Post on 06-Jan-2020
3rd Congress of the European Academy of Neurology
Amsterdam, The Netherlands, June 24 – 27, 2017
Teaching Course 13
How to manage a patient with autonomic dysfunction - Level 2
How to manage a patient with orthostatic
hypotension
Anne Pavy-Le Traon Toulouse, France
Email: pavy-letraon.a@chu-toulouse.fr
1
Conflict of interest: The author has no conflict of interest in relation to
this manuscript
Orthostatic Hypotension definition
OH is defined by consensus [1] as a drop in blood pressure (BP) of at least
20 mm Hg for systolic BP or 10 mm Hg for diastolic BP within 3 minutes of
standing (or during a head up tilt test to at least 60°). The clinical
features and pathophysiology of OH were reviewed in 2009 [2] and in
2011 [3] resulting in the publication of a new consensus. The authors
recommend using a drop of at least 30 mm Hg in patients with
hypertension (systolic blood pressure > 160 mm Hg) to define OH. This
consensus also identifies two other forms of OH: initial OH and delayed
OH. Initial OH is defined as an exaggerated fall in blood pressure within
the first few seconds of standing; this initial OH is considered excessive
when the transient blood pressure decrease is over 40 mm Hg (systolic
blood pressure) or 20 mm Hg (diastolic blood pressure) within 15-20
seconds of standing. This initial blood pressure fall is observed with
continuous blood pressure monitoring, generally during active orthostatic
tests and mainly in young subjects. It may be symptomatic when it occurs
within a few seconds of standing but is not due to anatomic lesions [3].
The second form is delayed OH; some patients present OH that occurs
beyond three minutes of standing (in general when orthostatic stress is
prolonged more than 5 minutes) [2]. The clinical significance of delayed
OH is less well known but may reveal an early or mild form of sympathetic
adrenergic failure [4].
2
Orthostatic intolerance may also be observed in cases of excessive
postural tachycardia (POTS for Postural Tachycardia Orthostatic
Syndrome). In this heterogeneous, multifactor syndrome, the clinical signs
of orthostatic intolerance are coupled with an excessive increase in heart
rate (>30 bpm with an HR in upright position >120 bpm) but without any
significant hypotension [5].
Pathophysiology of Orthostatic Hypotension
Under normal conditions, standing results in gravitational redistribution of
about 500 ml of blood in the splanchnic circulation and in the lower limbs.
As a consequence, venous return and cardiac filling pressure fall, resulting
in temporarily decreased cardiac output and blood pressure. In response,
the aortic and carotid baroreceptors which are sensitive to blood pressure
variations send the information to centers localized in the brainstem; as a
result the decrease in BP leads to cardiac parasympathetic inhibition and
sympathetic activation with increased heart rate and above all peripheral
vasoconstriction. Vasoconstriction in the lower members is also favored by
the veino-arterial reflex. Neuro-hormonal mechanisms rapidly take over,
triggering the renin-angiotensin system and secretion of noradrenaline (x 2
in upright position). An inadequate response from one of these
mechanisms may be responsible for OH.
Diagnosis of Orthostatic Hypotension
Blood pressure measurement
The BP must be measured in both lying and standing positions. It is
preferable to use an automatic measuring device than a manual one. The
BP and heart rate (HR) are measured after the patient has been lying
down for at least 5 min (or until BP values are stable), at a comfortable
3
temperature (20-24°C), with an empty bladder. Then the patient is asked
to stand up and BP and HR are measured every minute for three to five
minutes. The patient must be asked whether or not symptoms occur
during the test. The test may be interrupted in case of pre-syncopal
symptoms. If OH is suspected but the orthostatic test is negative, the test
must be repeated at other times. In patients with suspected neurogenic
OH, extending the orthostatic test up to 10 min is recommended in order
to check for delayed OH ([6] [7]).
Under certain conditions, a passive test on a tilt-table (+60 à +80°) may
be used to detect OH, either to sensitize the OH detection or in patients
who have physical disorders [8].
HR variations must be monitored. A limited or no increase in HR
associated with OH will indicate a neurogenic cause (Figure 1). A large
increase in heart rate will be a sign of hypovolemia or anemia. These HR
variations decrease significantly with age and should be interpreted
accordingly.
Figure 1: Changes in BP and HR during a tilt test of 5 minutes on a patient
showing neurogenic OH.
Figure from Low et al, 2013 [9]
4
In patients with autonomic failure characterized by neurogenic OH, OH is
often associated with supine hypertension [10]. In this case it may be
useful to carry out ambulatory blood pressure monitoring over 24h to
detect associated post-prandial hypotension, excessive pressure
variability, reduced or inverted circadian rhythm (non-dipping) or supine
hypertension.
Clinical signs
OH may be asymptomatic or symptomatic. There is not always a
correlation between the fall in BP and the symptoms severity.
Characteristic signs include lightheadedness, visual blurring, dizziness and
even loss of consciousness. These symptoms occur particularly when
standing, rapidly after standing up or as a result of continued standing.
Some symptoms are quite characteristic but less well known, such as a
lower cervical and shoulder pain known as “Coat hanger ache” induced by
reduced muscular flow. Some patients present non-specific complaints
such as fatigue, weakness, buzzing in their ears, lack of concentration,
orthostatic dyspnea, difficulty in walking and falls. The circumstances in
which the symptoms occur must be carefully analysed in order to identify
OH as a possible cause.
Questionnaires can also be used in particular during clinical trials to
quantify these OH symptoms; specific OH questionnaires [11] or more
general autonomic failure questionnaires could be used.
Favoring factors
Searching for favoring factors helps to identify OH. The symptoms may be
favored by heat, physical deconditioning such as bed rest, or meals; OH is
more common in the morning or after a meal. In patients with autonomic
5
failure, OH is often associated to postprandial hypotension which can be
defined as a systolic fall of over 20 mm Hg occurring within 90 minutes
following the meal. Elderly patients who are bed-ridden are particularly
susceptible to OH when getting up.
Orthostatic hypotension: a factor of morbidity-mortality
Several studies have shown that OH is an independent factor of morbidity-
mortality ([12]; [13, 14]). In a meta-analysis, Ricci et al [15] have re-
ported a relative risk of mortality of 1.5[1.24, 1.81] in patients with OH,
slightly higher in patients below 65 years (1.78 [1.25, 2.52]). OH may also
cause falls.
Main Causes of Orthostatic Hypotension
The prevalence of OH increases significantly with age (Figure 2), in
particular in institutionalised elderly individuals. [16].
Figure 2: Prevalence of OH by age group
From Wolters et al and Heart BrainConnection Collaborative Research
Group - PLoS Med. 2016 Performed on 6,204 community-dwelling
individuals participating in the Dutch population-based Rotterdam Study
(Cardiovascular Health Study )
6
In these patients the prevalence also increases with the amount of
medication. [17].
Indeed, drugs represent the first cause of OH. Some drugs may be
responsible for OH such as anti-hypertensive treatment, particularly
diuretics, vasodilators, some psychotropic drugs (antidepressants,
neuroleptics), anti-Parkinsonian agents or alpha-blockers (prescribed for
urinary disorders).
Other causes to be investigated include anemia, hypovolemia (dehydra-
tion, vomiting, diarrhea, adrenocortical insufficiency) or relative hypo-
volemia (severe venous insufficiency). OH may result from multiple factors
(hypovolemia, associated neuropathy) in patients suffering from renal
failure.
Neurogenic OH may be suspected when there are autonomic symptoms in
other areas: digestive symptoms (constipation, alternating constipation
and diarrhea ,..), urinary symptoms, erectile dysfunction, sweating dis-
orders, pupil disorders (photophobia, difficulty in accommodating), ptosis,
vasomotor symptoms, hypo-or-hyperhidrosis, cold/heat intolerance...
OH is common among diabetic patients; prevalence varies from 8.2
to 43% according to the criteria used and the studied population [18]. A
prevalence of 20% has been reported in the ACCORD (Action to Control
Cardiovascular Risk in Diabetes) study [19]. In diabetics, OH may be part
of the autonomic neuropathy which is common in this population.
7
Neurogenic OH may also be suspected in case of associated neurological
features, such as an extra-pyramidal syndrome or a peripheral neuro-
pathy. The diagnosis can be oriented according to the patient’s complaints
and associated neurological symptoms indicating a cerebral, spinal or
peripheral pathology [20]. Neurogenic OH is common in some neuro-
degenerative disorders such as Parkinson’s disease where on average 30%
of the patients are affected (Meta-analysis [21]) and up to 50% in some
studies [22]. OH may be dramatic in rarer neurodegenerative disorders
such as Multiple System Atrophy where autonomic failure is a key
symptom, associated with a Parkinson or cerebellar syndrome [23], Lewy
body dementia or pure autonomic failure (PAF) ([24], [25], [26]). PAF is a
rare neurodegenerative disorder of the autonomic nervous system
(sympathetic component) without motor symptoms; the disease duration
may last up to 20 years. However, these patients must be followed up
regularly to make sure no other neurological symptoms appear. In neuro-
degenerative disorders with autonomic failure, supine hypertension is
observed in at least 50% of the patients with neurogenic OH (NOH) [24] –
NOH severity is often correlated with supine hypertension severity ([7],
[26]). There are numerous other possible causes of autonomic failure
which may induce OH (metabolic, infectious, traumatic, paraneoplastic,
genetic and toxic). The table 1 (adapted from a document published by a
consensus of experts (French Society of Hypertension, French Society of
Geriatrics and Gerontology and European Federation of Autonomic
Societies) summarizes the main causes of OH [27].
8
Secondary OH Neurogenic OH Medications Antihypertensive
Psychotropics (neuroleptics,
antidepressants)
Vasodilatators (nitrates,
alpha-blockers, sildénafil…)
Antiparkinsonian
Anticholinergics
Opiates,
..
Hypovolemia Dehydration
Salt-free diet
Denutrition
Anemia
Adrenal insufficiency
Venous insufficiency
(relative hypovolemia)
Neurodegenerative Diseases (mainly synucleinopathies) - Parkinson’s Disease
- Lewy Body Disease
- Multiple System Atrophy *
- Pure Autonomic Failure *
Familial Dysautonomia **
Dopamine beta-hydroxylase deficiency**
Autoimmune Autonomic neuropathy - Autoimmune ganglionopathy
- Guillain-Barre syndrome
Amyloidosis
Diabetes mellitus
Chronic Renal Failure
Other metabolic causes : - Vitamin B deficiency
- Alcoholism
- Porphyria
- Fabry disease
Neoplasia : - Paraneoplastic
- Brain tumors (posterior
fossa, medullary)
- Cervical radiotheray
Spinal cord injuries - Traumatic
- Multiple sclerosis
- Myelitis
Other traumatic injuries : - Sympathectomy
- Cervical surgery
Infections : - Botulism
- HIV
- Chagas disease, …
Toxic substances : - Heavy metals
- Medications (ex :
vincristine , ..) - Ciguatera - …
Table 1: Main causes of Orthostatic Hypotension adapted from Pathak et
al, Expert Consensus, 2014, [27]. *In these diseases, OH is a main symptom
** These genetic diseases are very rare.
In some cases it may be useful to get the opinion of a specialist, to search
and quantify more precisely the autonomic failure through specific
investigations of the autonomic nervous system (ANS) available in some
centres. These tests are based on continuous monitoring of BP and HR and
assess the response of the sympathetic, parasympathetic and baroreflex
systems during physiological stimulations [9] Sweating may also be
studied, to detect associated sympathetic sudoro-motor impairment [28].
9
Treatment of Orthostatic Hypotension
Identification of the mechanism of OH (disease, drug or other causes) is
the first step in the treatment, followed by non-pharmacological
measures. OH must be treated whilst it is symptomatic and/or severe.
First of all, and when possible, treatments likely to induce OH should be
stopped or limited. The factors favoring OH should be investigated and
explained to the patient. Hot baths, large meals, especially meals high in
carbohydrate and alcohol which are vasodilators, should be avoided [29].
The patient must also avoid changing positions too quickly.
Non-pharmocological measures
Non-pharmacological measures can be used to limit OH and its symptoms:
• Wearing force 2 to 3 compression tights or stockings (to be put
on in the morning before getting up). Compression stockings
which prevent blood from being stored under the waist are
more efficient than stockings [25].
• Sufficient hydration, by drinking one to two large glasses of
water before each meal to limit post-prandial hypotension,
often associated with NOH. The increase in BP observed after
drinking water is induced by a reflex mechanism [30].
• Eating meals more often, in small quantities and poor in rapidly
absorbed carbohydrate, to limit post-prandial hypotension.
• Salty diet (to be adapted in case of edema/heart failure).
• Elevating the head and neck during the night (30° tilt) to
activate the carotid and aortic baroreceptors and the renin-
angiotensin-aldosterone system, in order to limit supine hyper-
tension and reduce early morning hypotension.
10
Pharmacological measures
The drugs generally used and recommended to treat neurogenic OH are
midodrine and fludrocortisone, either alone or together. Since 2014,
Droxi-Dopa (L-Threo DOPS) can be used in US to treat NOH (FDA
agreement); currently this drug does not have drug marketing approval for
NOH in Europe. Other drugs such as dihydroergotamine and etilefrine have
been prescribed for treating NOH but none of them proved to be effective
for NOH. Some drugs listed hereafter are more rarely used and should be
administered by a specialist.
- Midodrine is a prodrug which when hydrolysed becomes desmo-
glymidodrine, an α1 adrenoceptor agonist. This molecule has proved to
be effective on NOH by increasing peripheral vascular resistance ([31];
[32]; [33]). This α1-adrenoceptor agonist (2.5 mg/tablet) can be
administered up to maximum 30 mg/d, taken in three or four doses due
to its short half-life (3-4 h). The last dose should be taken at least 4-5
h before sleeping to prevent supine hypertension.
Midodrine may favor the occurrence of urinary retention. Other side-
effects are mainly piloerection (dose-dependent) and to a lesser degree
irritability and insomnia. Midodrine is eliminated through the kidneys so
renal function should also be monitored. Further studies are still
needed to assess the benefit/risk ratio of midodrine in the long term in
patients suffering from NOH.
- Fludrocortisone increases renal sodium re-absorption and expands
plasma volume, thus leading to increased blood pressure. Effects last
longer than those of midodrine, thus making it more difficult to avoid
nocturnal supine hypertension. Fludrocortisone's efficacy remains
11
insufficiently documented. The dosage of around 50 to 150µg per day
can be gradually incremented (up to a maximum of 300µg/day). Side-
effects, resulting from its mineralocorticoid activity, are salt and water
retention and hypokalemia. This drug may cause edema and may be
contra-indicated with patients with heart failure.
- L-threo DOPS or Droxidopa, is a noradrenergic precursor, initially
commercialised in Japan for Parkinson’s disease; it has been shown to
improve NOH in clinical trials carried out against placebo, in patients
suffering from neurodegenerative diseases (Parkinson’s Disease, Pure
Autonomic Failure, Multiple System Atrophy) and familial amyloid
neuro-pathy ([34]; [35]; [36]). This drug is also used in dopamine –
beta-hydroxylase deficiency (very rare genetic disease). The drug
received FDA approval for NOH treatment in US in February 2014 but is
not routinely available in Europe. A clinical trial in MSA patients is still
ongoing in France.
- Pyridostigmine is a cholinesterase inhibitor that may improve OH by
facilitating ganglionic transmission; it has been shown to improve OH in
comparison with placebo [37]. The same authors have suggested using
it alone to treat moderate OH, starting with a dose of 30 mg 2 to 3
times a day (maximum dose 180 mg/d). –
- Desmopressin, similar to vasopressin, reduces nocturnal polyuria and
might improve morning OH ([38]; [39]). This treatment requires blood
electrolyte monitoring.
- Erythropoietin which increases blood volume can also be used, when
autonomic failure is associated with a reduced red cell mass.
12
Treatment of associated supine hypertension
Patients with autonomic failure are often experiencing both NOH and
supine hypertension which may be severe. In these cases fludrocortisone
should be limited and using evening short-acting antihypertensive agents
may be proposed. However, long-term CV risks of supine hypertension in
this population are not well known and the decision to treat or not the
patient should be individualized [25].
Conclusion
OH is often under-estimated. Identification of OH mechanisms (disease,
drug or other causes) is the first step in the management of these
patients. Non-pharmacological measures are recommended first alone or
associated with pharmacological treatment. An expert advice may be
needed in some cases of NOH. There is no consensus regarding the
treatment of associated supine hypertension.
13
Orthostatic Hypotension
Sufficient
improvment
Maintain non-
pharmacological
measures
No or insufficient improvment-
symptomatic OH
No
Midodrine (or DroxiDopa*)
+ Fludrocortisone (under medical and biological follow-up)
Avoid and treat any potential factor which may favor OH ((hypovolemia, anemia, medications (in particular diuretics and alpha-blockers))
Non-pharmacological measures:
ü Educate the patient : avoid precipitating factors such as rapid postural change, hot baths, alcohol, prolonged bed rest )
ü Increase water intake (up to 1.5 to 2 L) and add salt to the diet (6 à 10 g Na Cl/day – to be adapted in case of edema/cardiac failure) –Intake of two glasses of water before meals
ü Compression tights or stockings ü Elevating the head of the bed of about 30° during the sleep
* available in US and Japan – no marketing approval in Europe. **Other medications could be used in some cases such as pyridostigmin or erythropoietin (see corresponding text)
Maintain treatment (under regular medical and biological follow-up)
Figure 3 : Management of Orthostatic Hypotension
Pharmacological treatment: Midodrine (or DroxiDopa*)
or Fludrocortisone (si contra-indication)
Improvment Yes
14
References
1. Consensus statement on the definition of orthostatic hypotension,
pure autonomic failure, and multiple system atrophy. The
Consensus Committee of the American Autonomic Society and the
American Academy of Neurology Neurology 1996;46:1470.
2. Wieling W and Schatz IJ. The consensus statement on the definition
of orthostatic hypotension: a revisit after 13 years. J Hypertens
2009; 27:935-93.
3. Freeman R, Wieling W, Axelrod FB et al. Consensus statement on
the definition of orthostatic hypotension, neutrally mediated
syncope and the postural tachycardia syndrome. Clin Auton Res
2011; 21: 69-72.
4. Gibbons CH, Freeman R. Delayed orthostatic hypotension: a
frequent cause of orthostatic intolerance. Neurology 2006;
67(1):28-32.
5. Mathias CJ1, Low DA, Iodice V, Owens AP, Kirbis M, Grahame R
Postural tachycardia syndrome--current experience and concepts.
Nat Rev Neurol. 2012 6;8(1):22-34
6. Jamnadas-Khoda J, Koshy S, Mathias CJ, Muthane UB, Ragothaman
M, Dodaballapur SK. Are current recommendations to diagnose
orthostatic hypotension in Parkinson's disease satisfactory Mov
Disord 2009;24(12):1747-51.
7. Pavy-Le Traon A, Piedvache A, Perez-Lloret S, Calandra-Buonaura
G, Cochen-De Cock V, Colosimo C, Cortelli P, Debs R, Duerr S,
Fanciulli A, Foubert-Samier A, Gerdelat A, Gurevich T, Krismer F,
Poewe W, Tison F, Tranchant C, Wenning G, Rascol O, Meissner
WG; European MSA Study Group. New insights into orthostatic
hypotension in multiple system atrophy: a European multicentre
cohort study. J Neurol Neurosurg Psychiatry. 2016 May;87(5):554-
61Lahrmann H1, Cortelli P, Hilz M, Mathias CJ, Struhal W, Tassinari
M. EFNS guidelines on the diagnosis and management of orthostatic
hypotension. Eur J Neurol. 2006;13(9):930-6.
8. Low PA, Tomalia VA, Park KJ. Autonomic function tests: some
clinical applications. J Clin Neurol. 2013;9(1):1-8.
9. Arnold AC, Shibao C. Current concepts in orthostatic hypotension
management. Curr Hypertens Rep 2013;15(4):304-12.
10. Kaufmann H, Malamut R, Norcliffe-Kaufmann L, Rosa K, Freeman R.
The Orthostatic Hypotension Questionnaire (OHQ): validation of a
novel symptom assessment. Clinical Autonomic Research, 2012, 22
(2), 79-90
15
11. Benvenuto LJ, Krakoff LR. Morbidity and mortality of orthostatic
hypotension: implications for management of cardiovascular
disease. Am J Hypertens 2011; 24(2):135-44.
12. Jones CD, Loehr L, Franceschini N, Rosamond WD, Chang PP,
Shahar E, Couper DJ, Rose KM. Orthostatic hypotension as a risk
factor for incident heart failure: the atherosclerosis risk in
communities study.Hypertension. 2012 ;59(5):913-8.
13. Jones PK, Shaw BH, Raj SR Orthostatic hypotension: managing a
difficult problem.. Expert Rev Cardiovasc Ther. 2015 ;13(11):
1263-76.
14. Ricci F, Fedorowski A, Radico F, Romanello M, Tatasciore A, Di
Nicola M, Zimarino M, De Caterina R.Cardiovascular morbidity and
mortality related to orthostatic hypotension: a meta-analysis of
prospective observational studies. Eur Heart J. 2015 ;36(25):
1609-17.
15. Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS.
Orthostatic hypotension in older adults. The Cardiovascular Health
Study. CHS Collaborative Research Group. Hypertension 1992;
19:508–519.
16. Poon IO, Braun U. High prevalence of orthostatic hypotension and
its correlation with potentially causative medications among
elderly veterans. J Clin Pharm Ther. 2005; 30(2):173–8.
17. Wu JS, Yang YC, Lu FH, et al. Population-based study on the
prevalence and risk factors of orthostatic hypotension in subjects
with pre-diabetes and diabetes mellitus. Diabetes Care 2009;
32: 69–74.
18. Fleg JL1, Evans GW2, Margolis KL2, Barzilay J2, Basile JN2, Bigger
JT2, Cutler JA2, Grimm R2, Pedley C2, Peterson K2, Pop-Busui R2,
Sperl-Hillen J2, Cushman WC2.Low PA1. Orthostatic Hypotension in
the ACCORD (Action to Control Cardiovascular Risk in Diabetes)
Blood Pressure Trial: Prevalence, Incidence, and Prognostic
Significance. Hypertension. 2016 ; 68(4):888-95.
19. Low and Tomalia VA. Orthostatic Hypotension: Mechanisms,
Causes, Management. J Clin Neurol. 2015 ; 11(3):220-6.
20. Velseboer DC, de Haan RJ, Wieling W, Goldstein DS, de Bie RM.
Prevalence of orthostatic hypotension in Parkinson's disease: a
systematic review and meta-analysis. Parkinsonism Relat Disord.
2011;17(10):724-9.
21. Senard JM, Brefel-Courbon C, Rascol O, Montastruc JL. Orthostatic
hypotension in patients with Parkinson's disease: pathophysiology
and management. Drugs Aging 2001; 18(7):495-505.
16
22. Gilman S1, Wenning GK, Low PA, Brooks DJ, Mathias CJ,
Trojanowski JQ, Wood NW, Colosimo C, Dürr A, Fowler CJ,
Kaufmann H, Klockgether T, Lees A, Poewe W, Quinn N, Revesz T,
Robertson D, Sandroni P, Seppi K, Vidailhet M. Second consensus
statement on the diagnosis of multiple system atrophy. Neurology.
2008 26;71(9):670-6.
23. Biaggioni I, Robertson RM. Hypertension in orthostatic hypotension
and autonomic dysfunction. Cardiol Clin. 2002;20:291–301
24. Biaggioni I. New developments in the management of neurogenic
orthostatic hypotension.Curr Cardiol Rep. 2014;16(11):542
25. Gibbons CH, Schmidt P, Biaggioni I, Frazier-Mills C, Freeman R,
Isaacson S, Karabin B, Kuritzky L, Lew M, Low P, Mehdirad A, Raj
SR, Vernino S, Kaufmann H.The recommendations of a consensus
panel for the screening, diagnosis, and treatment of neurogenic
orthostatic hypotension and associated supine hypertension.
J Neurol. 2017. doi: 10.1007/s00415-016-8375-x.
26. Pathak A, Elghozi Jl, Fortrat Jo , Senard Jm, Hanon O. Prise en
charge de l’hypotension orthostatique. P. Consensus d’experts de
la Société Française d’Hypertension Artérielle* (SFHTA), Société
Française de Gériatrie et Gérontologie (SFGG), European
Federation of Autonomic Societies (EFAS) –2014 -
http://www.sfhta.eu/
27. Vinik AI, Nevoret M, Casellini C, Parson H. Neurovascular function
and sudorimetry in health and disease.Curr Diab Rep. 2013
13(4):517-32.
28. Thompson P, Wright J, Rajkumar C. Non-pharmacological treat-
ments for orthostatic hypotension. Age Ageing 2011;40(3):292-293.
29. Jordan J, Shannon JR, Black BK, Ali Y, Farley M, Costa F, Diedrich
A, Robertson RM, Biaggioni I, Robertson D. The pressor response to
water drinking in humans : a sympathetic reflex?Circulation. 2000;
101(5):504-9.
30. Jankovic J, Gilden JL, Hiner BC, Kaufmann H, Brown DC, Coghlan
CH, et al. Neurogenic orthostatic hypotension: a double-blind,
placebo-controlled study with midodrine. Am J Med 1993;95(1):
38-48.
31. Low PA, Gilden JL, Freeman R, Sheng KN, McElligott MA. Efficacy of
midodrine vs placebo in neurogenic orthostatic hypotension.
A randomized, double-blind multicenter study. Midodrine Study
Group. JAMA 1997;277(13):1046-1051.
32. Wright RA, Kaufmann HC, Perera R, et al. A double-blind, dose-
response study of midodrine in neurogenic orthostatic hypotension.
Neurology 1998;51(1):120-124.
17
33. Freeman R, Landsberg L, Young J. The treatment of neurogenic
orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine:
a randomized, placebo-controlled, crossover trial. Neurology
1999;53(9):2151-7.
34. Mathias CJ, Senard JM, Braune S, Watson L, Aragishi A, Keeling JE,
et al. L-threo-dihydroxyphenylserine (L-threo-DOPS; droxidopa) in
the management of neurogenic orthostatic hypotension: a multi-
national, multi-center, dose-ranging study in multiple system
atrophy and pure autonomic failure. Clin Auton Res 2001;11(4):
235-42.
35. Kaufmann H, Freeman R, Biaggioni I, Low P, Pedder S, Hewitt LA,
et al. Droxidopa for neurogenic orthostatic hypotension: A
randomized, placebo-controlled, phase 3 trial. Neurology
2014;83(4):328-35.
36. Singer W, Sandroni P, Opfer-Gehrking TL, Suarez GA, Klein CM,
Hines S, et al. Pyridostigmine treatment trial in neurogenic
orthostatic hypotension. Arch Neurol 2006;63(4):513-8.
37. Freeman R. Treatment of orthostatic hypotension.Semin Neurol.
2003 ;23(4):435-42.
38. Sakakibara R, Matsuda S, Uchiyama T, Yoshiyama M, Yamanishi T,
Hattori T. The effect of intranasal desmopressin on nocturnal
waking in urination in multiple system atrophy patients with
nocturnal polyuria. Clin Auton Res 2003;13(2):106-8