EHLERS-DANLOS SYNDROME & DYSAUTONOMIA

EHLERS-DANLOS

SYNDROME &

DYSAUTONOMIA

Presented By

Lauren Stiles, JD

President & Co-Founder

New York Institute of Technology

December 8, 2017

Most studies are on hEDS

hEDS patients have more autonomic symptoms

than other EDS types

49% of hEDS patients have POTS, 31% have OI,

20% have normal hemodynamics1

In hEDS, autonomic dysfunction is classified as:

mild (47%)

moderate (33%)

Severe (3.3%)2

HOW MANY PEOPLE WITH EDS

HAVE AUTONOMIC DYSFUNCTION?

1 Celletti, C., Camerota, F., Castori, M., et al., 2017. Orthostatic intolerance and postural orthostatic

tachycardia syndrome in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type:

Neurovegetative dysregulation or autonomic failure? BioMed Res Int., 9161865.

2 De Wandele, I., Rombaut, L., Leybaert, L., et al., 2014b. Dysautonomia and its underlying mechanisms

in the hypermobility type of Ehlers-Danlos syndrome. Semin Arthritis Rheum. 44(1) 93-100.

Chronic

Migraine

Reflex

Syncope

Interstitial

Cystitis

Complex

Regional Pain

Syndrome

POTS/OI

Fibromyalgia

Syndromic

(Possibly Disease Based?)Disease-Based

Dysautonomias

PeripheralCentral

Pure

Autonomic

Failure

Multiple

System Atrophy

Small Fiber

Neuropathies

Parkinson’s/

Lewy Body

Dementias

DiabetesMetabolic

MitochondrialGenetic

Inflammatory ImmuneAdapted from Chelimsky T, Robertson D, Chelimsky G.

Disorders of the autonomic nervous system. In Daroff:

Bradley’s Neurology in Clinical Practice. 6th ed. Philadelphia,

PA; Elsevier: chap 77.

Chronic

Fatigue

Syndrome

IBS/CIPO/

Gastroparesis

HR increase of ≥30bpm from supine to standing within

10 minutes (≥40bpm for ages 12-18)

In the absence of orthostatic hypotension (defined

as ≥20/10mmHg drop within 3 min. of standing)

Symptoms of orthostatic intolerance lasting ≥6

months

Symptoms exacerbated by standing and improved

with recumbency

Absence of other overt causes of orthostatic

symptoms or tachycardia

POTS: DIAGNOSTIC CRITERIA

Pronounced orthostatic

tachycardia

Palpitations

Shortness of breath

Lightheadedness/pre-syncope

Syncope (20-30% with

overlapping NCS)

GI motility (33% too fast, 33%

too slow)

Nausea

Bladder dysfunction (17%)

POTS SYMPTOMS

Sensitivity to heat/cold

Sensitivity to l ight/sounds

Migraines

Profound fatigue

Weakness

Tremulousness

Exercise intolerance

Dependent acrocyanosis

Flushing

Increased allergies

Acrocyanotic legs after a few minutes of standing

Prolonged blanching/delayed capillary refill

DEPENDENT ACROCYANOSIS

Common form of orthostatic intolerance

US estimates, 500K-3M

Newer estimates are in the higher range

For comparison…

MS: 400K US estimate

Parkinson’s: 1M US estimate

Mayo Clinic estimates 1 in 100 teens (~500K)

About half of all patients have onset in adulthood

EPIDEMIOLOGY OF POTS

POTS IS NOT A

“TEENAGE SYNDROME”

1 Stiles L, Ross A. Physician

Patient Interaction in Postural

Orthostatic Tachycardia

Syndrome. Dysautonomia

International. 2014.

POTS “SUBTYPES” ARE

NOT DISTINCT DIAGNOSES

Hyperadrenergic

ORTHOSTATIC PAIN

ORTHOSTATIC PAIN

Orthostatic Headaches

Blood volume dysregulation

Chiari

CSF flow issues

CSF leak(s)

Check out Dr. Kinsella’s 2017 Conference Lecture on our Vimeo page:

www.vimeo.com/dysautonomia

POTS Controls P value

(n=65) (n=92)

Endometriosis 20% 5% .009

Uterine fibroids 25% 10% .015

Galactorrhea 9% 0% .004

Ovarian cysts 43% 13% <.001

Dysfunctional 14% 4% .042Bleeding

GYNECOLOGICAL

ABNORMALITIES IN POTS

Peggs KJ, Nguyen H, Enayat D, Keller NR, Al-Hendy A, Raj SR.

Gynecologic disorders and menstrual cycle lightheadedness in

postural tachycardia syndrome. Int J Gynaecol Obstet.

2012 Sept; 118(3): 242-246.

0 20 40 60 80

anxiety

stress from work/school/family

"all in your head"

depression

panic disorder

somatoform disorder

conversion disorder

munchausen's syndrome

factitious disorder

other mental/psychological illness

none of the above

Percent Total (%)

83% of POTS patients

given at least one psych

label prior to diagnosis

BEFORE your POTS diagnosis, were you ever told by a doctor that

your symptoms were due to the following diagnoses? Please

check all that apply:1

Other data suggests this is largely misdiagnosis…

Mayo 1992: Psychological domains similar amongst healthy

controls, CHF, COPD and POTS.

Vanderbilt 2009: POTS patients slightly less anxious than

general population, slight increase in mild depression .

Mayo 2016: mean mental composite score normal in

pediatric POTS.

When psychological comorbidity is present, it should be

addressed. Patients are often afraid to ask for help .

MISDIAGNOSIS

10g salt daily (3876mg sodium)

2-3L of hydrating fluids daily (avoid sugary drinks)

Medical compression stockings

Abdominal binders

Recumbent exercises

Good sleep habits

Learning about your illness can help you manage

symptoms better, and reduces fear of the unknown

Avoid heat, prolonged standing, hot showers, alcohol

Healthy diet

Cooling vests

POTS: NON-PHARMA TREATMENT

Avoid orthostatic stress during exercise until patient

builds up exercise tolerance, can take MONTHS/YEARS

Rowing,a recumbent bike, swimming, floor/core

Start SLOW and LOW

EDS - work with PT to stabilize & protect your joints

EXERCISE THERAPY

Vasoconstrictors

Midodrine

Octreotide

Droxidopa (Northera)

Phenylephrine (Sudafed PE)

Blood volume expansion

Fludrocortisone

Desmopressin

EPO

IV Saline

Beta blockers (less is more!)

Ivabradine

Mestinon

POTS: PHARMA TREATMENT

If mast cell dysfunction is

present:

H1/H2 blockers

Cromolyn (Gastrocrom)

Omalizumab (Xolair)

Ketotifen

Quercitin

Vitamin C

No FDA approved

treatment for POTS.

Maybe?

Assumption...

stretchy blood vessels due to EDS collagen probelms leads to

blood pooling, causing POTS

Reality.. .

No research documenting collagen deficits in hypermobile EDS

are causing stretchy blood vessels

No research showing that EDS/POTS patients have stretchier

blood vessels than non-EDS/POTS

Patients need answers backed by solid research that leads to

better treatments – we deserve more than assumptions!

IS EDS/POTS DIFFERENT

THAN NON-EDS/POTS?

AUTOIMMUNITY

SMALL FIBER NEUROPATHY

HYPOVOLEMIA

HYPERADRENERGIC STATE

HYPERTENSION

MAST CELL DYSFUNCTION

PEOPLE WITH EDS/POTS WHO RECOVER OR IMPROVE

“STRETCHY VEINS”

DON’T EXPLAIN…

Factors suggesting autoimmunity plays a role in POTS:

Female predominant condition (80-90% female)

50% have a post-viral onset

50% have small-fiber neuropathy

Increased rate of estrogen dependent co -morbidities

Mast cell abnormalities known to occur in early phases

of many autoimmune diseases

POTS & AUTOIMMUNITY

Dr. Francomano reported a high rate of autoimmunity

in her EDS patients in 2006, specifically:

RA/juvenile RA, lupus, Sjogren’s

12/72 consecutive EDS patients had one of these

autoimmune diseases.

7/72 had Raynaud’s, which is often seen in

autoimmune disorders.

“This raises the possibility that abnormalities of the

extracellular matrix might contribute to the

development of autoimmunity in the presence of other

genetic or environmental influences.”

EDS & AUTOIMMUNITY

Gustafson, Griswold, Burchett, Sherman, et al. Do abnormalities in the extracellular

matrix lead to autoimmune disorders? (2006) ASHG Annual Meeting; Program No. 608.

IRB approved structured online survey

3300 POTS patients, 400 variables

Patients from more than 15 countries

Largest POTS study to date – follow up surveys

in progress, plans to link to clinical data

THE BIG POTS SURVEY

2 Satish R. Raj MD MSCI, Lauren E. Stiles JD, Brett H Shaw MSc, Elizabeth A. Green MD, Cindy A. Dorminy MEd,

Cyndya A. Shibao MD MSCI, Luis E. Okamoto MD, Emily M. Garland PhD MSCI, Alfredo Gamboa MD MSCI, Andre

Diedrich MD PhD, Italo Biaggioni MD, David Robertson MD. The Face of Postural Tachycardia Syndrome (POTS): A

Cross-Sectional Community-Based Survey. Heart Rhythm 2016: 12 (5S):xx-xx (abstr) [in press].

Big POTS Survey results…

16% of all POTS patients report a confirmed

autoimmune disease.

18% of POTS patients also diagnosed with EDS report a

confirmed autoimmune disease.

Most commonly Hashimoto’s, Sjogren’s, lupus, celiac.

EDS, POTS & AUTOIMMUNITY

Initial 1993 description from Mayo suggested partial immune mediated neuropathy3

2012 Mayo Clinic: auto-immunoreactive IgGs to 40 different cardiac membrane proteins found in POTS 4

2014 Univ. of Oklahoma/Vanderbilt: 100% have adrenergic receptor antibodies (n=14),5 larger cohort in progress with EDS screening…

2014 Children’s Heart Institute: 15% of POTS subjects had significant expansion of double negative T cells, this correlated to the presence ofserum autoantibodies (n=60)6

POTS & AUTOIMMUNITY

VASOMOTOR NERVES & COLLAGEN

VIP

CD31

Col IV50 μm

• VIP-

Sympathetic

cholinergic

• CD31-

Vascular

marker

• Col IV-

Basement

membrane

Image courtesy of Dr. Roy Freeman, Harvard Medical School.

2015 SUNY Buffalo: 20% have comorbid autoimmune disease, 33% have commonly tested autoimmune markers (n=100 )7

2015 Mayo: 45% have thyroid and/or neural antibodies (n=33) compared to healthy controls (4.4%), 8 larger cohort in progress…

2015 Vanderbilt: increased IL -6, but normal CRP, in POTS9

2016 Stiles/Gudesblatt: 41% idiopathic dysautonomia patients with dry eyes or dry mouth have novel “early” Sjögren's antibodies SP-1, PSP, CA-6 (including 6 of 10 POTS patients in the study) (n=95)10

2016 UT Southwestern: Muscarinic receptor antibodies, 87.5% M1, 68.75% M2, 12.5% M3 (n=16), M1 & M2 statistically significant compared to 20 controls, M1 correlatedto cognitive impairment,11 larger cohort inprogress with EDS screening…

POTS & AUTOIMMUNITY

2016 Univ Oklahoma/Lund University: Swedish cohort

of 17 POTS, 7 VVS, and 11 healthy controls. All of the

POTS subjects had at least one type of adrenergic

receptor antibody (12 had beta-2, 11 had beta-1, 8 had

alpha-1). None of these antibodies were found in VVS

or controls.12

More research in progress...

POTS & AUTOIMMUNITY

AUTOIMMUNITY


HYPOVOLEMIA


HYPERTENSION


PEOPLE WHO RECOVER/IMPROVE


DON’T EXPLAIN…


Different types of small fiber nerves: sensory, sudomotor, vasomotor, etc.

Sudomotor dysfunction found in 65% of EDS patients

Sudomotor dysfunction found in 50% of all POTS patients

Vasomotor neuropathy/POTS research in progress at Harvard

Small fiber nerves help regulate blood vessel constriction

When nerves are damaged, blood vessels can’t constrict


DON’T EXPLAIN…

AUTOIMMUNITY


HYPOVOLEMIA


HYPERTENSION




DON’T EXPLAIN…

HYPOVOLEMIA

Almost all POTS patients have low blood volume

Plasma and red blood cells are equally low

Plasma volume controlled by aldosterone

Many other factors involved in regulating blood volume

Partial loss of sympathetic nerves in kidney suggested as

possible reason for low aldosterone (perhaps adrenergic

antibodies?)

Iron storage deficiency common in POTS


DON’T EXPLAIN…

AUTOIMMUNITY


HYPOVOLEMIA


HYPERTENSION




DON’T EXPLAIN…


Almost all POTS patients have elevated plasma NE

Some more than others

Experts don’t agree on a definition for what constitutes

“hyperadrenergic” POTS

Causes of elevated plasma NE:

autonomic neuropathy

hypovolemia

anxiety

NET: mutations, epigenetic changes & mRNA variants

antibodies?

do stretchy veins contribute?


DON’T EXPLAIN…

AUTOIMMUNITY


HYPOVOLEMIA


HYPERTENSION




DON’T EXPLAIN…

HYPERTENSION IN POTS

During tilt testing:

1/3 of POTS patients drop BP (not to the point of OH)

1/3 of POTS patients maintain normal BP

1/3 of POTS patients increase BP

Some EDS/POTS patients increase BP on tilt

Some EDS/POTS patients experience hypertension even

sitting or laying down, or in response to stressors


DON’T EXPLAIN…

AUTOIMMUNITY


HYPOVOLEMIA


HYPERTENSION




DON’T EXPLAIN…

MAST CELL ACTIVATION SYNDROME

No clear answer on % overlap between POTS/EDS/MCAS

Vanderbilt 2005: first recognition of POTS/MCAS overlap

Mayo 2014: many POTS patients tested positive for at least one MCAS

biomarker

NIH 2014: approx. 40 families with hereditary tryptase mutations.

POTS/EDS/MCAS occur in some of these families.

associated with elevated baseline tryptase, which Mayo suggests is found in

less than 1 in 1000 POTS patients

likely just a risk factor, not the “cause” of “the trifecta of EDS/POTS/MCAS”

Univ. Toronto 2015: POTS, EDS, MCAS may frequently overlap

Prior research in Germany: andrenergic antibodies cause mast cells to

mature faster and degranulate more readily (these antibodies reported in

POTS)

More studies in progress…


DON’T EXPLAIN…

AUTOIMMUNITY


HYPOVOLEMIA


HYPERTENSION




DON’T EXPLAIN…


There are some people who have POTS/EDS who see

significant improvement in their POTS symptoms over time,

and some who considered themselves recovered from POTS.

Then still have EDS, so something else must have caused their

POTS.

One example: Very hypermobile adolescent female, athletic/active

Acute onset POTS after a cold

Homebound, almost bedridden

Diagnosed with EDS and POTS

Had the adrenergic antibodies (Univ Oklahoma)

Received IVIG as part of a research study

Antibodies reduced, POTS symptoms improved, but not 100%

She still has EDS


DON’T EXPLAIN…

OUTCOMES IN ADOLESCENT POTS

19.2%

51.2%

15.7%

8.7%

3.5%

1.7%

Symptoms completely resolved

Symptoms persist, severity better

Remitting and relapsing

Symptoms persist, severity same

Symptoms persist, severity worse

Not reported

Adapted from: Bhatia R, Kizilbash SJ, Aherns SP,

Killian JM, Kimmes SA, Knoebel EE, Muppa P,

Weaver AL and Fischer PR. Outcomes of Adolescent-

Onset Postural Orthostatic Tachycardia Syndrome.

The Journal of Pediatrics. [Article in Press]. DOI:

dx.doi.org/10.1016/j.jpeds.2016.02.035.

Does Screening for Ehlers-Danlos Syndrome in Postural Tachycardia Syndrome Matter? Insights from a Cross-Sectional Community-Based Survey

Satish R. Raj MD MSCI1,3, Lauren E. Stiles JD2, Brett H. Shaw MSc1, Jessica Ng BSc1, Elizabeth A.

Green MD, Cyndya A. Shibao MD MSCI3, Luis E. Okamoto MD3, Emily M. Garland PhD MSCI3,

Alfredo Gamboa MD MSCI3, Andre Diedrich MD PhD3, Italo Biaggioni MD3 and David Robertson

MD3

1Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada; 2Dysautonomia International, East Moriches, NY, USA; 3Autonomic Dysfunction Center, Vanderbilt

University, Nashville, TN, USA

HEART RHYTHM SOCIETY 2017 ABSTRACT

STUDY AIM

To characterize the similarities

and differences between POTS

patients with and without EDS

SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017

METHODS

• Cross-sectional, web-based survey

• “Diagnosis and Impact of POTS” study

• Vanderbilt IRB Approval

• Survey l inks posted to Dysautonomia International website &

social media channels

• Survey data collected July 2015 - October 2016


RESULTS

• > 15 countries (primarily USA)

• Physician diagnosed POTS = 3389 patients

Female Male0

20

40

60

80

100

Perc

en

t (%

)

EDS No EDS0

20

40

60

80

100

Perc

en

t (%

)

Female vs. Male EDS vs. Non-EDS


RESULTS – ORTHOSTATIC

No dif ferences in orthostatic symptom reporting between

POTS patients with and without EDS

Lighth

eadedness

Syncope

Tachycardia

Palpita

tions

Dyspnea0

20

40

60

80

100

Per

cent

(%)

EDSNo EDS


RESULTS – SYMPTOMS ONSET

POTS patients with EDS

were less likely to report symptom onset after a triggering

event,

had a greater tendency to report dealing with POTS-like

symptoms for most of life

EDS No EDS0

20

40

60

80

100

Perc

en

t (%

)EDS No EDS

0

20

40

60

80

100

Perc

en

t (%

) p=0.009 p<0.001

Triggering Event Lifelong Symptoms


RESULTS – GI

GI symptoms are reported significantly more often by

patients with EDS

EDSNo EDS

Constip

ation

Vomiti

ng

Stom

ach pain

Heart

burn/G

ERD

Dysphagia

0

20

40

60

80

100

Perc

en

t (%

) p=0.003

p<0.001

p<0.001p<0.001

p<0.001


RESULTS – SENSORY

Sensory neuropathic symptoms reported significantly

more often in patients with EDS

EDSNo EDS

Skin b

urnin

g

Hand tinglin

g

Hand burn

ing

Hand num

bness

Cold h

ands0

20

40

60

80

100

Per

cen

t (%

)

p<0.001

p<0.001

p<0.001

p<0.001

p=0.001


Sensory neuropathic symptoms reported significantly

more often in patients with EDS

EDSNo EDS


RESULTS – SENSORY

Facial t

inglin

g

Facial n

umbness

Foot tin

gling

Foot num

bness

Cold fe

et0

20

40

60

80

100

Per

cen

t (%

)

p<0.001

p<0.001p<0.001

p<0.001p=0.001

BIG PICTURE

• There is a lot of neuropathy in EDS.

• We need detailed pathology studies to

know why.

Is the collagen in/around the nerve fibers impaired?

Are the nerves damaged by an inflammatory or

immune mediated process?

Some other reason?

• Why do EDS patients have

small fiber neuropathy?

CONNECT WITH US…

www.dysautonomiainternational.org

www.facebook.com/dysautonomiainternational

www.vimeo.com/dysautonomia

Twitter: @Dysautonomia

[email protected]

~ THANK YOU ~

3 . S c h o n d o r f R , L o w P A . I d i o p a t h i c p o s t u ra l o r t h o s ta t i c t a c h y c a r d i a s y n d r o m e : a n a t t e n u a t e d f o r m o f a c u t e p a n d y s a u t o n o m i a ? N e u r o l o g y . ( 1 9 9 3 ) 4 3 ( 1 ) ; 1 3 2 - 1 3 7 .

4 . W a n g X L , C h a i Q , C h a r l e s w o r t h M C , F i g u e r o a J J , e t a l . A u t o i m m u n e r e a c t i v e I g G s f r o m p a t i e n t s w i t h p o s t u r a l o r t h o s t a t i c t a c h y c a r d i a s y n d r o m e . P r o t e o m i c s C l i n . A p p l . ( 2 0 1 2 ) 6 ; 6 1 5- 6 2 5 .

5 . L i H , Y u X , L i l e s C , K h a n M , e t a l . A u t o i m m u n e B a s i s f o r P o s t u ra l T a c h y c a r d i a S y n d r o m e . J o u r A m e r H e a r t A s s n . ( 2 0 1 4 ) 3 ( 1 ) ; e 0 0 0 7 5 5 .

6 . A b d a l l a h H , P l a s s m e y e r M , R y h e r d M , A u s t i n L , e t a l . I m m u n o p h e n o t y p i c p r o f i l e s i n p a t i e n t s w i t h p o s t u r a l o r t h o s t a t i c t a c h y c a r d i a s y n d r o m e . C l i n A u t o n R e s . ( 2 0 1 4 ) 2 4 : 2 1 5 .

7 . B l i t s h t e y n S . A u t o i m m u n e m a r k e r s a n d a u t o i m m u n e d i s o r de r s i n p a t i e n t s w i t h p o s t u ra l t a c h y c a r d i a s y n d r o m e ( P O T S ) . L u p u s . ( 2 0 1 5 ) 0 ; 1 - 6 .

8 . S i n g e r W , K l e i n C J , L o w P A , L e n n o n V . A u t o a n t i bo d i e s i n t h e p o s t u r a l t a c h y c a r d i a s y n d ro m e . C l i n A u t o nR e s . ( 2 0 1 4 ) 2 4 : 2 1 4 .

9 . O a k a m o t o L E , R a j S R , G a m b o a A , S h i b a o C A , e t a l . S y m p a t h e t i c A c t i v a t i o n i s A s s o i c a t e d w i t h I n c r e a s e d I L - 6 , b u t n o t C R P i n t h e A b s e n c e o f O b e s i t y : L e s s o n s f r o m P o s t u r a l T a c h y c a r d i a S y n d r o m e a n d O b e s i t y . A M J P h y s i o l H e a t h C i r c P h y s i o l . ( 2 0 1 5 ) 3 0 9 ( 1 2 ) ; H 2 0 9 8 - 1 0 7 .

1 0 . A A N A n n u a l M e e t i n g a b s t r a c t p u b l i s h e d o n l i n e ( 2 0 1 6 ) : G u d e s b l a t t M , W i s s e m a n n K , S t i l e s L , X i a n S , e t a l . A u t o i m m u n i t y & A u t o n o m i c I m p a i r m e n t : P r e l i m i n a r y C h a r a c t e r i z a t i o n o f a C l i n i c a l S y n d ro m e w i t h S j ö g r e n ' s F e a t u re s A s s o c i a t e d w i t h N o v e l O r g a n S p e c i f i c A n t i b o d i e s . N e u r o l og y . ( 2 0 1 6 ) 7 8 ( M e e t i n g A b s t r a c t s ) ; P 5 . 1 0 8 .

1 1 . D u b e y D , H o p k i n s S , V e r n i n o S . M 1 a n d M 2 M u s c a r i n i c r e c e p to r a n t i b o d i e s a m o n g s t p a t i e n t s w i t h P o s t u r a l O r t h o s t a t i c T a c h y c a r d i a S y n d r o m e : p o t e n t i a l d i s e a s e b i o m a r k e r . J C l i n N e u r o m u s c u l D i s .( 2 0 1 6 ) 1 7 ( 3 ) .

1 2 . F e d e r o w s k i , L i , Y u , K o e l s c h , e t a l . A n t i a d r e n e r g i c a u t o i m m u n i t y i n p o s t u ra l t a c h y c a r d i a s y n d r o m e . E u r o p a c e . ( i n p r e s s ) .

POTS & AUTOIMMUNITY

CITATIONS

Documents

EHLERS-DANLOS SYNDROME & DYSAUTONOMIA