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Ehlers-Danlos Syndrome (EDS)

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Presentation on theme: "Ehlers-Danlos Syndrome (EDS)"— Presentation transcript:

1 Ehlers-Danlos Syndrome (EDS)
Robert Whittaker, SPT University of North Dakota

2 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 4A – primary prevention/risk reduction for LOB & falling 4B – impaired posture 4F – impaired joint mobility, motor function, muscle performance, ROM, & reflex integrity associated with spinal disorders 4I – impaired joint mobility, motor function, muscle performance, ROM, & reflex integrity associated with bony or soft tissue surgery 5B – impaired neuromotor development 5C – impaired motor function & sensory integrity associated with non-progressive disorders of the CNS – congenital origin or acquired in infancy or childhood Fibrillar collagens constitute a large family of structural ECM, represented by collagen types I, II, III, V, & XI. Fibrillar collagen proteins are trimeric molecules which consist of 3 either identical or genetically distinct polypeptide chains (α-chans) which form characteristic triple helical structures2 Involved in inter & intramolecular crosslinking necessary for stabilization of the collagen molecules Defects in transcription factors, intracellular trafficking of ECM molecules, proteoglycan metabolism, supramolecular organization of ECM & cell-matric interactions However, the presence of at least 1 major and 1 minor criteria is usually necessary for proceeding in molecular confirmation of Ehlers-Danlos syndrome subtypes with a known, prevalent molecular cause. The presence of at least two major criteria is strongly indicative for a definite diagnosis of the specific EDS subtype.

3 EDS Classic2 Skin hyperextensibility; widened atrophic scars; joint hypermobility Smooth, velvety skin; molluscoid pseudotumors (fleshy lesions over pressure points); subcutaneous spheroids (small, hard cyst- like 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

4 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 Facial appearance – prominent eyes (due to lack of subcutaneous adipose tissue around the eyes), thin pinched nose & small lips, hollow cheeks & lobe less ears)

5 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 Atrophy – wasting away

6 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 Chalasia - The inhibition and relaxation of a previously sustained contraction of a muscle or synergistic group of muscles, such as the cardiac sphincter.

7 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 an inherited defect in collagen synthesis caused by a deficiency of procollagen peptidase. Results in fragility, hyperelasticity and laxity of the skin. Occurs in cattle, some breeds of sheep, and Himalayan cats. Called also Ehlers-Danlos syndrome, hyperelastosis cutis, cutaneous asthenia.

8 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

9 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)

10 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 Gorlin’s Sign – able to touch tongue to nose (xero – dry)

11 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 Prolotherapy is also known as "proliferation therapy," "regenerative injection therapy,” or "proliferative injection therapy". It involves injecting an otherwise non-pharmacological and non-active irritant solution into the body, generally in the region of tendons or ligaments for the purpose of strengthening weakened connective tissue and alleviating musculoskeletal pain

12 Beighton Scale for JHM4 Joint/finding Negative Unilateral Bilateral
Criteria Passive DF of 5th finger >90° 1 2 Major Criteria Score 4/9 Arthralgia for >3 months in >4 joints Passive flexion of thumbs to forearm Hyperextension of elbows >10° Minor Criteria Score 1-3 Arthralgia in 1-3 joints Hx of joint dislocations Soft tissue lesions >3 Marfan like habitus Skin striae, hyper-extensibility, or scarring Eye signs, lid laxity Hx of varicose veins, hernia, visceral prolapse Hyperextension of knees >10° Forward flexion of the trunk with knees fully extended & palms resting on the floor Present = 1 Dx – both major, 1 major/2 minor, 4 minor, 2 minor & 1 primary family member

13 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 Thought to be primarily linked with joint damage – wider spectrum of pain features with recent evidence Enhanced echo intensity (EI) on ultrasonography images of skeletal muscle is believed to reflect muscle quality, atrophy can be objectified by measuring muscle thickness, while infiltration of fat and fibrous tissue increase muscle echo intensity, i.e. the muscles become whiter on the ultrasound image Ultrasound images and muscle histology of the tibialis anterior muscle (A) and (C) and rectus femoris muscle (B) and (D). The circles in the ultrasound images represent the complete cross-sectional area of the muscle under investigation. Of this region, mean muscle echo intensity was calculated. Muscle histology was examined in the same region (C) and (D). A trichrome staining was applied to the muscle specimen. With this staining perimysial tissue becomes green, whereas muscle tissue is pink. Note the increased amount of fibrous tissue in the rectus femoris muscle which corresponds well with the increased echo intensity (whiter muscle). The bar in the right lower corner of each image represents 1 mm. T - tibia; F - fibula; V - vastus intermedius

14 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 A change from the supine position to an upright position causes an abnormally large increase in HR (tachycardia) Atopy Of, relating to, or caused by a hereditary predisposition toward developing certain hypersensitivity reactions, such as hay fever, asthma, or chronic urticaria, upon exposure to specific antigens

15 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

16 EDS-HT Ocular Features4
Blepharacholasis, antimongoloid palpebral slant, & blue sclera Myopia, unilateral ptosis, & tilted optic disc less common Blepharochalasis is an inflammation of the eyelid that is characterized by exacerbations and remissions of eyelid edema, which results in a stretching and subsequent atrophy of the eyelid tissue resulting in redundant folds over the lid margins. It typically affects only the upper eyelids, and may be unilateral as well as bilateral.

17 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 Visceroptosis (or enteroptosis) is a prolapse or a sinking of the abdominal viscera (internal organs) below their natural position Dolicho – long running

18 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 Menorrhagia or Hematomunia is an abnormally heavy and prolonged menstrual period at regular intervals Metrorrhagia (metro = womb, -rrhagia = excessive flow[1]) is uterine bleeding at irregular intervals, particularly between the expected menstrual periods. Nullipara - A woman who has never given birth Dyspareunia (from Greek meaning "badly mated”) is painful sexual intercourse, due to medical or psychological causes An episiotomy, also known as perineotomy, is a surgically planned incision on the perineum and the posterior vaginal wall during second stage of labor Wound dehiscence is a surgical complication in which a wound ruptures along surgical suture. Risk factors are age, diabetes, obesity, poor knotting or grabbing of stitches, and trauma to the wound after surgery

19 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 Learning to live with chronic condition better than fighting something that isn’t going to change. Cognitive behavioral therapy (CBT) is a psychotherapeutic approach that addresses dysfunctional emotions, maladaptive behaviors and cognitive processes and contents through a number of goal-oriented, explicit systematic procedures.

20 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 Takes many consultations to get to a correct diagnosis!

21 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 Promote regular, aerobic fitness Promote fitness support with strengthening, gentle stretching and proprioception exercises Promote postural and ergonomic hygiene especially during sleep, at school and workplace Promote weight control (BMI <25) Promote daily relaxation activities Promote lubrication during sexual intercourse (women) Promote assumption of generous isotonic liquid intake (2–2.5 L/day) Promote assumption of high salt intake (avoided in case of arterial hypertension) Promote early treatment of malocclusion Avoid high impact sports/activities Avoid low environmental temperatures Avoid prolonged sitting positions and prolonged recumbency Avoid sudden head-up postural change Avoid excessive weight lifting/carrying Avoid large meals (especially of refined carbohydrates) Avoid hard foods intake and excessive jaw movements (ice, gums, etc.) Avoid bladder irritant foods (e.g., coffee and citrus products) intake Avoid nicotine and alcohol intake waterbeds, adjustable air mattress Florinef helps the kidneys retain more sodium which in turn increases blood volume. Florinef’s ability to constrict the blood vessels may help blood stop from pooling in the lower extremities when standing. Patients must increase their salt intake for this drug to work.

22 Treatment Continued Fatigue Surgical & Anesthetic
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 it may help with low blood volume, orthostatic intolerance and POTS.  Florinef helps the kidneys retain more sodium which in turn increases blood volume. Florinef’s ability to constrict the blood vessels may help blood stop from pooling in the lower extremities when standing. Patients must increase their salt intake for this drug to work. Modafinil is a wakefulness-promoting drug (eugeroic) that is approved by the United States' Food and Drug Administration (FDA) for the treatment of narcolepsy, shift work sleep disorder and excessive daytime sleepiness associated with obstructive sleep apnea In living cells, it is required for the transport of fatty acids from the cytosol into the mitochondria during the breakdown of lipids (fats) for the generation of metabolic energy. It is a component of the electron transport chain and participates in aerobic cellular respiration, generating energy in the form of ATP. Ninety-five percent of the human body’s energy is generated this way. Postpradial – post meal tired, octreotide though it is a more potent inhibitor of growth hormone, glucagon, and insulin than the natural hormone

23 PT Implications Proprioceptive Exercises Muscle Strengthening
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

24 Questions?

25 References 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): doi: /ajmg.a De Paepe A, Malfait F. The ehlers-danlos syndrome, a disorder with many faces. Clin Genet. 2012;82(1):1-11. doi: /j x. Goodman CC, Fuller KS. Pathology: Implications for the physical therapist. SAUNDERS W B Company; 2009. Castori M. Ehlers-danlos syndrome, hypermobility type: An underdiagnosed hereditary connective tissue disorder with mucocutaneous, articular, and systemic manifestations. ISRN dermatology. 2012;2012. Guide to physical therapy practice. 2nd ed. APTA; 2003. Jeno, S., Mohr, T. Connective Tissue, Department of PT UND School of Medicine and Health Science

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