EHLERS-DANLOS SYNDROME & DYSAUTONOMIA
Presented By Lauren Stiles, JD President & Co-Founder
New York Institute of Technology December 8, 2017 HOW MANY PEOPLE WITH EDS HAVE AUTONOMIC DYSFUNCTION? 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 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. Dysautonomias
Syndromic Disease-Based (Possibly Disease Based?)
Reflex Central Peripheral POTS/OI Syncope
Multiple Pure Complex Chronic System Atrophy Autonomic Regional Pain Fatigue Failure Syndrome Syndrome Parkinson’s/ Interstitial Lewy Body Small Fiber Fibromyalgia Dementias Neuropathies Cystitis IBS/CIPO/ Chronic Metabolic Diabetes Gastroparesis Migraine
Adapted from Chelimsky T, Robertson D, Chelimsky G. Inflammatory Immune Disorders of the autonomic nervous system. In Daroff: Bradley’s Neurology in Clinical Practice. 6th ed. Philadelphia, PA; Elsevier: chap 77. Genetic Mitochondrial POTS: DIAGNOSTIC CRITERIA
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 SYMPTOMS
Pronounced orthostatic Sensitivity to heat/cold tachycardia Sensitivity to light/sounds Palpitations Migraines Shortness of breath Profound fatigue Lightheadedness/pre-syncope Weakness Syncope (20-30% with Tremulousness overlapping NCS) Exercise intolerance GI motility (33% too fast, 33% Dependent acrocyanosis too slow) Flushing Nausea Increased allergies Bladder dysfunction (17%) DEPENDENT ACROCYANOSIS
Acrocyanotic legs after a few minutes of standing Prolonged blanching/delayed capillary refill EPIDEMIOLOGY OF POTS
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 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 GYNECOLOGICAL ABNORMALITIES IN POTS
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% .042 Bleeding
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. 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
Percent Total (%) 0 20 40 60 80 anxiety stress from work/school/family "all in your head" depression panic disorder somatoform disorder conversion disorder 83% of POTS patients munchausen's syndrome given at least one psych factitious disorder label prior to diagnosis other mental/psychological illness none of the above MISDIAGNOSIS
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. POTS: NON-PHARMA TREATMENT
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 EXERCISE THERAPY
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 POTS: PHARMA TREATMENT
Vasoconstrictors If mast cell dysfunction is present: . Midodrine . Octreotide . H1/H2 blockers . Droxidopa (Northera) . Cromolyn (Gastrocrom) . Phenylephrine (Sudafed PE) . Omalizumab (Xolair) Blood volume expansion . Ketotifen . Fludrocortisone . Quercitin . Desmopressin . Vitamin C . EPO . IV Saline No FDA approved Beta blockers (less is more!) treatment for POTS. Ivabradine Mestinon IS EDS/POTS DIFFERENT THAN NON-EDS/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! “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WITH EDS/POTS WHO RECOVER OR IMPROVE POTS & AUTOIMMUNITY
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 EDS & 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.” Gustafson, Griswold, Burchett, Sherman, et al. Do abnormalities in the extracellular matrix lead to autoimmune disorders? (2006) ASHG Annual Meeting; Program No. 608. THE BIG POTS SURVEY
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
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]. EDS, POTS & AUTOIMMUNITY
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. POTS & AUTOIMMUNITY
Initial 1993 description from Mayo suggested partial immune mediated neuropathy 3
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 of serum autoantibodies (n=60) 6 VASOMOTOR NERVES & COLLAGEN
• VIP- Sympathetic cholinergic • CD31- Vascular marker • Col IV- Basement
VIP membrane CD31 Col IV 50 μm
Image courtesy of Dr. Roy Freeman, Harvard Medical School. POTS & AUTOIMMUNITY
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 POTS 9
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 correlated to cognitive impairment, 11 larger cohort in progress 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... “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WHO RECOVER/IMPROVE “STRETCHY VEINS” DON’T EXPLAIN…
SMALL FIBER NEUROPATHY . 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 “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WHO RECOVER/IMPROVE “STRETCHY VEINS” 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 “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WHO RECOVER/IMPROVE “STRETCHY VEINS” DON’T EXPLAIN…
HYPERADRENERGIC STATE . 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? “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WHO RECOVER/IMPROVE “STRETCHY VEINS” 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 “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WHO RECOVER/IMPROVE “STRETCHY VEINS” 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… “STRETCHY VEINS” DON’T EXPLAIN…
AUTOIMMUNITY SMALL FIBER NEUROPATHY HYPOVOLEMIA HYPERADRENERGIC STATE HYPERTENSION MAST CELL DYSFUNCTION PEOPLE WHO RECOVER/IMPROVE “STRETCHY VEINS” DON’T EXPLAIN…
PEOPLE WHO RECOVER/IMPROVE . 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 OUTCOMES IN ADOLESCENT POTS
1.7% 3.5% Symptoms completely resolved 19.2% Symptoms persist, severity better 8.7% Remitting and relapsing Symptoms persist, severity same
15.7% 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: 51.2% dx.doi.org/10.1016/j.jpeds.2016.02.035. HEART RHYTHM SOCIETY 2017 ABSTRACT
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 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 links posted to Dysautonomia International website & social media channels
• Survey data collected July 2015 - October 2016
SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 RESULTS
• > 15 countries (primarily USA) • Physician diagnosed POTS = 3389 patients Female vs. Male EDS vs. Non-EDS 100 100
) 80 ) 80
%
%
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t 60 t 60
n
n
e
e
c
c
r r 40 40
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P P 20 20 0 0 Female Male EDS No EDS
SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 RESULTS – ORTHOSTATIC
No differences in orthostatic symptom reporting between POTS patients with and without EDS No EDS EDS 100
) 80
%
(
t 60
n
e
c
r 40
e P 20 0
s e a s a s p i n e e o rd io n n c a t p d n c ta s e y y i y d S h lp D a c a e a P th T h ig L SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 RESULTS – SYMPTOMS ONSET
Triggering Event Lifelong Symptoms 100 100 p=0.009 p<0.001
) 80 ) 80
% %
( (
t 60 t
n 60 n
e e
c c
r 40
r 40
e e
P 20 P 20 0 0 EDS No EDS EDS No EDS 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
SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 RESULTS – GI
GI symptoms are reported significantly more often by patients with EDS No EDS EDS 100 p<0.001
) p=0.003 80 p<0.001
%
(
p<0.001 t 60 n p<0.001
e
c
r 40
e P 20 0 n g in D ia io in a R g t it p E a a h ip m h /G p t o c n s s V a r y n m u D o o b C t rt S a e H SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 RESULTS – SENSORY
Sensory neuropathic symptoms reported significantly more often in patients with EDS No EDS EDS 100 p<0.001 p<0.001
) 80 p<0.001
%
(
t 60 p=0.001
n
e p<0.001
c
r 40
e P 20 0 g g g s s n n n s d i li i e n rn g rn n a u n u b h ti b b m ld n d d u o i n n n k a a d C S H H n a H SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 RESULTS – SENSORY
Sensory neuropathic symptoms reported significantly more often in patients with EDS No EDS EDS 100 p<0.001
) 80 p<0.001
% p<0.001
(
t 60 n p=0.001 e p<0.001
c
r 40
e P 20 0 t g s g s e in s in s e l e l e f g n g n d in b in b l t m t m o l u t u C ia n o n c l o t a ia F o F c o a F F SR Raj et al., Heart Rhythm Society Scientific Sessions, Chicago IL, May 2017 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? ~ THANK YOU ~
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3 . S c h o n d o r f R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia ? Neurology. (1993)43(1);132- 1 3 7 .
4 . Wang XL, Chai Q, Charlesworth MC, Figueroa JJ, et al. Autoimmunereactive I g G s from patients with postural orthostatic tachycardia syndrome. Proteomics C l i n . A p p l . (2012)6;615- 6 2 5 . 5 . L i H, Yu X, Liles C, Khan M, et al. Autoimmune Basis for Postural Tachycardia Syndrome. J o u r A m e r H e a r t A s s n .(2 0 1 4 )3(1);e000755. 6 . A b d a l l a h H , P l a s s m e y er M , R y h e r d M, Austin L, et al. Immunophenotypic profiles in patients with postural orthostatic tachycardia syndrome. C l i n A u t o n R e s . (2014)24: 2 1 5 . 7 . B l i t s h t ey n S. Autoimmune markers and autoimmune disorders in patients with postural tachycardia syndrome (POTS). L u p u s . (2015)0;1 -6 .
8. Singer W, Klein CJ, Low PA, Lennon V. Autoantibodies in the postural tachycardia syndrome. C l i n A u t o n R e s . (2014)24:214.
9 . O a k a m o t o LE, Raj SR, G a m b o a A , S h i b a o CA, et al. Sympathetic Activation is A s s o i c a t ed with Increased IL- 6, but not CRP in the Absence of Obesity: Lessons from Postural Tachycardia Syndrome and Obesity. A M J P h y si ol H e a t h C i r c P h y s i ol . (2015)309(12);H2098-1 0 7 . 10. AAN Annual Meeting abstract published online (2016): G u d es b l a t t M , W i s s e m a n n K, Stiles L, Xian S, et al. Autoimmunity & Autonomic Impairment: Preliminary Characterization of a Clinical Syndrome with S j ö g r en' s Features Associated with Novel Organ Specific Antibodies. N e u r ol og y. (2016)78(Meeting Abstracts);P5.108. 11. Dubey D, Hopkins S, V e r n i n o S. M1 and M2 Muscarinic receptor antibodies amongst patients with Postural Orthostatic Tachycardia Syndrome: potential disease biomarker. J C l i n Neuromuscul D i s . (2016)17(3). 1 2 . F e d er o ws k i , L i , Y u , K o e l s c h , et al. Antiadrenergic autoimmunity in postural tachycardia s y n d r o me . E u r o p a c e . (in press ).