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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. - PowerPoint PPT Presentation
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Postural Tachycardia Syndrome
Blair P. Grubb MD FACCDepartments of Medicine and Pediatrics
Health Science CampusUniversity of ToledoToledo, 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. Heart Rate2. Blood Pressure Control3. Body Temperature4. Bowel Motility5. Sweating6. Breathing7. Genital-urinary function
Autonomic Nervous System
Periods of autonomic decompensationResulting in hypotension (with or withoutBradycardia) may have a wide variety of Clinical manifestations, such as:
Vertigo/dizzinessLightheadednessConvulsive ActivityTIASSyncope/near syncopeFatigueCognitive Impairment
100/70 mm/hg
70 b/m
Normal and AbnormalTilt Response Patterns
Venous Pooling in POTS
Pooling
Supine Upright
Normal
Orthostatic Intolerance:
Provocation of symptoms upon standingthat 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 andthe American Academy of Neurology
Manningham 1750 An account of Febricula.Archives
of the Boston Medical Society
Chronically fatigued and broken down women, whowere healthy until a febrile illness (febricula) made them:“weak, pallid, flabby… poor eaters; digesting ill,incapable of exercise. They lie in bed hopeless andhelpless” The least bit of exertion” would cause theirhearts to pound rapidly and violently”
Da Costa JM: On Irritable heart: A clinical study of aFunctional cardiac disorder and it’s consequences.Am J Med Sci 1871:61:17-52
“Dizziness,headache, chest pain, faintness andExtreme 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 andGiddiness”“when completely rested the heart rate averaged 85 bpmAnd when up and about would rise to rates of 120 bpm”He documented BP drop of between 20 - 40 mmHg uponStanding
“the potential reservoir in the veins takes up the blood,The supply to the heart falls away , and arterial pressureFalls rapidly”
POTS – Reported descriptions
1. Low et al Mayo Clinic 1993 16 pt2. Schondorf et al McGill 1995 20 pt3. Khurana et al Un. Of Md 1995 10 pt4. Grubb et al MCO 1997 28 pt5. Karas et al MCO 2000 30 pt
Symptoms in POTS Pts. (%)
Lightheadedness 85-95Dizziness 60-80Palpitations 40-55Exercise Intolerance 50-85Blurred Vision 70Chest discomfort 60Clamminess 60
Symptoms in POTS Pts. (%) cont.Near Syncope 50Anxiety 50Flushing 50Syncope 40-45Fatigue 45-75Headache 50Dyspnea 40
Criteria for POTS1. Longstanding (>6 months) and disabling orthostatic
symptoms2. 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/ml5. Excessive isoproterenol response
So just how many people are wetalking 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 Med2002;137:753-763
POTS patients suffer a degree of functionalimpairment similar to that of patientswith COPD or CHF
Benrud-Larson et al, Quality of life in patients with posturaltachycardia syndrome. Mayo Clinic Proceedings 2002: 77, 531-537
Approximately 25% of POTS/OIpatients are considered functionally disabled
and unable to work
Benrud-Larson et al ; Correlates of functional disability in patientswith Postural Tachycardia syndrome: Preliminary Cross sectionalfindings. 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
Robertson D. New Eng J Med 2000;342:541-49
Orthostatic Intolerance and Tachycardia Associated with Norepinephrine-Transporter Deficiency
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 thethe 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 andeasy bruising. Stretch marks were common.
In the late 1990s investigators at the JohnsHopkins Hospital realized that many of
these patients met the criteria forType III Ehlers-Danlos Syndrome (now called
the joint hypermobility syndrome).
J Pediatrics 1999;135:494-9
So just what isJoint Hypermobility/Ehlers-Danlos
Syndrome?
Ehlers-Danlos Syndrome (Type III orjoint hypermobility syndrome))
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 of1. nausea and bloating (due to gastroparisis and GB disease)2. orthostatic acrocyanosis3. joint pain and dislocations4. hernias5. constipation 6. hemorrhoids7. 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 100Post-exertional malaise 100Unrefreshing sleep 100Impaired memory/concentration 92Multi-joint pain 83New headaches 83Muscle pain 58Sore throat 25Tender glands 25
In July 2000 a new classification ofEDS was made along with a new setof diagnostic criteria.
The previous Beighton score was replaced with what are now called the Brightoncriteria
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 jointsMINOR CRITERIA:2. Beighton score of 1,2 or 3/9 (0,1,2 or 3 if aged 50+3. Arthralgia (>3 months) in 1-3 joints or back pain (>3 M) spondylosis, spondylosis/spondyloisthesis3. Dislocation/subluxation in more than one joint4. Soft tissue rheumatism >3 lesions (epicondylitis etc.)5. Marfanoid habitus6. Abnormal skin: striae, hyperextensibility,thin,scarring7. Eye signs: drooping eyelids or myopia8. Varicose veins, hernia or utero/rectal prolapse
Diagnosis is made by the presence of:
1. two major criteria2. one major and two minor criteria3. four minor criteria4. two minor criteria with an unequivocally affected first degree relative
Diagnosis excluded by presence of Marfansor the other EDS subtypes
J Rheumatology 2000;27:1777-1779
A picture from childhood from one of our patients
Another picture froma patients childhood
Many of these patientsexcelled at gymnasticsand 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 hypermobilitysyndrome. Am J Med 2003; 115: 33-44
48 pts with Joint Hypermobility Syndrome(JHS) werecompared 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 intoleranceand abnormal autonomic testing (on every one of thetests mentioned above), as compared to 10%of control subjects
They concluded that JHS/EDS IIIpredisposed people to develop OI
Disorders of autonomic Control Associated
With Orthostatic Tolerance
Reflex SyndromePOTS 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
POTSReflex Syncope
Pure Autonomic Failure
Multiple System Atrophy
Parkinsonian Mixed
Parkinson’s Disease
Cerebelluar
Diabetic JHS
Other
Paraneoplastic Diabetic
Other
NCS: Neurocardiogenic SyncopeCSH: Carotid Sinus HypersensitivityPOTS: Postural Orthostatic Tachycardia SyncopeJHS: Joint Hypermobility Syndrome
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
Autonomic Evaluation1. BP/HR supine, sitting, standing at least 2 minutes
between each2. Head up tilt3. Serum catacholamine determinations4. Baroreflex testing5. Thermoregulatory Sweat Test6. Sudomotor axon testing7. Cold pressor test
Treatment
Identify the Problem!EducationAvoid predisposing factorsSupport hose
Before embarking on Medical Therapy one must:1. Avoid predisposing conditions or
medications2. Have adequate fluid & salt intake3. Reconditioning and lower extremity
strength building a. aerobic training 30 min. 3/week b. resistance training
Pharmacotherapy is employed tomake the patient feel well enoughso that they can begin a reconditioningprogram
“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.
Pharmacotherapy1. Fludrocortisone / DDAVP2. Methylphenidate3. Midodrine4. Beta blockers5. SSRIs6. Clonidine7. Erythropoietin8. Yohimbine9. Pyridostigmine10. Norepinephrine reuptake inhibitors11. Octreotide
Potential Treatment Modalities (Cont.)
TreatmentMidodrine
Application2.5-10 mg every 2-4 hrs; can titrate to
40 mg/day Drawbacks
Nausea, supine hypertension
Midodrine - Neurocardiogenic Syncope
Months
p < 0.001Sym
ptom
– F
ree
Inte
rval
180160140120100806040200
100
80
60
40
20
0
FluidMidodrine
Perez-Lugones, et al. J Cardiovas Electrophysiol 2001;12:935-938
All data not so robust for alpha agonistsRaviele A. Etilefrine Circulation 1999;99:1452-7
SSRI
Girolamo et al JACC 1999: Randomized, double blind,
placebo-controlled trial of Paroxetine in NCS
SSRI
Recurrence rate over 25 months17.6% paroxetine52.9% placebo
(p <0.0002)
Pyridostigmine:An acetlycholinesterase inhibitorIncreases acetlycholine levels atthe autonomic ganglia Prevents drop in BP without causingsupine hypertension
Usual dose:60 mg PO BID
Pyridostigmine
The Vanderbilt group published a randomizeddouble blind placebo controlled crossover trialof pyridostigmine in POTS pts. finding that it reduced heart rate + blood pressure changes aswell as symptoms (Circulation 2005)
The Mayo group published a double blind placebocontrolled 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 POTS5 OI2 Dyautonomia
Syncope Palpitations Fatigue
Effect of Octreotide in Patients suffering from Refractory OI
Syncope and Palpitations improved in almost 50%
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
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 theentire family dynamic. Counselingis often critical in getting the patientand the family through this difficultperiod.
“We shall not cease from exploration,and the end of all our exploringwill be to arrive where we startedand to know the placefor 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.
Albert Einstein
“The most beautiful thing that we can experienceis the mysterious. It is the source of all true artand science…” Albert Einstein