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