Transcript Ehlers-Danlos Syndrome (EDS) - Robert Whittaker

Ehlers-Danlos
Syndrome (EDS)
Robert Whittaker, SPT
University of North Dakota
Overview
 Genetic defects affecting biosynthesis & structure of collagen type
(autosomal recessive – AR, autosomal dominant – AD)2
 Villefranche Criteria 6 subtypes: classic, hypermobility (HT),
vascular, kyphoscoliotic, arthrochalasis, & dermatosporaxis
 Emerging Forms: cardiac-valvular, vascular-like,
musculocontractural, spondylocheirodysplastic, brittle cornea
syndrome, EDS/OI overlap, tenascin x deficient, progeroid,
parodontitis, fribronectin deficient4
 Can lead to serious adult complications including subluxations,
sprains & chronic joint pain difficult to treat, may lead to
devastating physical, social & emotional disability
 ICD-9-CM Code 756: Other congenital musculoskeletal anomalies
(Pattern 4A, 4B, 4F, 4I, 5B, 5C)5
EDS Classic2
 Skin hyperextensibility; widened atrophic scars; joint hypermobility
 Smooth, velvety skin; molluscoid pseudotumors (fleshy lesions
over pressure points); subcutaneous spheroids (small, hard cystlike nodules); Complications of joint hypermobility; muscle
hypotonia, motor delay; easy bruising; manifestations of tissue
extensibility and fragility; surgical complications; (+) family history
 AD – COL5A1, COL5A2, & COL5A3 genes (Type V collagen:
pericellular collagen which is ubiquitous in the CT space6; widely
distributed in skin, bone, tendon, cornea, placenta, & foetal
membranes)
 Ultrastructural electron microscopy examination of skin shows
irregular & loosely packed collagen fibrils & presence of typical
‘cauliflower’ fibrils
EDS Vascular2

Thin, translucent skin (fragile & splits easy); arterial/intestinal/uterine fragility or rupture; extensive
bruising; characteristic facial appearance (worst type, tendency to rupture arteries & hollow organs,
major vascular or intestinal complications)
 Acrogeria (old looking); hypermobility of small joints; tendon & muscle rupture; talipes equinovarus; early-

onset varicose veins; arteriovenous, carotid-cavernous sinus fistula; pneumothorax/pneumohemothorax;
gingival recessions; (+) family history, sudden death in a close relative
AD – COL3A1 (Type III collagen: fetal skin, blood vessels, organs, skin where reticular fibers are located,
also seen in initial stages of wound healing & scar formation6)

Aneurysm, dissection or rupture of medium sized abdominal vessels (carotid, subclavian, ulnar,
popliteal, and tibial arteries - coronary rupture rare)

Prophylactic measure – catheterization & arteriography should be avoided, could be fatal (ultrasound
& subtraction angiography preferred)
 Thorough investigation of platelet function & clotting if surgery required
 Pregnant women high risk obstetrical program (unclear for caesarean section vs. vaginal delivery
preference)

Celiprolol – Long acting β1 antagonist with partial β2 agonist properties decreased incidence of arterial
rupture by 3x

Strenuous activity should be avoided with aortic regurgitation due weakness of aortic wall3
EDS Kyphoscoliotic2
 Generalized JHM, congenital hypotonia; congenital &
progressive scoliosis; scleral fragility & rupture of the
ocular globe
 Tissue fragility, including atrophic scars; easy bruising;
arterial rupture; marfanoid habitus; microcornea;
osteopenia/porosis; (+) family history
 Deficient activity of lysyl hydroxylase 1 (LH1)
 Dx: ↑LP/HP ratio crosslinks in urine, ↓LH1 activity in cultured
skin fibroblasts, presence of mutation of PLOD1 gene (AR)
 Type I: skin, tendon, bone, ligaments, joint capsules, annulus
fibrosus2
EDS Arthrochalasis2
 Generalized JHM with recurrent subluxations;
congenital bilateral hip dislocations
 Skin hyperextensibility; tissue fragility, including atrophic
scars; easy bruising; hypotonia; kyphoscoliosis;
osteopenia/porosis
 AD – COL1A1 & COL1A2
 Type I: skin, tendon, bone, ligaments, joint capsules,
annulus fibrosus6
EDS Dermatosparaxis2
 Severe skin fragility; sagging, redundant skin
 Soft, doughy skin texture; easy bruising; premature
rupture of fetal membranes; large hernias (umbilical,
inguinal); blue sclera & edema of eyelids; short stature &
fingers
 AR – ADAMTS2
 Type I: skin, tendon, bone, ligaments, joint capsules,
annulus fibrosus2
EDS Hypermobility2
 1/5000, >females4 , most common type
 Hyperextensible &/or smooth, velvety skin; generalized JHM


Recurring joint dislocations, chronic joint/limb pain, (+) family history
AD?
 Severe JHM with recurrent joint dislocation and chronic mod-severe pain (also
muscle cramps, tendinitis, headache, & fatigue) – leads to physical, social,
emotional disability (>RA and comparable to fibromyalgia)
 Impaired proprioception, postural control & muscular strength contribute to
instability
 LE muscle weakness caused by intrinsic muscular dysfunction associated with
muscle pain & fatigue rather than reduced muscle mass
EDS-HT Cutaneous Features4
 Hyper extensible - stretched beyond normal limit & immediately
returns to original state
 ≥1.5-2cm at dorsum of hand = hyperextensible
 Velvety & smooth skin – skin texture difficult in toddlers
 Can facilitate the development of striae
rubrae/distensae/atrophicae (stretch marks)
 Abdominal fascia reduced CT stiffness can cause formation of
hernias in conjunction with increased abdominal pressure.
 Minor wound healing defects & capillary fragility – may present as
atrophic, nonpapyraceous scars
 Capillary fragility causes increased tendency and delayed
ecchymosis (bruising)
 Disturbed perspiration (diaphoresis/hypohidrosis)
EDS-HT Mucosal &
Oropharyngeal Features4
 Xerostomia, xeropthalmia, & vaginal dryness
 Hypohidrosis, with mucosal xerosis could be remote
consequence of autonomic dysregulation
 Gingival bleeding due to mucosal fragility (brushing teeth?)
 Blue sclera likely caused by more visible uveal blood
vessels though thinner sclera
 Lack of frenulum – Gorlin’s Sign
 Oropharyngeal dysphagia may impede feeding with
consequent excessive weight loss, exacerbation of fatigue,
and failure to thrive in children
Orthopedic Features4
 Congenital capsuloligmentous laxity – subluxations, sprains, & soft
tissue lesions (i.e. bursitis, tendonitis, synovitis, tenosynovitis, &
fasciitis)
 Precocious osteoarthrits, spondylosis, & lower bone mass are potential
degenerative complications – may delay repair of fractures1
 Muscle contractions, growth & molding of skeleton likely more effective in a
body with lax joints
 Decreased proprioceptive functions and JHM likely contributors of
dysfunctions1
 C-spine instability of OA junction, intracranial hypotension due to CSF
leaks, TMJ dysfunction – migraine w/ w/out aura, tension headache,
combination, post traumatic headache, craniofacial pain1
 10% dextrose prolotherapy for TMJ to reduce pressure induced pain
Beighton Scale for JHM4
Joint/finding
Negative Unilateral
Bilateral
Criteria
Passive DF of 5th
finger >90°
0
1
2
Passive flexion of
thumbs to forearm
0
1
2
Major Criteria
• Score 4/9
• Arthralgia for >3 months
in >4 joints
Hyperextension of
elbows >10°
0
1
2
Hyperextension of
knees >10°
0
1
2
Forward flexion of the
trunk with knees fully
extended & palms
resting on the floor
0
Present = 1
Minor Criteria
• Score 1-3
• Arthralgia in 1-3 joints
• Hx of joint dislocations
• Soft tissue lesions >3
• Marfan like habitus
• Skin striae, hyperextensibility, or scarring
• Eye signs, lid laxity
• Hx of varicose veins,
hernia, visceral prolapse
EDS-HT Neurological
Features4
 High rate of myopathic electrophysiologic findings combined with
reduced sensation & muscle weakness, increased muscle echo
intensity, & myopathic changes at biopsy
 Chronic/recurrent pain & fatigue most common complaints
 Widespread & involve the musculoskeletal system, nervous system, &
internal organs
 Pain associated with regular analgesic use, JHM, previous surgery, &
related to functional impairment independently from fatigue1
 Headache – migraine most common
 Impaired proprioception at various joints (proximal interphalangeal
and knee joints)
 Impairs balance & posture
 Delayed autonomous walking, tip-toe walking, lack of crawling,
clumsiness, and possibly dyspraxia in infancy
EDS-HT Cardiopulmonary
Features4
 Dysautonomia most clinically relevant – orthostatic
intolerance, postural tachycardia syndrome most
common form
 Mild mitral, tricuspid, & aortic valve regurgitation (25%),
true mitral valve prolapse (6%)
 rate of asthmatic symptoms & atopy associated with
increased lung volumes, impaired gas exchange, &
tendency of both the lower & upper airways to
collapse
 Persistent childhood wheezing by causing airway
collapse through CT defect affecting airways structure
EDS-HT & Fatigue1
 Fatigue – sleep disturbances, concentration problems,
social functioning, self-efficacy concerning fatigue,
muscle weakness, & pain
 EDS-HT/JHM possibly affects a significant number of
CFS patients.
 OSA may be leading cause of sleep difficultness (restless
leg syndrome/periodic limb movements)
 Dysautonomia major factor (high analgesic use amplifies)
& malabsorption possible triggers to fatigue
EDS-HT Ocular Features4
 Blepharacholasis, antimongoloid palpebral slant, & blue
sclera
 Myopia, unilateral ptosis, & tilted optic disc less common
EDS-HT Gastrointestinal
Features4
 Chronic constipation, hiatus hernia, Crohn’s disease, fecal
incontinence, rectal evacuatory dysfunction, & functional GI disorder
 Gastroesophageal reflux (with/without hiatus hernia), chronic/recurrent
gastritis, symptoms of delayed gastric emptying, recurrent abdominal pain,
constipation/diarrhea
 Unexplained abdominal pain in up to 86% of cases – bloating, reflux,
heartburns, N/V, diarrhea, and consipitaiton1
 Reduced fixation to adjacent structures causing visceroptosis &
hernias, gut hypotonia/hypomobility, structural anomalies (i.e.
dolichocolon)
 Poorly localized forms of “organic” pain, such as fibromyalgia,
headache, and irritable bowel disease, possibly related to an
abnormal and intense enhancement of pain generated from external
and visceral stimuli by CNS mechanisms (central sensitization)1
EDS-HT Pelvic/Gynocologic
Features4
 Irregular menses, meno/metrorrhagias, & sever dysmenorrhea
 Fertility & pregnancy usually unaffected


Obstetric & anesthetic interventions in order to prevent life threatening/disabling
complications
Anesthesia induced hypotension facilitated by dysautonomia, meningeal fragility
complicating CFS hypotension in case of epidural anesthesia, proneness to pelvic
prolapse after episiotomy, apparently increased rate of suture dehiscence & minor
hemorrhages after surgery
 Pelvis – multiple/severe prolapses in nulliparous women – pain/discomfort due
to specific complications such as constipation and recurrent urinary infections,
dyspareunia partly due to vaginal dryness common form of pelvic pain
(endometriosis, pelvic ring instability, and coccygeal joint dysfunction, likely
more common)1
 Urinary stress incontinence, uterine prolapse, & fecal incontinence
 Prolapse - Cesarean should be considered when vaginal delivery without episiotomy
cannot be anticipated
EDS-HT Psychological
Features4
 Psychology – inadequate adaption to the physical and
social consequences of the disease (anxiety,
depression, and other features of CNS fatigue), sense
of stigmatization and limitation of the possibility of self
actualization in daily living and social life are likely
generated and induce sensation of living “a restricted
life” in the affected individuals1
 Secondary to chronic pain & disability, ostracism, &
avoidance of relationships
 Cognitive Behavioral Therapy
Differential Diagnosis4
 Ultrastructural & molecular findings, skin biopsy, vascular imaging, &
molecular testing not part of diagnosis
 Molecular testing & extensive vascular imaging for other EDS subtypes
 Overlapping Disorders
 Mucocutaneous fragility, JHM, chronic musculoskeletal pain & fatigue
 Neurologic Disorders
 MS, ALS, hereditary & acquired sensory-motor &/or autonomic
polyneuropathies, & CFS
 Other Hereditary Connective Tissue Disorders with JHM
 “Battered child” syndrome, bleeding disorders, various rheumatologic
conditions with chronic musculoskeletal pain, such as ankylosing
spondylitis, RA, & fibromyalgia
Treatment
 Lifestyle! Most cost & time effective solution (education - avoid exacerbating)

Multidisciplinary approach (geneticist, rheumatologist, neurologist, psychiatrist,
PT/OT, urologist/gynecologist, orthopedist, cardiologist, pneumologist,
gastroenterologist, other)
 Drugs



Low-mod pain: ibuprofen, naproxen, paracetamol (NSAIDs - stomach!)
Topical lidocaine & local injection of anesthetic/steroids (limited success)
Inefficacy – tramadol, COX2 inhibitor, pain modulator dugs (tricyclic antidepressants
& serotonin/norepinephrine receptor inhibitors, amytriptyline best choice for
neuropathic pain), duloxetine
 Help with satellite symptoms such as depression/sleep/irritable bowel disease with
limited side effects

Ascorbic acid for capillary fragility, cofactor of polyl & lysyl hydroxylase enzymes for
biogenesis of collagens, Vitamin D for osteopenia, melatonin for sleep, & other
neutraceuticals
Treatment Continued
 Fatigue
 Fludrocortisone/vasoconstrictors – contraindicated in pts. with systemic
HTN (βblockers or clonidine may improve BP & HR, β blockers should be
avoided in pts. with asthma; octreotide with marked postprandial tiredness;
modafinil for managing chronic fatigue in orthostatic intolerance
 Additional water intake (isotonic solutions), high salt (HTN), carnitine &/or
coenzyme Q10
 Surgical & Anesthetic
 Surgery not contraindicated, increased time for soft tissue repair may lead
to muscle deconditioning postsurgical recovery
 Mild soft tissue fragility and delayed wound healing (double waiting time
before suture removal)
 Intubation should be carefully performed due to TMJ and C-spine and
mucosal fragility
 Epidermal CSF hypotension from leakage
PT Implications
 Proprioceptive Exercises

Wobble board/rhythmic stabilization
 Muscle Strengthening

Mid-range – stability (low resistance, high reps),
 Modalities


Heat/cold – inspect skin (heat can increase extensibility)
TENS – pain, NMES – joint position
 Assistive Devices

May stress UE, W/C decrease stress on LE, silver ring splints for digits, collar/braces
 Swimming (cardiac volume!), gentle stretching, massage, prevention (pads),
education, lifestyle recommendations, energy conservation
Questions?
References
1.
Castori M, Morlino S, Celletti C, et al. Management of pain and fatigue in the
joint hypermobility syndrome (a.k.a. ehlers-danlos syndrome, hypermobility
type): Principles and proposal for a multidisciplinary approach. American
Journal of Medical Genetics Part A. 2012;158A(8):2055-2070. doi:
10.1002/ajmg.a.35483.
2.
De Paepe A, Malfait F. The ehlers-danlos syndrome, a disorder with many
faces. Clin Genet. 2012;82(1):1-11. doi: 10.1111/j.1399-0004.2012.01858.x.
3.
Goodman CC, Fuller KS. Pathology: Implications for the physical therapist.
SAUNDERS W B Company; 2009.
4.
Castori M. Ehlers-danlos syndrome, hypermobility type: An underdiagnosed
hereditary connective tissue disorder with mucocutaneous, articular, and
systemic manifestations. ISRN dermatology. 2012;2012.
5.
Guide to physical therapy practice. 2nd ed. APTA; 2003.
6.
Jeno, S., Mohr, T. Connective Tissue, Department of PT UND School of
Medicine and Health Science