Postural Tachycardia Syndrome
Blair P. Grubb MD FACC
Departments of Medicine and Pediatrics
Health Science Campus
University of Toledo
Toledo, Ohio USA
Somatic nerve
A Linear System
Autonomic Nerve
A Non-Linear System
The autonomic centers control most of
the functions considered essential to life
itself
1.
2.
3.
4.
5.
6.
7.
Heart Rate
Blood Pressure Control
Body Temperature
Bowel Motility
Sweating
Breathing
Genital-urinary function
Autonomic Nervous System
Periods of autonomic decompensation
Resulting in hypotension (with or without
Bradycardia) may have a wide variety of
Clinical manifestations, such as:
Vertigo/dizziness
Lightheadedness
Convulsive Activity
TIAS
Syncope/near syncope
Fatigue
Cognitive Impairment
70 b/m
100/70 mm/hg
Normal and Abnormal
Tilt Response
Patterns
Venous Pooling in POTS
Supine
Normal
Upright
Pooling
Orthostatic Intolerance:
Provocation of symptoms upon standing
that are relieved when becoming supine
Symptoms include exercise intolerance,
fatigue, lightheadedness, diminished
concentration, tremulousness, nausea,
headache, near syncope, and syncope
Joint Consensus Statement of the American Autonomic Society and
the American Academy of Neurology
Manningham 1750 An account of Febricula.Archives
of the Boston Medical Society
Chronically fatigued and broken down women, who
were healthy until a febrile illness (febricula) made them:
“weak, pallid, flabby… poor eaters; digesting ill,
incapable of exercise. They lie in bed hopeless and
helpless” The least bit of exertion” would cause their
hearts to pound rapidly and violently”
Da Costa JM: On Irritable heart: A clinical study of a
Functional cardiac disorder and it’s consequences.
Am J Med Sci 1871:61:17-52
“Dizziness,headache, chest pain, faintness and
Extreme fatigue associated with a rapid heart rate upon
Standing that fell to normal levels with recumbency”
Case # 12 : 122 beats/min standing- 90 bpm supine
“in all, the immediate effect of the
Exchange in position was most striking”
Lewis T. The soldier’s heart and the effort syndrome.
London, Shaw and Sons: 1919
“among them fatigue is an almost universal complaint,
Which is aggravated by exertion, associated with chest
Pain, excessive sweating,fainting spells, palpations and
Giddiness”
“when completely rested the heart rate averaged 85 bpm
And when up and about would rise to rates of 120 bpm”
He documented BP drop of between 20 - 40 mmHg upon
Standing
“the potential reservoir in the veins takes up the blood,
The supply to the heart falls away , and arterial pressure
Falls rapidly”
POTS – Reported descriptions
1.
2.
3.
4.
5.
Low et al Mayo Clinic
Schondorf et al McGill
Khurana et al Un. Of Md
Grubb et al MCO
Karas et al MCO
1993
1995
1995
1997
2000
16 pt
20 pt
10 pt
28 pt
30 pt
Symptoms in POTS Pts. (%)
Lightheadedness
Dizziness
Palpitations
Exercise Intolerance
Blurred Vision
Chest discomfort
Clamminess
85-95
60-80
40-55
50-85
70
60
60
Symptoms in POTS Pts. (%) cont.
Near Syncope
Anxiety
Flushing
Syncope
Fatigue
Headache
Dyspnea
50
50
50
40-45
45-75
50
40
Criteria for POTS
1.
2.
3.
4.
5.
Longstanding (>6 months) and disabling orthostatic
symptoms
Orthostatic Tachycardia:
>30 bpm increase of HR on tilt or standing
> 120 bpm HR on tilt on standing
Absence of an underlying cause (debilitating disease,
dehydration, medications, etc…)
Upright plasma norepinephrine >600 pg/ml
Excessive isoproterenol response
So just how many people are we
talking about?
Estimated # of patients with orthostatic
intolerance syndromes:
Vanderbilt (1999) : 500,000 in U.S.
Robertson et al Am J Med Sci
1999;317:75-77
NIH Estimate (2002) : 750,000 to
1,000,000 in USA
Goldstein et al Annals of Int Med
2002;137:753-763
POTS patients suffer a degree of functional
impairment similar to that of patients
with COPD or CHF
Benrud-Larson et al, Quality of life in patients with postural
tachycardia syndrome. Mayo Clinic Proceedings 2002: 77, 531-537
Approximately 25% of POTS/OI
patients are considered functionally disabled
and unable to work
Benrud-Larson et al ; Correlates of functional disability in patients
with Postural Tachycardia syndrome: Preliminary Cross sectional
findings. Health Psychology 2003; 22: 643-648
POTS
The Vanderbilt group has isolated a
gene defect in a hereditary form of
POTS affecting a norepinephrine
transporter substance.
NEJM 2000
Orthostatic Intolerance and Tachycardia Associated
with Norepinephrine-Transporter Deficiency
Robertson D. New Eng J Med 2000;342:541-49
POTS
In every study a large number of
patients reports onset of symptoms
after a febrile (viral) illness,
suggesting an immune-mediated
pathogenesis
Recent Studies at the Mayo Clinic have
demonstrated antibodies that bind to or block
acetylcholine receptors in apparent autoimmune
dysautonomias
NEJM 2000-343-897-55
Over the years it became evident that many of the
the patients referred to the MCO Syncope/Autonomic
clinic looked remarkably similar in appearance:
Pale, fair skinned, caucasian women.
Usually blond haired, blue eyed, often tall
and thin. Many complained of joint pain and
easy bruising. Stretch marks were common.
In the late 1990s investigators at the Johns
Hopkins Hospital realized that many of
these patients met the criteria for
Type III Ehlers-Danlos Syndrome (now called
the joint hypermobility syndrome).
J Pediatrics 1999;135:494-9
So just what is
Joint Hypermobility/Ehlers-Danlos
Syndrome?
Ehlers-Danlos Syndrome (Type III or
joint hypermobility syndrome))
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Heterogeneous disorder of connective tissue
Prevalence unknown, perhaps 1 per 5000
Characterized by varying degrees of:
Skin hyperextensibility (not present in many)
Joint hypermobility
Cutaneous scarring
Early varicose veins, easy bruising
Easy fatigability and widespread pain common, of
unclear etiology
Many EDS/JHS Pts also complain of
1. nausea and bloating (due to
gastroparisis and GB disease)
2. orthostatic acrocyanosis
3. joint pain and dislocations
4. hernias
5. constipation
6. hemorrhoids
7. early arthritis
8. stretch marks
ORTHOSTATIC INTOLERANCE AND
CFS ASSOCIATED WITH EDS
Among approximately 100 adolescents seen
in the CFS/OI clinic at JHH over a 1 year
period, they identified 12 subjects with EDS
11 females, 1 male
All had either POTS or NMH
6 classical-type, 6 hypermobile-type EDS
Rowe PC, Barron DF, Calkins H, Maumanee IH, Tong PY, Geraghty MT. J
Pediatr 1999;135:494-9
FEATURES ASSOCIATED WITH CFS
IN 12 WITH EDS
Feature
%
Fatigue > 6 mo
Post-exertional malaise
Unrefreshing sleep
Impaired memory/concentration
Multi-joint pain
New headaches
Muscle pain
Sore throat
Tender glands
100
100
100
92
83
83
58
25
25
In July 2000 a new classification of
EDS was made along with a new set
of diagnostic criteria.
The previous Beighton score was replaced
with what are now called the Brighton
criteria
Journal of Rheumatology 2000; 27: 1777-9
Revised Criteria for JHS (EDS III)
MAJOR CRITERIA:
1. A Beighton score 4/9 or more (current or
historically).
2. Arthralgia for longer than 3 months in 4 or
more joints
MINOR CRITERIA:
1. Beighton score of 1,2 or 3/9 (0,1,2 or 3 if aged 50+
2. Arthralgia (>3 months) in 1-3 joints or back pain (>3 M)
spondylosis, spondylosis/spondyloisthesis
3. Dislocation/subluxation in more than one joint
4. Soft tissue rheumatism >3 lesions (epicondylitis etc.)
5. Marfanoid habitus
6. Abnormal skin: striae, hyperextensibility,thin,scarring
7. Eye signs: drooping eyelids or myopia
8. Varicose veins, hernia or utero/rectal prolapse
Diagnosis is made by the presence of:
1. two major criteria
2. one major and two minor criteria
3. four minor criteria
4. two minor criteria with an unequivocally
affected first degree relative
Diagnosis excluded by presence of Marfans
or the other EDS subtypes
J Rheumatology 2000;27:1777-1779
A picture from childhood from one
of our patients
Another picture from
a patients childhood
Many of these patients
excelled at gymnastics
and dance
JOINT HYPERMOBILITY IS MORE
COMMON IN CHILDREN WITH CFS
Study question: do children with CFS have a
higher prevalence of joint hypermobility?
Beighton scores obtained in 58 new & 58
established CFS patients, and in 58 controls
Median Beighton scores higher in CFS (4 vs. 1)
Beighton score > 4 higher in CFS (60% vs. 24%)
Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC. J Pediatr
2002;141:421-5
Gazit Y. et al Dysautonomia in the joint hypermobility
syndrome. Am J Med 2003; 115: 33-44
48 pts with Joint Hypermobility Syndrome(JHS) were
compared to 30 healthy controls with a battery of
Autonomic Tests : HUTT, Valsalva Ratio, HRV,
catecholamine levels and baroreflex testing.
78% of JHS pts demonstrated Orthostatic intolerance
and abnormal autonomic testing (on every one of the
tests mentioned above), as compared to 10%
of control subjects
They concluded that JHS/EDS III
predisposed people to develop OI
Disorders of autonomic Control Associated
With Orthostatic Tolerance
Reflex Syndrome
POTS
Neurocardiogenic Carotid Sinus Orthostatic
Syndrome
Hypersensitivity Intolerance
Hypersensitivity
Multiple
System
Atrophy
Pure Autonomic
Failure
Acute
Chronic
Parkinsonian Cerebellar
Mixed
Miscellaneous
(micturition, defecation, etc)
Primary
Secondary
Disorders of the Autonomic Nervous
System Associated with
Orthostatic Intolerance
Reflex
Syncope
Autonomic
Failure
POTS
CSH
NCS
Secondary
Acute Autonomic
Neuropathy
Primary
Situational
Diabetic
Chronic
JHS
Secondary
Defecation
Micuration???
Other
Other
Diabetic
Paraneoplastic
Primary
Partial
Dysautonomic
Beta
Hypersensitive
Other
Pure Autonomic
Failure
Multiple System
Atrophy
Parkinson’s
Disease
NCS: Neurocardiogenic Syncope
CSH: Carotid Sinus Hypersensitivity
POTS: Postural Orthostatic Tachycardia
Syncope
JHS: Joint Hypermobility Syndrome
Parkinsonian
Mixed
Cerebelluar
Figure I: Subtypes of Postural Tachyca rdia Synd rome
POTS
primary
hype radrene rgic
partial
dys autonomic
deve lopmental
post
vir al
seconda ry
JHS
diabetes
paraneop lastic
other
other
POTS = Postural Tachycardia Syndrome
JHS = Joint Hypermobility Syndrome
Autonomic Evaluation
1.
2.
3.
4.
5.
6.
7.
BP/HR supine, sitting, standing at least 2 minutes
between each
Head up tilt
Serum catacholamine determinations
Baroreflex testing
Thermoregulatory Sweat Test
Sudomotor axon testing
Cold pressor test
Treatment
 Identify
the Problem!
 Education
 Avoid predisposing factors
 Support hose
Before embarking on Medical
Therapy one must:
1.
2.
3.
Avoid predisposing conditions or
medications
Have adequate fluid & salt intake
Reconditioning and lower extremity
strength building
a. aerobic training 30 min. 3/week
b. resistance training
Pharmacotherapy is employed to
make the patient feel well enough
so that they can begin a reconditioning
program
“Doctors pour drugs of which
they know “little” into patients
about whom they know “less”
with diseases of which they
know nothing.”
-Voltaire
1770 C.E.
Pharmacotherapy
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Fludrocortisone / DDAVP
Methylphenidate
Midodrine
Beta blockers
SSRIs
Clonidine
Erythropoietin
Yohimbine
Pyridostigmine
Norepinephrine reuptake inhibitors
Octreotide
Potential Treatment Modalities (Cont.)
Treatment
Midodrine
 Application
2.5-10 mg every 2-4 hrs; can titrate to
40 mg/day
 Drawbacks
Nausea, supine hypertension

Symptom – Free Interval
Midodrine - Neurocardiogenic Syncope
100
80
60
Midodrine
Fluid
40
All data not so robust for alpha agonists
Raviele A. Etilefrine Circulation 1999;99:1452-7
20
p < 0.001
0
0
20
40
60
80
100
120
140
160
180
Months
Perez-Lugones, et al. J Cardiovas Electrophysiol 2001;12:935-938
SSRI
Girolamo et al JACC 1999:
Randomized, double blind,
placebo-controlled trial of
Paroxetine in NCS
SSRI
Recurrence rate over 25 months
17.6% paroxetine
52.9% placebo
(p <0.0002)
Pyridostigmine:
An acetlycholinesterase inhibitor
Increases acetlycholine levels at
the autonomic ganglia
Prevents drop in BP without causing
supine hypertension
Usual dose:
60 mg PO BID
Pyridostigmine
The Vanderbilt group published a randomized
double blind placebo controlled crossover trial
of pyridostigmine in POTS pts. finding that it
reduced heart rate + blood pressure changes as
well as symptoms (Circulation 2005)
The Mayo group published a double blind placebo
controlled crossover trial of pyridostigmine in
OH, finding that it prevented a fall in BP without
causing supine hypertension (Ann Neurol April 2006)
Erythropoietin:
Stimulates RBC Production,
Also a vasoconstrictor,
(may also be a neurotransmitter)
First Reports of Epogen use in
Pure Autonomic Failure
Hoeldtke et al Nejm 1993
Biaggioni et al Ann Int Med 1994
Kosinski et al Clin Auto Res 1994
Kaufman et all Clin Auto Res 1995
Octreotide in the treatment of
Refractory OI
There have been reports on the use of
octreotide in patients with orthostatic
hypotension, postural tachycardia syndrome
and orthostatic syncope. However there are
little if any data on the use Octreotide in
patients With refractory OI who fail
multiple medications
Methods:
The study was a retrospective chart analysis
and was approved by our institutional
review board.
A total of 12 patients were identified for
inclusion in this study.
These patients had failed multiple
medications and were ultimately tried with
octreotide.
Results:
Twelve Patients
Age 33±18,
Eight (66.7%) females were found to have
symptoms of refractory OI,
5 POTS
5 OI
2 Dyautonomia
Effect of Octreotide in Patients suffering
from Refractory OI
Syncope
Palpitations
Fatigue
Syncope and Palpitations improved in almost 50%
Effect of Octreotide on Heart Rate
140
120
120
P<0.05
111
105
95
95
88
84
80
78
70
68
35
0
1
2
3
4
5
Heart rate before treatment
Heart rate after treatment
Effect of Octreotide on Standing
SBP
160
P<0.05
140
140
130
125
138
120
121
100
90
95
114
Systolic blood pressure at
baseline
80
80
Systolic blood pressure after
treatment
80
60
40
20
0
1
2
3
4
5
Effect of Octreotide on Standing
DBP
120
P=NS
95
100
97
84
72
80
85
60
55
Diastolic Blood pressure at
Baseline
80
60
60
50
Diastolic Blood pressure after
treatment
40
20
0
1
2
3
4
5
Illness effects and can disrupt the
entire family dynamic. Counseling
is often critical in getting the patient
and the family through this difficult
period.
“We shall not cease from exploration,
and the end of all our exploring
will be to arrive where we started
and to know the place
for the first time… “
T.S. Eliot
Four Quartet
“May I never forget that the
patient is a fellow creature in
pain. May I never consider him
only a vessel of disease”
Maimonidies:
The Physicians’ Oath
12th Century C.E.
“The most beautiful thing that we can experience
is the mysterious. It is the source of all true art
and science…”
Albert Einstein
Albert Einstein