Ehlers Danlos Syndrome: Recognition, Diagnosis &

ManagementHoward P. Levy, M.D., Ph.D.

Assistant Professor, Johns Hopkins University

Johns Hopkins Adolescent Medicine Grand Rounds

Baltimore, MDOctober 12, 2012

Disclosures

1. No relevant financial relationships

2. I will discuss non-FDA labeled use of the following medications: Tricyclic antidepressants for neuropathic pain SNRI antidepressants for neuropathic pain Anti-seizure medications for neuropathic pain

Learning Objectives

• Recognize features of EDS• Initiate appropriate evaluation• Understand activity and other

management recommendations

Case 1: 18 yo Girl With Knee Pain & Instability

• 5-6 yrs bilat knee pain & patellar instability• Failed:

steroid & Synvisc injections debridement, chondroplasties, plication,

synovectomy, lateral release, osteotomies, ligament reconstruction (11 total procedures)

aquatic resistance exercise• Gave up lacrosse, soccer, horse riding• Easy bruising, no other skin sx’s

Case 1: Exam• Palate: normal• Tender paralumbar spasm• Laxity in all joints

Pes planus Beighton score 8/9

• Skin normal

Case 2: 32 yo Man With Left Shoulder Pain

• Acute onset weightlifting 1 year prior• Improves w/rest; recurs w/weightlifting• Also pain in forearms & knees• No subluxations/dislocations• Failed resistance bands & light weights• Easy bruising, prolonged bleeding• Fatigue on/off x 15 years

Case 2: Exam• Palate: high, narrow, intact• Tender left trapezius spasm• Laxity

Shoulders, elbows, wrists, fingers Left knee only (muscular, especially LE) Pes planus Beighton score 8/9

• Skin normal

Case 3: 15 yo Girl With Shoulder Pain & Instability

• 10 months of pain w/push ups subluxation w/swimming

• Hip subluxation (spont vs. traumatic?)• Gave up volleyball• Continues to tolerate swimming,

cross-country, and track

Case 3: Exam• Palate: normal• Tender paralumbar spasm• Laxity

moderate in shoulders; mild in wrists/fingers none elsewhere Beighton score 2/9 (thumbs only)

• Skin normal

Diagnoses

• Case 1: Ehlers Danlos Hypermobility Type• Case 2: Ehlers Danlos Hypermobility Type• Case 3: Isolated shoulder pain/instability

Ehlers Danlos Syndrome

HYPERMOBILITY TYPE (III)• Joint laxity• Pain (arthralgia, myalgia, headache)• Fatigue• Worse with resistance & activity• High narrow palate/dental crowding• Easy bruising, mildly soft skin

Ehlers Danlos Syndromes

• Heritable disorders of connective tissue

• Collagen• Prevalence 1:5000?

(probably more common)

Ehlers Danlos Syndromes

• Joint laxity• Soft skin• Easy

bruisability

• High narrow palate

• Gastritis & IBS• POTS & NMH

EDS Types

EDS: Revised Nosology Beighton et al, Am J Med Genet (1998) 77:31-37

TYPE OLD # PATTERN

Hypermobility III

Autosomal Dominant

Classical I & II

Vascular IV

Arthrochalasia VIIA & B

Kyphoscoliosis VI Autosomal RecessiveDermatosparaxis VIIC

EDS: Hypermobility (III)• “Benign Joint Hypermobility Syndrome”1

• Joint laxity• Soft skin• Easy bruisability• Least severe, BUT paindisability• Autosomal dominant• Genetic cause unknown

1. Tinkle et al. Am J Med Genet A. 2009;149A:2368–70

Assessing Joint LaxitySubjective

• ROM• Hyperextension• Lateral instability• A/P instability• Varus/valgus• Telescoping

Objective

Beighton Scale1

• 9 possible points• “+” = 5 or more • Doesn’t assess

all joints• Not “Gold Std”

1. Beighton et al. Ann Rheum Dis. 1973;32:413–8

Beighton ScalePalms to floor, knees straight: 1 point

Beighton ScaleHyperextend elbow >10o: 1 point each

Radial Styloid

Lateral Humeral

Epicondyle

Humeral Head

Beighton ScaleHyperextend knee >10o: 1 point each

Lateral Malleolus

Lateral Femoral Condyle

Greater Trochanter

Beighton Scale

Dorsiflex 5th finger >90o: 1 point each

Appose thumb to forearm: 1 point each

Assessing Joint LaxityCaveats

• Age Young children: loose Older adults: stiff

• Sex: Female looser than male• Trauma/DJD/Surgery• Muscle tone or bulk• Guarding

EDS: Classical (I & II)

• All features of Hypermobility Type• More severe skin and soft tissue• Autosomal Dominant• Type 5 collagen in 50% of pts

90-95% w/stricter clinical criteria1

• Clinical DNA test available clinical utility?

1. Symoens et al. Hum Mutat. 2012; 33:1485–1493

• Very soft, sometimes doughy• Hyperelasticity Avoid loose skin Volar wrist—

normal ~1 cm

EDS: Classical - Skin

• Very soft, sometimes doughy• Hyperelasticity• Skin fragility Extensor surfaces

EDS: Classical - Skin

• Molluscoid pseudotumor Thickened Hyperpigmented Elbows Knees

Atrophic Scars

EDS: Classical - Skin

EDS: Classical – Soft Tissue

• Wound dehiscence

• Soft tissue fragility (“wet toilet paper”)

• Ligaments & Tendons

• Rarely vascular tears

EDS: Vascular (IV)• Joint laxity

Small >> large Wrists, fingers, ankles, toes

EDS: Vascular (IV)• Joint laxity • Fragile skin• Thin translucent skin

EDS: Vascular (IV)

• Wound dehiscence• Dissection/rupture

Arteries Intestine Uterus Tendons

• Some never dissect/rupture 80% of 1st events ages 10-39

EDS: Vascular (IV)

• Autosomal Dominant• Type 3 Collagen (100% of pts.)

Skin, vessels, hollow organs• Clinical DNA sequencing• Biochemical assay from skin fibroblasts

also available

Differential Dx: Joint LaxityWWW.OMIM.ORG

Differential Dx: Joint Laxity

• Marfan• Loeys-Dietz• Stickler• Fragile X• Turner

Dozens other than EDS

Diagnostic Work-up• Joint & skin exam

• Echo (diff dx & clinical mgmt) Aortic root dilation (up to 1/3 patients)

Other abnormalities

• Ophtho if suspect Marfan or Stickler

• Genetics consultation

Management

What We Know• Laxity & instability

• Pain—out of proportion to exam/x-rays

• Fatigue

• Osteoarthritis (DJD)

What We Don’t Know

Why?

Working Hypothesis

Laxity

Frequent minor subluxations

Reflexive muscle spasm Osteoarthritis

Pain Fatigue

Working Hypothesis

Laxity

Frequent minor subluxations

Reflexive muscle spasm Osteoarthritis

Pain Fatigue

Joint Instability

MUSCLE TONINGStrength: A source of power or force

Tone: The normal state of elastic tension or partial contraction in resting muscles

Increased strength can sublux the joints

Increased tone can improve joint stability

“Resistance is Useless” -Vogon guard, The Hitchhiker's Guide to the

Galaxy, Douglas Adams

Avoid (minimize)• Hyperextension• Impact• Resistance

Caution With• Elastic bands• Isometrics• Weights

Toning Exercise• Low or non-resistance exercise

Walking, Elliptical, Bicycle Swimming/Aquatherapy ROM

• Add repetitions, duration & frequency• Start low, go slow• Long horizon

Months to stop getting worse Years to start getting better

Joint Instability• External bracing when needed• Joint stabilizing surgery?

Increased rate of immediate & short-term failure1,2

Soft tissue fragility & wound dehiscence in Classical & Vascular EDS

1. Rombaut et al. Arch Phys Med Rehabil. 2011;92:1106–122. Rose et al. J Arthroplasty. 2004;19:190–6

Working Hypothesis

Laxity

Frequent minor subluxations

Reflexive muscle spasm Osteoarthritis

Pain Fatigue

Muscle Spasm• Myofascial release

Heat, massage, TENS, acupuncture… Hours-days of relief

• Special mattress Water, air, viscoelastic foam

• Medications Skeletal muscle relaxers Benzodiazepines (caution)

Working Hypothesis

Laxity

Frequent minor subluxations

Reflexive muscle spasm Osteoarthritis

Pain Fatigue

Pain: Etiology?• Myofascial spasm?

aching, throbbing, tight…• Neuropathic?

burning, tingling, electric…• DJD?

dull, aching, throbbing…

Pain: Passive & Mechanical Therapy

• Myofascial release: ice, heat, massage, acupuncture/pressure, u/s, TENS…

• Nerve blocks, joint/bursa injections Limited benefit; can’t repeat indefinitely

• Implantable stimulators• Other? (individualized therapy)

Pain: Medication• Analgesics & Anti-inflammatories

Acetaminophen, NSAIDs,Tramadol• Transdermal lidocaine• Muscle Relaxers• Neuropathic pain control

Tricyclics, SNRIs, Anti-seizure• Opioids—last resort

Pain: Medication

• Cocktail of multiple medications• Scheduled, preventive medication

more effective than as-needed• Goal is to limit, but not eliminate pain• Pain management specialists

Pain: Psychology“90% of the game is half mental”

-Yogi Berra• The underlying problems are real• But pain is a subjective experience

• Emotional State• Goals and expectations• Fears• Avoidance, disability, isolation• others…

Emotional StateCommon in EDS:• Anxiety & Depression• Low self-confidence• Negative thinking• Hopeless/helpless• Desperation• Low self-efficacyBaeza-Velasco et al (2011) Rheumatol Int. 31:1131; Branson et al (2011) Harv Rev Psychiatry 19:259; Castori et al(2010) Am J Med Genet A. 152A:556; Hagberg et al (2004) Orthod Craniofac Res. 7:178; Rombaut et al (2011) Arthritis Rheum. 63:1979

Expectation Management

High Bar• No pain• No dislocations

or subluxations• “Normal” activity

tolerance

Low Bar• Less pain• Fewer dislocation

or subluxations• Improved activity

tolerance

Pain: Psychological Tx• Relationships with healthcare providers.

Clinician must validate symptoms as real Patient must trust that psych components

play a role• Counseling

Depression, anxiety… Accepting & coping w/pain & dysfunction

• Cognitive Behavioral Therapy, conscious relaxation, hypnosis, meditation…

Resources• www.genereviews.org

clinically oriented reviews• www.omim.org

encyclopedic genetic catalog

• www.ednf.org patient support group

Additional References & Information

Levy, GeneReviews, 2012

http://www.ncbi.nlm.nih.gov/books/NBK1279/#eds3