Presentation on theme: "Ehlers-Danlos Syndrome (EDS)"— Presentation transcript:
1 Ehlers-Danlos Syndrome (EDS) Robert Whittaker, SPTUniversity of North Dakota
2 OverviewGenetic defects affecting biosynthesis & structure of collagen type (autosomal recessive – AR, autosomal dominant – AD)2Villefranche Criteria 6 subtypes: classic, hypermobility (HT), vascular, kyphoscoliotic, arthrochalasis, & dermatosporaxisEmerging Forms: cardiac-valvular, vascular-like, musculocontractural, spondylocheirodysplastic, brittle cornea syndrome, EDS/OI overlap, tenascin x deficient, progeroid, parodontitis, fribronectin deficient4Can lead to serious adult complications including subluxations, sprains & chronic joint pain difficult to treat, may lead to devastating physical, social & emotional disabilityICD-9-CM Code 756: Other congenital musculoskeletal anomalies (Pattern 4A, 4B, 4F, 4I, 5B, 5C)54A – primary prevention/risk reduction for LOB & falling4B – impaired posture4F – impaired joint mobility, motor function, muscle performance, ROM, & reflex integrity associated with spinal disorders4I – impaired joint mobility, motor function, muscle performance, ROM, & reflex integrity associated with bony or soft tissue surgery5B – impaired neuromotor development5C – impaired motor function & sensory integrity associated with non-progressive disorders of the CNS – congenital origin or acquired in infancy or childhoodFibrillar 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 structures2Involved in inter & intramolecular crosslinking necessary for stabilization of the collagen moleculesDefects in transcription factors, intracellular trafficking of ECM molecules, proteoglycan metabolism, supramolecular organization of ECM & cell-matric interactionsHowever, 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 Classic2Skin hyperextensibility; widened atrophic scars; joint hypermobilitySmooth, 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 historyAD – 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 Vascular2Thin, 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 relativeAD – 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 requiredPregnant 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 3xStrenuous activity should be avoided with aortic regurgitation due weakness of aortic wall3Facial 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 Kyphoscoliotic2Generalized JHM, congenital hypotonia; congenital & progressive scoliosis; scleral fragility & rupture of the ocular globeTissue fragility, including atrophic scars; easy bruising; arterial rupture; marfanoid habitus; microcornea; osteopenia/porosis; (+) family historyDeficient 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 fibrosus2Atrophy – wasting away
6 EDS Arthrochalasis2Generalized JHM with recurrent subluxations; congenital bilateral hip dislocationsSkin hyperextensibility; tissue fragility, including atrophic scars; easy bruising; hypotonia; kyphoscoliosis; osteopenia/porosisAD – COL1A1 & COL1A2Type I: skin, tendon, bone, ligaments, joint capsules, annulus fibrosus6Chalasia - 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 & fingersAR – ADAMTS2Type I: skin, tendon, bone, ligaments, joint capsules, annulus fibrosus2an 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 JHMRecurring joint dislocations, chronic joint/limb pain, (+) family historyAD?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 instabilityLE 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 = hyperextensibleVelvety & smooth skin – skin texture difficult in toddlersCan 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 scarsCapillary fragility causes increased tendency and delayed ecchymosis (bruising)Disturbed perspiration (diaphoresis/hypohidrosis)
10 EDS-HT Mucosal & Oropharyngeal Features4 Xerostomia, xeropthalmia, & vaginal drynessHypohidrosis, with mucosal xerosis could be remote consequence of autonomic dysregulationGingival bleeding due to mucosal fragility (brushing teeth?)Blue sclera likely caused by more visible uveal blood vessels though thinner scleraLack of frenulum – Gorlin’s SignOropharyngeal dysphagia may impede feeding with consequent excessive weight loss, exacerbation of fatigue, and failure to thrive in childrenGorlin’s Sign – able to touch tongue to nose(xero – dry)
11 Orthopedic Features4Congenital 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 fractures1Muscle contractions, growth & molding of skeleton likely more effective in a body with lax jointsDecreased proprioceptive functions and JHM likely contributors of dysfunctions1C-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 pain110% dextrose prolotherapy for TMJ to reduce pressure induced painProlotherapy 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 CriteriaPassive DF of 5th finger >90°12Major CriteriaScore 4/9Arthralgia for >3 months in >4 jointsPassive flexion of thumbs to forearmHyperextension of elbows >10°Minor CriteriaScore 1-3Arthralgia in 1-3 jointsHx of joint dislocationsSoft tissue lesions >3Marfan like habitusSkin striae, hyper-extensibility, or scarringEye signs, lid laxityHx of varicose veins, hernia, visceral prolapseHyperextension of knees >10°Forward flexion of the trunk with knees fully extended & palms resting on the floorPresent = 1Dx – 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 biopsyChronic/recurrent pain & fatigue most common complaintsWidespread & involve the musculoskeletal system, nervous system, & internal organsPain associated with regular analgesic use, JHM, previous surgery, & related to functional impairment independently from fatigue1Headache – migraine most commonImpaired proprioception at various joints (proximal interphalangeal and knee joints)Impairs balance & postureDelayed autonomous walking, tip-toe walking, lack of crawling, clumsiness, and possibly dyspraxia in infancyThought to be primarily linked with joint damage – wider spectrum of pain features with recent evidenceEnhanced 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 imageUltrasound 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 formMild 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 collapsePersistent childhood wheezing by causing airway collapse through CT defect affecting airways structureA 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 & Fatigue1Fatigue – sleep disturbances, concentration problems, social functioning, self-efficacy concerning fatigue, muscle weakness, & painEDS-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 scleraMyopia, unilateral ptosis, & tilted optic disc less commonBlepharochalasis 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 disorderGastroesophageal reflux (with/without hiatus hernia), chronic/recurrent gastritis, symptoms of delayed gastric emptying, recurrent abdominal pain, constipation/diarrheaUnexplained abdominal pain in up to 86% of cases – bloating, reflux, heartburns, N/V, diarrhea, and consipitaiton1Reduced 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)1Visceroptosis (or enteroptosis) is a prolapse or a sinking of the abdominal viscera (internal organs) below their natural positionDolicho – long running
18 EDS-HT Pelvic/Gynocologic Features4 Irregular menses, meno/metrorrhagias, & sever dysmenorrheaFertility & pregnancy usually unaffectedObstetric & anesthetic interventions in order to prevent life threatening/disabling complicationsAnesthesia 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 surgeryPelvis – 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)1Urinary stress incontinence, uterine prolapse, & fecal incontinenceProlapse - Cesarean should be considered when vaginal delivery without episiotomy cannot be anticipatedMenorrhagia or Hematomunia is an abnormally heavy and prolonged menstrual period at regular intervalsMetrorrhagia (metro = womb, -rrhagia = excessive flow) is uterine bleeding at irregular intervals, particularly between the expected menstrual periods.Nullipara - A woman who has never given birthDyspareunia (from Greek meaning "badly mated”) is painful sexual intercourse, due to medical or psychological causesAn episiotomy, also known as perineotomy, is a surgically planned incision on the perineum and the posterior vaginal wall during second stage of laborWound 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 individuals1Secondary to chronic pain & disability, ostracism, & avoidance of relationshipsCognitive Behavioral TherapyLearning 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 diagnosisMolecular testing & extensive vascular imaging for other EDS subtypesOverlapping DisordersMucocutaneous fragility, JHM, chronic musculoskeletal pain & fatigueNeurologic DisordersMS, ALS, hereditary & acquired sensory-motor &/or autonomic polyneuropathies, & CFSOther Hereditary Connective Tissue Disorders with JHM“Battered child” syndrome, bleeding disorders, various rheumatologic conditions with chronic musculoskeletal pain, such as ankylosing spondylitis, RA, & fibromyalgiaTakes many consultations to get to a correct diagnosis!
21 TreatmentLifestyle! Most cost & time effective solution (education - avoid exacerbating)Multidisciplinary approach (geneticist, rheumatologist, neurologist, psychiatrist, PT/OT, urologist/gynecologist, orthopedist, cardiologist, pneumologist, gastroenterologist, other)DrugsLow-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), duloxetineHelp with satellite symptoms such as depression/sleep/irritable bowel disease with limited side effectsAscorbic acid for capillary fragility, cofactor of polyl & lysyl hydroxylase enzymes for biogenesis of collagens, Vitamin D for osteopenia, melatonin for sleep, & other neutraceuticalsPromote regular, aerobic fitnessPromote fitness support with strengthening, gentle stretching and proprioception exercisesPromote postural and ergonomic hygiene especially during sleep, at school and workplacePromote weight control (BMI <25)Promote daily relaxation activitiesPromote 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 malocclusionAvoid high impact sports/activitiesAvoid low environmental temperaturesAvoid prolonged sitting positions and prolonged recumbencyAvoid sudden head-up postural changeAvoid excessive weight lifting/carryingAvoid 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) intakeAvoid nicotine and alcohol intakewaterbeds, adjustable air mattressFlorinef 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 intoleranceAdditional water intake (isotonic solutions), high salt (HTN), carnitine &/or coenzyme Q10Surgical & AnestheticSurgery not contraindicated, increased time for soft tissue repair may lead to muscle deconditioning postsurgical recoveryMild 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 fragilityEpidermal CSF hypotension from leakageit 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 apneaIn 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 stabilizationMuscle StrengtheningMid-range – stability (low resistance, high reps),ModalitiesHeat/cold – inspect skin (heat can increase extensibility)TENS – pain, NMES – joint positionAssistive DevicesMay stress UE, W/C decrease stress on LE, silver ring splints for digits, collar/bracesSwimming (cardiac volume!), gentle stretching, massage, prevention (pads), education, lifestyle recommendations, energy conservation
25 ReferencesCastori 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.aDe 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