The Science and Diagnosis of

the Hypermobility Syndrome

Dr. Anne Stanwix

SARAA Congress, Durban, March 2019

Outline of presentation

• History of Talk

• 1995 SARAA Prof Rodney Grahame

• 2017 Prof Alan Hakim

• Personal and Academic Disclosures

• Answered and Unanswered Questions

• Features of Conditions

• New and Old Classifications 1973; 1998; 2017

• New Names EDS Type III and JHS, hEDS and HSD

• Dysautonomia and links to many conditions

• hEDS with other AIDs

• 2 Case Studies dealing with complexities

Personal

• hEDS family

• Dental woes

• Local anaesthetic failure

• Knee effusions after hiking

• Snapping hip (iliotibial band)

• Phobias

• Difficult to correct myopias

• Smaller step/ slower gait

• ADHD; ASD; OCD

• Syncope and near-syncope

EDS – the term

• 1901 Ehlers

• 1908 Danlos

• 1936 EDS

• 1973 Beighton – genetics and score

• 1998 Brighton Criteria

• 2017 International EDS Consortium

• EDS patients are not listened to, believed, diagnosed or correctly Rxed

• Prof Rodney Grahame

Academic Questions

• Why is HM so common in our South African context ?

• Why is hEDS so over-represented in Askenazi Jews ?

• 3 Answers

• Why are there so many HM patients at our clinics?

• Pain (local; widespread; neuropathic)

• Misdiagnosis ?

hEDS + other autoimmune disease (AID)

Problem of assessing HM in context

• What do we know?

• If prior laxity do worse with RA

• Autonomic dysfunction (RP/hyperhidrosis) worse activity and

outcomes

Studies in 1990’s :

• Percentage of remission of RA in pregnancy linked to the increased stability of

ANS

• eg: POTS (Postural Orthostatic Tachycardia Syndrome)

• 60-70% improve during pregnancy

• Kaiser Study AJM 1998 (VJ Felitti et al)

• Comparison of Current Adult Health Status to Childhood Experiences

• ACE’s (Adverse childhood experiences) associated with CVD; DM; AIDs;

Cancer; Mood disorders

• A harsh painful childhood leads to a lifetime of health problems

• Over the years – Asthma/ Anxiety/ PTSD associated with increased risk of

SLE

• 2017 PTSD linked to almost 3 x higher risk of Lupus

• Severe life stresses predate onset AIDs - in one study 80%

• hEDS has an increased incidence of AIDs

• hs EDS in itself a risk factor for development of AIDs?

• Through what mechanism ? Genetics or epigenetics

• Autonomic dysfunction associated many AIDs

• Scl; SS; SLE; RA; DM; HypoTH

• Autonomic dysfunction in AID consequence or cause?

hEDS vs HSD (Hypermobility Spectrum Disorder) • Identical concerns and management

• Musculoskeletal

• Visceral

• Autonomic

• Anxiety-related

• Use HSD when not all criteria fulfilled for hEDS

How common?

• Both Autosomal Dominant No gene, High penetrance + variable expression

• HSD very UK study 2013 HSD + CWP 3%

• HSD alone 10-20%

• > child below 5 or even < 10 difficult to evaluate

> women

Asians

(West) Africans

• HSD (JHS) most common of the HDCT

• Hereditary Disorders of CT – JHS; EDS; Marfan; OI

Why are they of NB?

-Recurrent soft tissue injuries -Decreased physical fitness

-Fatigue -Anxiety States

-CRPS + CWP -Affect ADL + QOL

-Autonomic CV and bowel & bladder disturbances

What about EDS?

• Skin / Joint / Tissue fragility

Kyphoscoliosis/ brittle corneas/ myopathic/peridontal

• 2017 Classification 13 types

classic EDS (cEDS) COL5A1/5A2

vascular EDS (vEDS) COL3A1

classic-like (clEDS)

• hs EDS 1 in 5000 > 1 in 1000

Features hEDS

• MUSCULOSKELETAL

• Joints – small and large

• Spine – thoracolumbar scoliosis leads to degenerative back

• Dislocation - shoulder/patella/TMJ

• Acute pain – joint/tendon/ligament - -universal

• Chronic joint pain cf FMS CWP

• SKIN

• modest cf classic form

• Soft translucent velvety – easy bruising

• Wide scars – often sunken (atrophic)

• Foot lesions – Piezogenic papules side feet (fat herniations)

• Striae (pubertal) – Varicose veins

• Keratosis pilaris – hyperkeratosis extensor surfaces

• Marfanoid habitus – 60% men 31% women

• GUT

• Delayed gastric emptying early satiety Hiatus hernia + GORD

• IBS constipation/ diarrhea

• Bloating + pain

• PELVIC

• Floor weakness with bladder dysfunction

• AUTONOMIC DYSFUNTION

• POTS (postural orthostatic tachycardia syndrome) 30%

• Tilt table test

• Syncope- presyncope

• Sleep disturbances – apnoea

• Swelling and vv legs Postural acrocyanosis after standing

• Postural hypotension 36% > 20mmHg drop in BP

• Neurally mediated orthostatic intolerance

Poor proprioception – clumsiness/loss of balance

Aortic root dilatation12% MVP 6%

• PAIN

• Multifactorial - injuries + neuropathic Chronic 60%

• FATIGUE

• 90% Pain/Poor sleep/ Autonomic Dysfunction

• ANXIETY

• overrepresented ; higher than in other pain states, especially 15-30 years

• CNS

• Headaches 1/3 (migraine; M-T; Tension) from CSF leak;

• Poor regulation of blood flow

• CM1; Cx spine hypermobility

• Brain fog

• Chiari Malformation Type 1

• Occipito-atlanto-axial malformation

• Connections between migraine and EDS &MCAS &POTS & DIET

• Ps.Tumor cerebri ; Primary intracranial hypertension strong assoc

• ADHD; ASD; Eating Disorders; OCD; Depression

• CNS – CONTINUED

• Movement Disorders – dystonia; tics; tremors; jerky; night cramps;

POTS most prevalent feature

Most likely based on sympathetic neurogenic dysfunction

Alpha and beta adrenergic hyper-responsiveness in hEDS

• EYES

• Eyelids droopy –Metenier sign upper eyelid everted

• Myopia

• Lateral canthus lower than medial

• Increased blurred vision Light sensitive

• Optical migraines – scintillating scotomas

• Floaters

• Vision not able to be fixed -prescription errors

• Retinal holes/detachment

• Bluish sclerae

• Angioid streaks

• Cavernous haemiangiomas

• Dry eyes ‘watery” reflex tearing

• Keratoconus

• Resistance to lignocaine (LAs) some to opioids 1990

• Gorlin’s sign – Tongue touch nose Absence of lingular frenula

• Reverse- Namaskar Sign - hands behind back

SPINAL CORD

• Tethered cord syndrome Tarlov cysts

• Spinal segmental instability Spondylotic ; spondylolisethesis

• Myelopathy

• Discopathy

NEW and OLDER CLASSIFICATIONS

• 1973 BEIGHTON CRITERIA (best tool)

2017 hEDS Standardised Performance

1. 5TH (little) finger passive dorsiflexion > 90 degrees

Palm and forearm resting on flat surface

2. Passive apposition of each thumb to flexor surface to forearm

elbow extended hand pronated

3. Hyperextension of each elbow greater than 10 degrees goniometer hand supinated; elbow fully extended; Shoulder abducted to 90 degrees

4. Hyperextend > 10 degrees each knee standing knees fully extended

5. Palms flat on floor with knees extended locked; feet together;

total palm flat on floor just in front of feet.

SCORING

• = OR > 5 Generalised Joint HM

• = OR > 6 Pre-pubertal

• = OR > 5 Pubertal & adults up to 50

• = OR > 4 for those over 50

• If one point below age-specific cut-off generalized HM

• If 2 or more positive answers to 5PQ

Devised by Hakim and Grahame (2003)

1. can you now (or could you ever) place your hands flat on the floor?

2. Can you now (or could you ever) bend your thumb to touch your forearm ?

3. As a child did you amuse your friends by contorting your body or do the splits?

4. As a child or teenager, did your shoulder or kneecap dislocate on more than one occasion?

5. Do you consider yourself “double-jointed”?

5PQ

• MAJOR:

1. BEIGHTON SCORE 4/9 OR >

• Current or historical

2. Arthralgia > 3 months in 4 or > joints

BRIGHTON CRITERIA (1998)

• MINOR:1. Score 1-3/9 > 50 years

2. > 3 months 1-3 joints or Back pain > 3 mo

3. Dislocations/subluxations in > 1 joint or in > 1 occasion

4. Soft Tissue Rheumatism epicondylitis;tenosynovitis;bursitis

5. Marfanoid

6. Skin – Striae/ hyperextenive/ atrophic scars (papyrus)

7. Eyes – Eyelids/Myopia/ ‘anti-mongoloid’ slant

8. Varicose veins + Hernia Rectal/Uterine

2 MAJOR

1 MAJOR + 2 MINOR

4 MINOR

General HM Beighton Score newer cut-offs = or > 6 / 5/ 4

If score 1 point below + at least 2 +ve of 5PQ

2 or > of following (A&B; B&C; A&C)

A.Systemic Features B +ve Family history C Musculoskeletal complications

Skin not too bad

If other AIDs - then cannot use C - only A&B

Exclude other alternative Dx

INTERNATIONAL EDS CONSORTIUM (2017) 3 Criteria

• FEATURE A.

• Five or more of systemic manifestations of generalized CT

• Skin - soft or velvety

• Mild skin hyperextensiblitiy

• Gently pulling until resistance met

• Volar surface of non-dominant forearm

• Upper limit of normal extensibility 1,5 cm

• Unexplained Striae

• Bilateral piezogenic papules of heel – visible standing

• FEATURE A – CONTINUED

• Recurrent or multiple abdominal hernias

• Atrophic scarring in at least 2 sites

• Pelvic floor, rectal and/or uterine prolapse in children; men or

nulliparous women

• Dental crowding + high or narrow palate

• Arachnodactyly

• bilateral positive wrist sign or positive thumb sign

• Arm span to height = or > 1,05

• MVP on echo

• Aortic root dilatation with Z score > + 2

• FEATURE B.

• Positive family history – one or more 1st degree relative with hEDSdiagnostic current criteria

• FEATURE C

– At least one of the following

• Musculoskeletal pain in 2 or more limbs, daily for at least 3 mo

• CWP for at least 3 mo.

• Recurrent joint dislocation or frank instability in absence of trauma

• 3 or more atraumatic dislocations in the same joint or 2 or more

atraumatic dislocations in 2 different joints occurring at different

times

OR

• medical confirmation of joint instability at 2 or more sites not related

to trauma

What about chronic pain and fatigue?

• Subset of FMS may have hEDS underlying

• Coeliac disease can co-exist with EDS or overlooked as dx

• Vit D deficiency

Why the gender bias?

• Gender bias in seeking medical care

• Pain + major complications less common among affected males

• Pain perception; inherent joint stability; sex hormones effects

FURTHER EVALUATION :

• Baseline echo to evaluate aortic root diameter

• If normal aortic root in child – echo every 2-3 years until 25

• In adults if normal aortic root no further monitoring

• If aortic root normal prior to pregnancy no further monitoring

• If abnormal – echo every trimester

NOT ROUTINE:

• If significant orthostatic intolerance and/or tachycardia consider tilt-table

testing to confirm POTS or neurally mediated hypotension

• ? check cortisol

• IBS ? GIT referral rule out coeliac/ IBD etc

• DEXA if height loss > 1 inch or osteopaenia on xrays

• Prolonged bleeding ? check other causes

• Significant pain or fatigue – Vit D;VitB12;Fe; TSH; Coeliac +

• ? Pain Management referral

• If ? suspicion of Chiari malformation do cerebral MRI ? with CSF flow studies

ASSOCIATIONS OF AUTONOMIC DYSFUNCTION :

• eg POTS

• 1993 previous called Da Costa ;Soldiers heart ; MVP

• Increased HR for = or > 30 minutes supine to standing in absence of low

BP

• Check HR at 2min; 5min and 10 min

• + symptoms worsen on change + 6/12

• standing NA (noradrenalin) > 600pg/ml

• absence of orthostatic hypotension

• Fainting/ near fainting 60,5%

POTS vs CIDP

• Fatigue

• Burning pain

• Clumsiness

• Difficulty in swallowing

• Double vision

• Weakness

• Decreased deep tendon reflexes

LONG LIST OF ASSOCIATIONS: Dysautonomia (AD)

• Amyloid

• Antiphospholipid Syndrome (Primary APS)

• Coeliac – assoc AIDs + O/P + Cancer

• CMT

• Chiari Malformation

• CIDP

• Crohn’s/Ulc Colitis 50% AD

• Deconditioning

• Diabetes/Pre-diabetes

• EDS especially hEDS 20% cardiac and orthostatic intolerance

• Mast Cell Disorders

• Mitochondrial

• Paraneoplastic

• Parkinson’s 80% AD – BP/gut/bladder/sex function

• Sarcoid

• 60-70% go into remission without Rx

• Sjogren’s

• one of the most common AIDs in world

• 5 years to Dx

• dry eyes and mouth

• POTS may be presentation in younger and less dryness

• 50 % of SS have AD

• 50% of SS with neurological dysfunction do not test +ve for any of the antibody test

• Salivary lip gland bx

• 50% of SS have primary SS with no other AIDs

• Some SS cause

• immune system activation 3 or > AIDs

• Toxicity

• alcohol; chemoRx; Heavy metals – Pb; Hg (Fe;Cu)

• Physical Trauma/Surgery/after Pregnancy

• onset of AD -POTS

ASSSOCIATION OF EDS WITH ADDITIONAL AIDs :• Study Boston 2017

• Electronic Records of 379 hEDS Retrospective

• Comprehensive Work-up (CWU) or Limited or No Work-up

• > females 85 vs 15 % ( 66 vs 33 Rheumatology Clinics)

• 23,9 % had HLA B27 vs 6,1% of general population

• Most common described

• FMS 22

• Psoriasis 22

• AS 11

• PsA 11

• RA 9

•

• % of patients with advanced erosive disease on Xrays

• PsA 27 %

• RA 33 % (sero-negative and seropositive)

• Arthralgia major complaint in hEDS as well as in PsA; RA etc

• Sample bias

LIST OF ASSOCIATIONS of hEDSand Rheumatic • Club foot

• hereditary angioedema

• primary hypogammaglobulinaemia + FM + erythromelalagia and Ps;

• PsA

• AS

• RA

• inflammatory eye disease

• Autoimmune thyroid

• Pernicious anaemia

• SLE

• Crohn’s

• TRAPS (TNF Receptor Assoc Periodic Syndrome - <4 years)

• Unknown cause – genetic or immune activation

• CWU for all hEDS

Case Report :

• Mr AH 75 year old man Married Clinical Psychologist

• hEDS

• Soft Tissue Pain ( Fibromyalgia)

• GORD

• Metabolic syndrome - poor tolerance of statins; smoking; glucose

intolerance; gout

• Degenerative back problems - lumbar and Cx

Background :

• 1996 – Balance issues and burning of both feet

• Marked palmar erythema > erythromelalgia

• MRI – White matter lesions (UBO’s)

• On various therapies over the years – low dose prednisone; trepeline;

chloroquine

• Poor hand function – had seen hand therapist

• 2012 – investigated for dizziness and (L) elbow nerve entrapment on NCS

• Neurology studies for fatigue; weakness arms and legs and reduced deep

tendon reflexes ; mildly raised isolated CSF protein; mild peripheral

neuropathy

• Dx as CIDP on 3 monthly and then monthly IVIG

• Ongoing issues of fatigue > pain; orthostatic intolerance.

• 6 months of biokinetics with no marked change BMI 30

• Treated for SVT in 2014 – cardioverted and treated with Bilacor and Xarelto

Opinion :

• POTS (Postural Orthostatic Tachycardia Syndrome) - associated with

• hEDS; Diabetes and pre-diabetes and CIDP

• POTS associated with deconditioning itself

• 48 % of people with POTS report chronic fatigue and reduced exercise

tolerance

• 32 % report sleep disturbances

• POTS even can explain the hyperaemic skin changes of the hands and feet –

indicative of blood pooling

• Recent survey in Neurology 2015 – up to half the dx of CIDP do not meet the

actual criteria

• CSF protein elevations mild and NCS showing demyelination more in keeping

with

• a process other than CIDP

• hEDS and Metabolic syndrome both associated with mild increase in CSF

protein

• and peripheral neuropathy.

• Ulnar nerve neuropathy feature of hEDS

• ? POTS vs CIDP

Case Report :

• Mrs. J.D 51year old woman Married No children

• Computer technician in Banking

• Stopped full-time work in 2015 because of health issues

• Returned to Bank on a flexible time in 2018

Conditions under review :

• Hypermobile EDS

• Widespread Chronic Pain associated with FMS

• Relapsing CNS Manifestations - ? immunotherapy for neurological features

Co-morbid Metabolic Conditions

• Hypertension

• Dyslipidaemia

• Hyperuruicaemia

• Raised CRP

• Glucose Intolerance

• Perimenopausal

Background :

• Congenital VSD – closed spontaneously

• Ankle injuries in childhood

• Foot surgery (L) at age of 18 further ® foot surgery neuroma in 20’s

• Lens implant at 40

• Longstanding balance problems

• Beighton’s Criteria was 6/9 - extreme laxity at hips and back and (L) thumb

• Recurrent Whiplash related to MVA’s - felt the back and widespread pain

subsequent to initial episode

Neurological Issues :

• Neuropathic pains

• Long term headaches and poor sleeping

• Long term cognitive issues

• Significant palmar erythema (mast cell activation in hEDS)

• 2001 presented with vertigo

• MRI scan had lesion in corpus callosum

• Tests for possible MS negative

• No progression on follow-up scans (brain and Cx cord)

January 2018

• Vertigo and decreased hearing &visual loss on RHS

• Abnormal VEP and AEP prolonged on ®

• ENT opinion – hearing loss due to nerve deafness on ®

• ANF 1: 80 pANCA (MPO) borderline +ve

• CSF oligoclonal bands on 2 occasions (prolonged post-LP headache)

October 2018

• Bilateral upper limb sensory symptoms > RHS + constitutional symptoms

• (Oligoclonal bands are also found in SLE and Sjogren’s as well as MS)

• Treated with IVI steroids + high dose steroids weaning over time

• Improved the vision and hearing

• Imuran not tolerated

Other Rx :

• Cymgen 60

• Trazadone 100

• BP drugs x 4 including Bilacor

• Topzole 40mg daily

• Adcodol, one at night

Further Options :

• hEDS + MS

• hEDS + Sjogrens or SLE

• Incidence of MS in hsEDS is 10-11 x more common than normal

• Increased incidence of autoimmune conditions in hEDS

• Increased incidence of autoimmune syndromes in perimenopause

• Autoimmunity + mast cell activation may play role in neurological features of

hEDS

Is this NINJA ?

• Normal-appearing, neuroimmunologically justified, autoimmune-mediated

encephalomyelitis

• Therapies included; Plasmapheresis; Periodic IVIGs; Prednisone + Tarcolimus

(or +MTX)

• Rituximab has been used for all 3 - MS/Lupus/Sjogren’s

US STUDY in hEDS

• 92,4% take treatment

• 70% have had surgery

• 51,9% on Physical therapy

“A man can have as many diseases as he damn well pleases.

Hickam’s Dictum versus Occam’s Razor

Thank you.