EDNF 2011 Conference 8/2/11
All rights reserved. 1
Postural Tachycardia Syndrome
Blair P. Grubb MD FACC Departments of Medicine and Pediatrics
Health Science Campus University of Toledo
Toledo, Ohio USA
EDNF 2011 Conference 8/2/11
All rights reserved. 2
Somatic nerve
A Linear System
Autonomic Nerve
A Non-Linear System
EDNF 2011 Conference 8/2/11
All rights reserved. 3
The autonomic centers control most of the functions considered essential to life itself
1. Heart Rate 2. Blood Pressure Control 3. Body Temperature 4. Bowel Motility 5. Sweating 6. Breathing 7. Genital-urinary function
EDNF 2011 Conference 8/2/11
All rights reserved. 4
Autonomic Nervous System
EDNF 2011 Conference 8/2/11
All rights reserved. 5
EDNF 2011 Conference 8/2/11
All rights reserved. 6
EDNF 2011 Conference 8/2/11
All rights reserved. 7
EDNF 2011 Conference 8/2/11
All rights reserved. 8
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
EDNF 2011 Conference 8/2/11
All rights reserved. 9
EDNF 2011 Conference 8/2/11
All rights reserved. 10
100/70 mm/hg
70 b/m
EDNF 2011 Conference 8/2/11
All rights reserved. 11
Normal and Abnormal Tilt Response Patterns
EDNF 2011 Conference 8/2/11
All rights reserved. 12
Venous Pooling in POTS
Pooling
Supine Upright
Normal
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
EDNF 2011 Conference 8/2/11
All rights reserved. 13
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”
EDNF 2011 Conference 8/2/11
All rights reserved. 14
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”
EDNF 2011 Conference 8/2/11
All rights reserved. 15
POTS – Reported descriptions
1. Low et al Mayo Clinic 1993 16 pt 2. Schondorf et al McGill 1995 20 pt 3. Khurana et al Un. Of Md 1995 10 pt 4. Grubb et al MCO 1997 28 pt 5. Karas et al MCO 2000 30 pt
Symptoms in POTS Pts. (%)
Lightheadedness 85-95 Dizziness 60-80 Palpitations 40-55 Exercise Intolerance 50-85 Blurred Vision 70 Chest discomfort 60 Clamminess 60
EDNF 2011 Conference 8/2/11
All rights reserved. 16
Symptoms in POTS Pts. (%) cont. Near Syncope 50 Anxiety 50 Flushing 50 Syncope 40-45 Fatigue 45-75 Headache 50 Dyspnea 40
Criteria for POTS 1. Longstanding (>6 months) and disabling orthostatic
symptoms 2. Orthostatic Tachycardia:
>30 bpm increase of HR on tilt or standing > 120 bpm HR on tilt on standing
3. Absence of an underlying cause (debilitating disease, dehydration, medications, etc…)
4. Upright plasma norepinephrine >600 pg/ml 5. Excessive isoproterenol response
EDNF 2011 Conference 8/2/11
All rights reserved. 17
So just how many people are we talking about?
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
Estimated # of patients with orthostatic intolerance syndromes:
Goldstein et al Annals of Int Med 2002;137:753-763
EDNF 2011 Conference 8/2/11
All rights reserved. 18
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
EDNF 2011 Conference 8/2/11
All rights reserved. 19
POTS
The Vanderbilt group has isolated a gene defect in a hereditary form of POTS affecting a norepinephrine transporter substance.
NEJM 2000
Robertson D. New Eng J Med 2000;342:541-49
Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency
EDNF 2011 Conference 8/2/11
All rights reserved. 20
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
EDNF 2011 Conference 8/2/11
All rights reserved. 21
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
EDNF 2011 Conference 8/2/11
All rights reserved. 22
So just what is Joint Hypermobility/Ehlers-Danlos
Syndrome?
Ehlers-Danlos Syndrome (Type III or joint hypermobility syndrome))
n Heterogeneous disorder of connective tissue n Prevalence unknown, perhaps 1 per 5000 n Characterized by varying degrees of: Skin hyperextensibility (not present in many) Joint hypermobility Cutaneous scarring n Early varicose veins, easy bruising n Easy fatigability and widespread pain common, of
unclear etiology
EDNF 2011 Conference 8/2/11
All rights reserved. 23
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
EDNF 2011 Conference 8/2/11
All rights reserved. 24
FEATURES ASSOCIATED WITH CFS IN 12 WITH EDS
Feature % Fatigue > 6 mo 100 Post-exertional malaise 100 Unrefreshing sleep 100 Impaired memory/concentration 92 Multi-joint pain 83 New headaches 83 Muscle pain 58 Sore throat 25 Tender glands 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
EDNF 2011 Conference 8/2/11
All rights reserved. 25
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
EDNF 2011 Conference 8/2/11
All rights reserved. 26
A picture from childhood from one of our patients
Another picture from a patients childhood Many of these patients excelled at gymnastics and dance
EDNF 2011 Conference 8/2/11
All rights reserved. 27
EDNF 2011 Conference 8/2/11
All rights reserved. 28
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
EDNF 2011 Conference 8/2/11
All rights reserved. 29
Disorders of autonomic Control Associated
With Orthostatic Tolerance
Reflex Syndrome POTS Pure Autonomic
Failure
Multiple System Atrophy
Neurocardiogenic Syndrome
Miscellaneous (micturition, defecation, etc)
Carotid Sinus Hypersensitivity
Orthostatic Intolerance
Hypersensitivity Acute Chronic
Primary Secondary
Parkinsonian Cerebellar
Mixed
Chronic
Primary
Secondary
Acute Autonomic Neuropathy
Partial Dysautonomic
Primary
Secondary
Beta Hypersensitive
Micuration???
Other
Defecation
NCS CSH
Situational
Autonomic Failure
Disorders of the Autonomic Nervous System Associated with Orthostatic Intolerance
POTS Reflex Syncope
Pure Autonomic Failure
Multiple System Atrophy
Parkinsonian Mixed
Parkinson’s Disease
Cerebelluar
Diabetic JHS
Other
Paraneoplastic Diabetic
Other
NCS: Neurocardiogenic Syncope
CSH: Carotid Sinus Hypersensitivity
POTS: Postural Orthostatic Tachycardia Syncope
JHS: Joint Hypermobility Syndrome
EDNF 2011 Conference 8/2/11
All rights reserved. 30
Figure I: Subtypes of Postural Tachycardia Syndrome
POTS = Postural Tachycardia SyndromeJHS = Joint Hypermobility Syndrome
secondary
JHS
POTS
primary
partialdysautonomic
hyperadrenergic diabetes
other
postviral
developmental paraneoplastic
other
EDNF 2011 Conference 8/2/11
All rights reserved. 31
Autonomic Evaluation 1. BP/HR supine, sitting, standing at least 2 minutes
between each 2. Head up tilt 3. Serum catacholamine determinations 4. Baroreflex testing 5. Thermoregulatory Sweat Test 6. Sudomotor axon testing 7. Cold pressor test
Treatment
n Identify the Problem! n Education n Avoid predisposing factors n Support hose
EDNF 2011 Conference 8/2/11
All rights reserved. 32
Before embarking on Medical Therapy one must: 1. Avoid predisposing conditions or
medications 2. Have adequate fluid & salt intake 3. 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
EDNF 2011 Conference 8/2/11
All rights reserved. 33
“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. Fludrocortisone / DDAVP 2. Methylphenidate 3. Midodrine 4. Beta blockers 5. SSRIs 6. Clonidine 7. Erythropoietin 8. Yohimbine 9. Pyridostigmine 10. Norepinephrine reuptake inhibitors 11. Octreotide
EDNF 2011 Conference 8/2/11
All rights reserved. 34
Potential Treatment Modalities (Cont.)
n Treatment Midodrine
n Application 2.5-10 mg every 2-4 hrs; can titrate to
40 mg/day n Drawbacks
Nausea, supine hypertension
Midodrine - Neurocardiogenic Syncope
Months
p < 0.001 Sym
ptom
– F
ree
Inte
rval
180 160 140 120 100 80 60 40 20 0
100
80
60
40
20
0
Fluid Midodrine
Perez-Lugones, et al. J Cardiovas Electrophysiol 2001;12:935-938
All data not so robust for alpha agonists Raviele A. Etilefrine Circulation 1999;99:1452-7
EDNF 2011 Conference 8/2/11
All rights reserved. 35
EDNF 2011 Conference 8/2/11
All rights reserved. 36
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)
EDNF 2011 Conference 8/2/11
All rights reserved. 37
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)
EDNF 2011 Conference 8/2/11
All rights reserved. 38
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
EDNF 2011 Conference 8/2/11
All rights reserved. 39
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.
EDNF 2011 Conference 8/2/11
All rights reserved. 40
Results: " Twelve Patients " Age 33±18, " Eight (66.7%) females were found to have
symptoms of refractory OI, " 5 POTS " 5 OI " 2 Dyautonomia
Syncope Palpitations Fatigue
Effect of Octreotide in Patients suffering from Refractory OI
Syncope and Palpitations improved in almost 50%
EDNF 2011 Conference 8/2/11
All rights reserved. 41
Effect of Octreotide on Heart Rate
95
111
120 120
95
80
88
7884
68
0
35
70
105
140
1 2 3 4 5
Heart rate before treatmentHeart rate after treatment
P<0.05
Effect of Octreotide on Standing SBP
121114
80
138
80
125130
90
140
95
0
20
40
60
80
100
120
140
160
1 2 3 4 5
Systolic blood pressure atbaselineSystolic blood pressure aftertreatment
P<0.05
EDNF 2011 Conference 8/2/11
All rights reserved. 42
Effect of Octreotide on Standing DBP
50
60
9772
84
95
80
60
85
55
0
20
40
60
80
100
120
1 2 3 4 5
Diastolic Blood pressure atBaselineDiastolic Blood pressure aftertreatment
P=NS
Illness effects and can disrupt the entire family dynamic. Counseling is often critical in getting the patient and the family through this difficult period.
EDNF 2011 Conference 8/2/11
All rights reserved. 43
“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 Quartets
“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.
EDNF 2011 Conference 8/2/11
All rights reserved. 44
Albert Einstein
“The most beautiful thing that we can experience is the mysterious. It is the source of all true art and science…” Albert Einstein
Top Related