Grubb POTS 2slides

EDNF 2011 Conference 8/2/11

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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



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



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



100/70 mm/hg

70 b/m



Normal and Abnormal Tilt Response Patterns



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



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.  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



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



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



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

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 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))

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



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 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



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 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



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 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



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



“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



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



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

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 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 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 experience is the mysterious. It is the source of all true art and science…” Albert Einstein

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