diagnosis is definite or equivocal.
 Goldstein and Sharabi Neurogenic Orthostatic Hypotension 141

Figure 1. Algorithm for clinical evaluation of OH. The algorithm asks if OH is persistent and consistent; if it is neurogenic; and if it is
associated with postganglionic, sympathetic, noradrenergic denervation. BP indicates blood pressure; CNS, central nervous system;
LBD, Lewy body dementia; and NE, norepinephrine.

Neurochemical Tests to Identify Sympathetic normal plasma norepinephrine levels in PD⫹NOH does not
Noradrenergic Denervation necessarily indicate normal overall sympathetic noradrener-
In PAF, MSA, and PD, NOH is associated with attenuated gic innervation. Plasma levels of dihydroxyphenylglycol
Downloaded from http://ahajournals.org by on April 5, 2022

orthostatic increments in plasma norepinephrine levels. The
conditions differ, however, in terms of plasma norepinephrine
levels during supine rest.10,13,14 In MSA and PD⫹NOH,
plasma norepinephrine is generally normal, whereas in PAF,
plasma norepinephrine is generally low. The finding of
(DHPG) provide a better measure of noradrenergic innerva-
tion,15 and plasma DHPG is subnormal in both PD⫹NOH and
PAF.13
One can assess the density of noradrenergic innervation of
skeletal muscle by measuring concentrations of catechols in

Valsalva
140
Valsalva
120 100
Heart Rate
100 80
bpm
80 60
60 40

I II III IV I II III IV
180
180 160
160 140
140 120
Blood Pressure
120 100
mm Hg
100 80
80 60
60 40

Control Neurogenic
Orthostatic Hypotension

Figure 2. Heart rate and blood pressure responses in the 4 phases of the Valsalva maneuver in (left) a control subject and (right) a
patient with NOH. NOH is characterized by a progressive decline in blood pressure in phase II (arrow), slow recovery of blood pressure
in phases III and IV (gray polygon), and absence of overshoot in pressure above baseline in phase IV (thick black line).
 142 Circulation January 6/13, 2009
MSA PD+NOH PD+NOH
6-[18F]FDA 6-[18F]FDA [13 N]NH3
Figure 3. Cardiac positron emission tomographic scans after
intravenous injection of 6-[18F]fluorodopamine (6-[18F]FDA) or the
perfusion imaging agent [13N]-ammonia ([13N]NH3) in a patient
with MSA and a patient with PD⫹NOH. Note absence of detect-
able 6-[18F]fluorodopamine– derived radioactivity in the left ven-
tricular myocardium, despite normal perfusion as indicated by
[13N]-ammonia– derived radioactivity, in the patient with
PD⫹NOH.
microdialysate. Microdialysate DHPG concentrations are
similarly low in PD⫹NOH and PAF compared with MSA
and control subjects.16 These results point to generalized
peripheral noradrenergic denervation in PD⫹NOH and PAF.
Sympathetic noradrenergic denervation is associated not
only with decreased norepinephrine turnover, as indicated by
low plasma DHPG levels, but also with decreased neuronal
uptake of norepinephrine from the extracellular fluid, via the
uptake-1 process mediated by the cell membrane norepineph-
rine transporter. Patients with PAF have decreased uptake-1
activity in the body as a whole, whereas MSA patients have
normal uptake-1 activity.17,18 Collectively, the neurochemical
Downloaded from http://ahajournals.org by on April 5, 2022
profile identifies 2 groups of patients: those with postgangli-
onic noradrenergic denervation, as in PD⫹NOH and PAF,
and those with intact postganglionic innervation, as in MSA.
Neuroimaging Tests to Identify Sympathetic
Noradrenergic Denervation
The aforementioned suggestion of grouping by pathophysi-
ology is supported by many reports in which neuroimaging
methods have been used. The introduction of cardiac sympa-
thetic neuroimaging in the mid-1990s added a new dimension
to assessment of the sympathetic nervous system in NOH.
6-[18F]Fluorodopamine positron emission tomographic scan-
ning and [123I]metaiodobenzylguanidine ([123I]MIBG) scintig-
raphy (superseded by single photon emission tomographic
scanning) revealed cardiac noradrenergic denervation in vivo
for the first time in patients with NOH.19,20 Over the past
decade, ⬎50 studies in which these and analogous radioactive
drugs were used21,22 have reported results of cardiac sympa-
thetic neuroimaging in PAF, PD, and MSA that in general
have confirmed cardiac noradrenergic denervation in PAF
and PD⫹NOH and normal innervation in most patients with
MSA (Figures 3 and 4).23
Important confirmation of the validity of cardiac sympa-
thetic neuroimaging to identify cardiac noradrenergic dener-
vation in NOH syndromes has come from neurochemical
studies demonstrating decreased cardiac spillovers of norepi-
nephrine and DHPG18 and from several postmortem studies
showing profound loss of tyrosine hydroxylase immunoreac-
tivity in all patients who during life had neuroimaging
evidence of cardiac sympathetic denervation.24,25 Patients
20000
RADIOACTIVITY (nCi-kg/cc-mCi)
15000
10000
5000
0
NOH CONTROL
GROUP
Figure 4. Individual values for interventricular septal myocardial
concentrations of 6-[18F]fluorodopamine– derived radioactivity in
patients with NOH or control subjects. Dashed line shows 2
SDs below the normal mean. Note bimodal distribution of
6-[18F]fluorodopamine– derived radioactivity in NOH patients,
with approximately half having low radioactivity and half normal
radioactivity.
with PD from parkin gene mutation, which is not associated
with NOH and is thought not to be a Lewy body disease, have
been found to have normal cardiac [123I]MIBG-derived
radioactivity.26
Although patients with PAF have neuroimaging evidence
of cardiac sympathetic denervation, a few have approxi-
mately normal innervation. This subgroup includes at least
some who have a circulating antibody to the nicotinic
cholinergic receptor, resulting in a diagnosis of AAG.27 All 3
patients we have tested with AAG and high titers of antibod-
ies to the neuronal nicotinic receptor have had normal cardiac
6-[18F]fluorodopamine– derived radioactivity (D.S.G., unpub-
lished data, 2008), and another patient evaluated by
[123I]MIBG scanning also had normal results.28 Moreover,
animal models of AAG have intact postganglionic neurons.29
Even in patients with NOH and evidence of central
neurodegeneration in whom the neurological diagnosis is
equivocal, cardiac sympathetic neuroimaging clearly sepa-
rates a group with cardiac noradrenergic denervation from a
group with normal innervation, in a manner closely resem-
bling the distributions among patients with a definite diagno-
sis (Figure 5).
Neuropharmacological Tests to Identify
Sympathetic Noradrenergic Denervation
Several neuropharmacological tests have been used to iden-
tify sympathetic noradrenergic denervation in primary NOH
syndromes. In general, patients with sympathetic noradrener-
gic denervation would be expected to have attenuated neuro-
chemical or hemodynamic responses to drugs that work by
releasing norepinephrine from sympathetic nerves and nor-
mal or augmented responses to drugs that stimulate adreno-
ceptors directly.
Yohimbine
Yohimbine is an ␣2-adrenoceptor blocker. This drug increases
release of norepinephrine from sympathetic nerves via in-
 Goldstein and Sharabi Neurogenic Orthostatic Hypotension 143

20000 Table 2. Correlation Coefficients for Relationships Between

Cardiac 6-关18F兴Fluorodopamine–Derived Radioactivity and
RADIOACTIVITY (nCi-kg/cc-mCi)

Neurochemical and Neuropharmacological Indices of Overall

15000
Noradrenergic Innervation: Supine Plasma DHPG, DHPG in
Microdialysate of Skeletal Muscle, Change in Plasma
Norepinephrine Level in Response to Yohimbine and
Isoproterenol, and Change in Systolic Blood Pressure in
10000 Response to Yohimbine
All Subjects Patients With NOH
5000 Variable r n P r n P
DHPG plasma 0.22 158 0.006 0.23 105 0.02
DHPG microdialysate 0.48 33 0.005 0.56 24 0.004
0
DEFINITE EQUIVOCAL ⌬Norepinephrine/ yohimbine 0.27 60 0.06 0.28 52 0.05

GROUP
⌬Norepinephrine/ 0.40 27 0.04 0.50 22 0.02
isoproterenol
Figure 5. Individual values for interventricular septal myocardial
concentrations of 6-[18F]fluorodopamine– derived radioactivity in ⌬BP/yohimbine 0.37 43 0.02 0.39 39 0.02
patients with NOH and central neurodegeneration who had BP indicates blood pressure.
either a definite or an equivocal diagnosis. Note bimodal distri-
butions of radioactivity regardless of surety of diagnosis.
fore, in detecting noradrenergic denervation by the intrave-
creasing sympathetic neuronal outflows and inhibiting ␣2- nous tyramine infusion test, neurochemical responses are
adrenoceptors on sympathetic nerves.30 Yohimbine infusion more sensitive than systemic physiological responses.
evokes large increases in both blood pressure and plasma
norepinephrine levels in patients with intact noradrenergic Isoproterenol
Infusion of isoproterenol, a nonselective ␤-adrenoceptor ag-
innervation, in contrast to attenuated increases in patients
onist, evokes release of norepinephrine from sympathetic
with noradrenergic denervation.31–33
nerves via reflexive increases in sympathetic nerve traffic in
Trimethaphan response to systemic vasodilation and stimulation of ␤2-
Trimethaphan decreases sympathetic neuronal outflows by adrenoceptors on sympathetic nerves.40,41 The plasma norepi-
Downloaded from http://ahajournals.org by on April 5, 2022

blocking nicotinic receptors mediating ganglionic neurotrans-
mission. Blood pressure and plasma norepinephrine levels
therefore decrease. The decrements are relatively large in
patients with intact noradrenergic innervation.31,33
Tyramine
Sympathetic nerves take up tyramine via the cell membrane
norepinephrine transporter, and the vesicles in sympathetic
nerves take up tyramine via the vesicular monoamine trans-
porter, displacing norepinephrine. The norepinephrine dis-
placed into the cytoplasm undergoes deamination catalyzed
by monoamine oxidase to form DHPG, which readily crosses
the cell membrane and enters the plasma. Plasma DHPG
responses to tyramine therefore provide a measure of
uptake-1 activity and of norepinephrine turnover in sympa-
thetic nerves.34 Plasma DHPG responses to tyramine are
attenuated in patients with noradrenergic denervation.35
Some of the norepinephrine displaced by tyramine enters
the extracellular fluid by a nonexocytotic process and binds to
␣-adrenoceptors, thereby increasing blood pressure.36,37 The
absence of vasoconstriction responses to tyramine has been
associated with absence of catecholamine-specific fluores-
cence in skeletal muscle,38 supporting the validity of the
tyramine infusion test as a means to detect sympathetic
denervation. Pressor responses to tyramine, however, can be
normal in patients with partial noradrenergic denervation,
possibly due to effects of concurrent, counterbalancing
baroreflex failure and denervation supersensitivity. PAF pa-
tients have a shift to the left of the curve relating pressor
responses to increments in plasma norepinephrine.39 There-
nephrine response to isoproterenol therefore provides a mea-
sure of the ability to release norepinephrine by exocytosis
from sympathetic nerves. Patients with noradrenergic dener-
vation have attenuated plasma norepinephrine responses for
given isoproterenol plasma levels.16
Isoproterenol infusion increases heart rate via direct stim-
ulation of ␤-adrenoceptors on myocardial cells. For a given
plasma isoproterenol level, patients with cardiac noradrener-
gic denervation detected by sympathetic neuroimaging have
an augmented tachycardia response, consistent with upregu-
lation of cardiac ␤-adrenoceptors.35
Agreement Among Modalities to Identify
Sympathetic Noradrenergic Denervation
Individual values for concentrations of 6-[18F]fluorodopam-
ine– derived radioactivity in the interventricular septal myo-
cardium are correlated positively with a variety of neuro-
chemical and neuropharmacological indices of noradrenergic
innervation, whether data from all subjects or from patients
with NOH (Table 2) specifically are considered. Positive
correlations between DHPG levels in plasma or skeletal
muscle microdialysate and cardiac 6-[18F]fluorodopamine–
derived radioactivity indicate that loss of cardiac noradrener-
gic nerves is associated with more generalized noradrenergic
denervation. Smaller norepinephrine or DHPG responses to
tyramine, yohimbine, and isoproterenol in subjects with low
cardiac 6-[18F]fluorodopamine– derived radioactivity indicate
decreased turnover of stored norepinephrine in sympathetic
nerves in patients with cardiac noradrenergic denervation.
 144 Circulation January 6/13, 2009
Isoproterenol levels for 25-bpm increments in heart rate
correlated positively with cardiac 6-[18F]fluorodopamine–
derived radioactivity (Table 2). Analogously, a positive
relationship was found between the increment in cardiac
contractility (reflected by the acceleration index, an imped-
ance cardiographic measure of cardiac contractility)42 and
cardiac 6-[18F]fluorodopamine– derived radioactivity. These
findings are consistent with upregulation of cardiac
␤-adrenoceptors. The positive relationship between the ratio
of ⌬systolic pressure to ⌬plasma norepinephrine and cardiac
6-[18F]fluorodopamine– derived radioactivity is consistent
with upregulation of ␣-adrenoceptors on vascular smooth
muscle cells.
In general, neurochemical responses to the test drugs
correlate more closely with cardiac 6-[18F]fluorodopamine–
derived radioactivity than with hemodynamic responses. An
explanation for these differences is that the physiologically
dependent measures are more indirect, influenced by adreno-
ceptor upregulation and individual differences in baroreflex
function.
The ratio of cerebrospinal fluid to plasma norepinephrine,
a neurochemical index of central norepinephrine deficiency,
is approximately normal in PD⫹NOH, whereas MSA pa-
tients have low ratios of cerebrospinal fluid to plasma
compared with control subjects.43 Individual values for car-
diac 6-[18F]fluorodopamine– derived radioactivity are corre-
lated negatively with this index of central norepinephrine
deficiency (r⫽⫺0.37, P⫽0.0003). Therefore, the central
noradrenergic abnormalities in primary NOH seem to be a
Downloaded from http://ahajournals.org by on April 5, 2022
mirror image of those in the periphery. PD⫹NOH seems to
be associated with more severe peripheral noradrenergic
deficiency, whereas MSA seems to be associated with more
severe central noradrenergic deficiency.
Pathophysiological Classification of NOH
The clinical importance of NOH warrants special and sepa-
rate consideration by medical practitioners. This analysis has
identified 2 distinct groups of patients with primary NOH,
regardless of clinical diagnosis. Patients with neuroimaging
evidence of cardiac noradrenergic denervation also have
evidence of loss of noradrenergic innervation in the body as
a whole, corresponding abnormalities in neurochemical re-
sponses to test drugs, and evidence of compensatory upregu-
lation of adrenoceptors. Patients with central neurodegenera-
tion and neuroimaging evidence of intact cardiac
noradrenergic innervation have neurochemical abnormalities
suggesting central norepinephrine deficiency. Collectively,
the neurochemical, neuroimaging, and neuropharmacological
results complement each other.
Considering the many positive intercorrelations across a
variety of assessment modalities, we propose a classification
for patients with NOH based on evidence of peripheral
noradrenergic denervation. An algorithm for clinical evalua-
tion of OH therefore emphasizes identifying NOH and then
peripheral noradrenergic deficiency (Figure 1).
Diagnostic and Therapeutic Implications
This classification schema has implications for the clinical
management of patients with NOH in terms of both diagnosis
Table 3. Some Causes of Primary NOH and Diagnostic
Challenges
PD
OH can precede the movement disorder, leading to diagnosis of PAF
Difficult to distinguish clinically from the parkinsonian form of MSA
Levodopa/carbidopa and dopamine receptor agonists exert vasodilator
actions
OH may not be sought formally by neurologists
Lewy body dementia
Lewy body dementia can be difficult to distinguish clinically from
PD⫹NOH; the conditions may overlap
Alzheimer disease is usually not associated with NOH
MSA
Uncommon disease
The parkinsonian form can be difficult to distinguish clinically from
PD⫹NOH
Some MSA patients have improved symptoms with levodopa/carbidopa
PAF
Rare disease
PAF with subtle, nondiagnostic parkinsonism can be early PD⫹NOH
Can be distinguished from AAG by normal nAChR antibody titers
AAG
Recently described, rare disease
Prominent evidence of cholinergic failure (constipation, sicca syndrome,
urinary retention, anhidrosis) can be clues
High titer of antibodies to the neuronal nicotinic receptor (nAChR)
Familial dysautonomia
Rare disease in individuals of Ashkenazic extraction
Diagnosed in childhood
Dopamine-␤-hydroxylase (DBH) deficiency
Rare disease
Normal sweating and orthostatic tachycardia can be clues
Remarkable improvement with L -dihydroxyphenylserine treatment
and predicted responses to treatment. Table 3 lists some
causes of NOH and diagnostic challenges.
In patients with NOH who have no clinical evidence of
central neurodegeneration, the finding of normal peripheral
noradrenergic innervation casts doubt on the diagnosis of
PAF. Testing for a circulating antibody to the neuronal
nicotinic receptor (nAChR) is appropriate in this situation
because of the potential for improvement of AAG by total
plasma exchange or immunosuppressive therapy.12,44 In pa-
tients with NOH and central neurodegeneration, the finding
of normal cardiac noradrenergic innervation seems to exclude
PD⫹NOH and favors a diagnosis of MSA.
Once the patient has been placed into 1 of the 2 categories,
therapy may be tailored according to the pathophysiological
classification. Patients with NOH and intact peripheral nor-
adrenergic innervation might benefit from oral yohimbine.
One must exercise caution because of the likelihood of oral
yohimbine worsening supine hypertension.45 An indirectly
acting sympathomimetic amine such as tyramine given with a
monoamine oxidase inhibitor might also be tried,46 but with
the same precaution.
 Goldstein and Sharabi
Patients with NOH have baroreflex failure and therefore
have exaggerated responses to vasoactive drugs. For the same
severity of baroreflex failure, patients with peripheral norad-
renergic denervation have larger responses to drugs that
increase occupation of adrenoceptors and smaller responses
to drugs that work by releasing norepinephrine. In NOH with
peripheral noradrenergic denervation, when evidence for
adrenoceptor upregulation is obtained, a directly acting adre-
noceptor agonist would seem appropriate. Midrodrine is the
only orally acting ␣-adrenoceptor agonist approved for mar-
keting in the United States. Norepinephrine precursor treat-
ment with L-threo-3,4-dihydroxyphenylserine might play a
role here in the future47,48 because conversion of L-threo-3,4-
dihydroxyphenylserine to norepinephrine does not require
intact noradrenergic nerves. Patients with noradrenergic de-
nervation would be less likely to respond well to yohimbine
or to an indirectly acting sympathomimetic amine.
Patients with symptomatic OH despite treatment with these
drugs may also be treated with the salt-retaining steroid
fludrocortisone (on a high-salt diet), octreotide, or desmo-
pressin because these drugs have separate mechanisms of
action from those acting directly or indirectly on
adrenoceptors.
Because of supine hypertension in NOH patients,5 drugs
that increase blood pressure should be given only during
active hours. At night, patients should be instructed to sleep
with the head of the bed elevated. Bedtime medications in
patients with supine hypertension might include nitrates or
calcium channels blockers such as nifedipine.49 These agents
Downloaded from http://ahajournals.org by on April 5, 2022
should be used only with great caution during active hours
because of baroreflex-sympathoneural failure attending NOH
of all types; patients would be expected to have large
hypotensive responses to these agents, regardless of
diagnosis.
Conclusions
NOH adversely affects well-being and is associated with
increased morbidity, especially in the elderly. Advances in
the understanding of the pathophysiology of NOH have led us
to propose a classification of NOH based on the occurrence of
peripheral noradrenergic denervation. Categorizing patients
in terms of the presence or absence of peripheral noradren-
ergic denervation can aid diagnosis and rationalize treatment.
Acknowledgments
The authors thank the many individuals who have contributed to the
research summarized in this review, including (in alphabetical order)
Graeme Eisenhofer, PhD; Basil Eldadah, MD, PhD; Courtney
Holmes, CMT; Richard Imrich, MD, PhD; Tereza Jenkins; Irwin J.
Kopin, MD; Shengting Li, MD, PhD; Jeffrey Moak, MD; Sandra
Pechnik, RN; and Ahmed Saleem, MD.
Sources of Funding
The research was supported by the intramural research program of
the National Institutes of Health.
Disclosures
None.
Neurogenic Orthostatic Hypotension 145
References
1. Kaufmann H. Consensus statement on the definition of orthostatic hypo-
tension, pure autonomic failure and multiple system atrophy. Clin Auton
Res. 1996;6:125–126.
2. Shibao C, Grijalva CG, Raj SR, Biaggioni I, Griffin MR. Orthostatic
hypotension-related hospitalizations in the United States. Am J Med.
2007;120:975–980.
3. Rose KM, Eigenbrodt ML, Biga RL, Couper DJ, Light KC, Sharrett
AR, Heiss G. Orthostatic hypotension predicts mortality in
middle-aged adults: the Atherosclerosis Risk In Communities (ARIC)
Study. Circulation. 2006;114:630 – 636.
4. Applegate WB, Davis BR, Black HR, Smith WM, Miller ST, Burlando
AJ. Prevalence of postural hypotension at baseline in the Systolic Hyper-
tension in the Elderly Program (SHEP) cohort. J Am Geriatr Soc. 1991;
39:1057–1064.
5. Goldstein DS, Pechnik S, Holmes C, Eldadah B, Sharabi Y. Association
between supine hypertension and orthostatic hypotension in autonomic
failure. Hypertension. 2003;42:136 –142.
6. Robertson D, Robertson RM. Causes of chronic orthostatic hypotension.
Arch Intern Med. 1994;154:1620 –1624.
7. Goldstein DS, Tack C. Non-invasive detection of sympathetic neurocir-
culatory failure. Clin Auton Res. 2000;10:285–291.
8. Vogel ER, Sandroni P, Low PA. Blood pressure recovery from Valsalva
maneuver in patients with autonomic failure. Neurology. 2005;65:
1533–1537.
9. Bannister R, Ardill L, Fentem P. Defective autonomic control of blood
vessels in idiopathic orthostatic hypotension. Brain. 1967;90:725–746.
10. Ziegler MG, Lake CR, Kopin IJ. The sympathetic-nervous-system defect
in primary orthostatic hypotension. N Engl J Med. 1977;296:293–297.
11. Goldstein DS. Cardiovascular aspects of Parkinson disease. J Neural
Trans. 2006;70:339 –342.
12. Vernino S. Autoimmune and paraneoplastic channelopathies. Neurotherapeutics.
2007;4:305–314.
13. Goldstein DS, Holmes C, Sharabi Y, Brentzel S, Eisenhofer G. Plasma
levels of catechols and metanephrines in neurogenic orthostatic hypo-
tension. Neurology. 2003;60:1327–1332.
14. Goldstein DS, Polinsky RJ, Garty M, Robertson D, Brown RT, Biaggioni
I, Stull R, Kopin IJ. Patterns of plasma levels of catechols in neurogenic
orthostatic hypotension. Ann Neurol. 1989;26:558 –563.
15. Goldstein DS, Eisenhofer G, Kopin IJ. Sources and significance of
plasma levels of catechols and their metabolites in humans. J Pharmacol
Exp Ther. 2003;305:800 – 811.
16. Sharabi Y, Imrich R, Holmes C, Pechnik S, Goldstein DS. Generalized
and neurotransmitter-selective noradrenergic denervation in Parkinson
disease with orthostatic hypotension. Mov Disord. 2008;23:1725–1732.
17. Polinsky RJ, Goldstein DS, Brown RT, Keiser HR, Kopin IJ. Decreased
sympathetic neuronal uptake in idiopathic orthostatic hypotension. Ann
Neurol. 1985;18:48 –53.
18. Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO III.
Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med.
2000;133:338 –347.
19. Goldstein DS, Holmes C, Cannon RO III, Eisenhofer G, Kopin IJ.
Sympathetic cardioneuropathy in dysautonomias. N Engl J Med. 1997;
336:696 –702.
20. Satoh A, Serita T, Tsujihata M. Total defect of metaiodobenzylguanidine
(MIBG) imaging on heart in Parkinson’s disease: assessment of cardiac
sympathetic denervation. Nippon Rinsho. 1997;55:202–206.
21. Berding G, Schrader CH, Peschel T, van den Hoff J, Kolbe H, Meyer GJ,
Dengler R, Knapp WH. [N-Methyl 11C]meta-hydroxyephedrine positron
emission tomography in Parkinson’s disease and multiple system atrophy.
Eur J Nucl Med Mol Imaging. 2003;30:127–131.
22. Raffel DM, Koeppe RA, Little R, Wang CN, Liu S, Junck L, Heumann
M, Gilman S. PET measurement of cardiac and nigrostriatal denervation
in parkinsonian syndromes. J Nucl Med. 2006;47:1769 –1777.
23. Goldstein DS. Cardiac denervation in patients with Parkinson disease.
Cleve Clin J Med. 2007;74(suppl 1):S91–S94.
24. Orimo S, Oka T, Miura H, Tsuchiya K, Mori F, Wakabayashi K, Nagao
T, Yokochi M. Sympathetic cardiac denervation in Parkinson’s disease
and pure autonomic failure but not in multiple system atrophy. J Neurol
Neurosurg Psychiatry. 2002;73:776 –777.
25. Amino T, Orimo S, Takahashi A, Uchihara T, Mizusawa H. Profound
cardiac sympathetic denervation occurs in Parkinson disease. Brain Path.
2005;15:29 –34.
26. Orimo S, Amino T, Yokochi M, Kojo T, Uchihara T, Takahashi A,
Wakabayashi K, Takahashi H, Hattori N, Mizuno Y. Preserved cardiac
 146 Circulation January 6/13, 2009
sympathetic nerve accounts for normal cardiac uptake of MIBG in
PARK2. Mov Disord. 2005;20:1350 –1353.
27. Goldstein DS, Holmes C, Dendi R, Li ST, Brentzel S, Vernino S.
Pandysautonomia associated with impaired ganglionic neurotransmission
and circulating antibody to the neuronal nicotinic receptor. Clin Auton
Res. 2002;12:281–285.
28. Maki T, Nakamura M, Nakamura M, Suenaga T. A case of autoimmune
autonomic neuropathy with marked orthostatic hypotension, decreased
salivation, constipation, and Adie pupil. Rinsho Shinkeigaku. 2006;46:
218 –222.
29. Vernino S, Low PA, Lennon VA. Experimental autoimmune autonomic
neuropathy. J Neurophysiol. 2003;90:2053–2059.
30. Grossman E, Rea RF, Hoffman A, Goldstein DS. Yohimbine increases
sympathetic nerve activity and norepinephrine spillover in normal vol-
unteers. Am J Physiol. 1991;260:R142–R147.
31. Shannon JR, Jordan J, Diedrich A, Pohar B, Black BK, Robertson D,
Biaggioni I. Sympathetically mediated hypertension in autonomic failure.
Circulation. 2000;101:2710 –2715.
32. Senard JM, Rascol O, Durrieu G, Tran MA, Berlan M, Rascol A, Mon-
tastruc JL. Effects of yohimbine on plasma catecholamine levels in
orthostatic hypotension related to Parkinson disease or multiple system
atrophy. Clin Neuropharmacol. 1993;16:70 –76.
33. Sharabi Y, Eldadah B, Li ST, Dendi R, Pechnik S, Holmes C, Goldstein
DS. Neuropharmacologic distinction of neurogenic orthostatic hypo-
tension syndromes. Clin Neuropharmacol. 2006;29:97–105.
34. Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ.
Plasma dihydroxyphenylglycol and the intraneuronal disposition of nor-
epinephrine in humans. J Clin Invest. 1988;81:213–220.
35. Imrich R, Eldadah B, Bentho O, Pechnik S, Sharabi Y, Holmes C,
Grossman E, Goldstein DS. Functional effects of cardiac sympathetic
denervation in neurogenic orthostatic hypotension. Parkinsonism Relat
Disord. May 28, 2008. DOI: ƒ10.1016/j.parkreldis.2008.04.002.
Available at http://www.ncbi.nlm.gov/sites/entrez. Accessed December
19, 2008.
36. Scriven AJI, Dollery CT, Murphy MB, Macquin I, Brown MJ. Blood
pressure and plasma norepinephrine concentrations after endogenous nor-
epinephrine release by tyramine. Clin Pharmacol Ther. 1983;33:
Downloaded from http://ahajournals.org by on April 5, 2022
710 –716.
37. Bianchetti MG, Minder I, Beretta-Piccoli C, Meier A, Weidmann P.
Effects of tyramine on blood pressure and plasma catecholamines in
normal and hypertensive subjects. Klin Wochenschr. 1982;60:465– 470.
38. Kontos HA, Richardson DW, Norvell JE. Norepinephrine depletion in
idiopathic orthostatic hypotension. Ann Intern Med. 1975:336 –341.
39. Polinsky RJ, Kopin IJ, Ebert MH, Weise V. Pharmacologic distinction of
different orthostatic hypotension syndromes. Neurology. 1981;31:1–7.
40. Goldstein DS, Zimlichman R, Stull R, Keiser HR. Plasma catecholamine
and hemodynamic responses during isoproterenol infusions in humans.
Clin Pharmacol Ther. 1986;40:233–238.
41. Hjemdahl P, Martinsson A, Larsson K. Improvement of the isoprenaline
infusion test by plasma concentration measurements. Life Sci. 1986;39:
629 – 635.
42. Goldstein DS, Cannon RO, Zimlichman R, Keiser HR. Clinical eval-
uation of impedance cardiography. Clin Physiol. 1986;6:235–251.
43. Goldstein DS, Holmes C, Patronas N, Kopin IJ. Cerebrospinal fluid levels
of catechols in patients with neurogenic orthostatic hypotension. Clin Sci
(Lond). 2003;104:649 – 654.
44. Schroeder C, Vernino S, Birkenfeld AL, Tank J, Heusser K, Lipp A,
Benter T, Lindschau C, Kettritz R, Luft FC, Jordan J. Plasma exchange
for primary autoimmune autonomic failure. N Engl J Med. 2005;353:
1585–1590.
45. Grossman E, Rosenthal T, Peleg E, Holmes C, Goldstein DS. Oral
yohimbine increases blood pressure and sympathetic nervous outflow in
hypertensive patients. J Cardiovasc Pharmacol. 1993;22:22–26.
46. Nanda RN, Johnson RH, Keogh HJ. Treatment of neurogenic orthostatic
hypotension with a monoamine oxidase inhibitor and tyramine. Lancet.
1976;2:1164 –1167.
47. Freeman R, Landsberg L, Young J. The treatment of neurogenic ortho-
static hypotension with 3,4-DL-threo-dihydroxyphenylserine: a ran-
domized, placebo-controlled, crossover trial. Neurology. 1999;53:
2151–2157.
48. Kaufmann H, Saadia D, Voustianiouk A, Goldstein DS, Holmes C, Yahr
MD, Nardin R, Freeman R. Norepinephrine precursor therapy in neu-
rogenic orthostatic hypotension. Circulation. 2003;108:724 –728.
49. Shannon J, Jordan J, Costa F, Robertson RM, Biaggioni I. The hyper-
tension of autonomic failure and its treatment. Hypertension. 1997;30:
1062–1067.
KEY WORDS: hypotension 䡲 nervous system, sympathetic 䡲 norepineph-
rine 䡲 orthostatic hypotension 䡲 tomography