Ehlers- Danlos Syndrome Update 2011

1. Ehlers-Danlos SyndromeUpdate 2011 What We Know – And What We Don’t Know Clair A. Francomano, M.D.

2. Overview • Classification • Pain • Neurologic Complications • Autonomic dysfunction • Chiari malformation • Occult tethered cord • Increased intracranial pressure • Immune Function, including autoimmunity • Mast Cell Disease • Drug Metabolism

3. Classification – Types of Ehlers Danlos Syndrome • Classical type • Joint hypermobility • Skin involvement (soft, stretchy, translucent) • Hypermobile type • Joint hypermobility • Minimal skin involvement • Vascular type • Aneurysms (typically medium-sized arteries in the abdominal cavity)

4. EDS Classification, cont. • Kyphoscoliosistype • friable, hyperextensible skin, thin scars, and easy bruising • generalized joint laxity • severe muscle hypotonia at birth • progressive scoliosis, present at birth or within the first year of life; • scleral fragility and increased risk of rupture of the globe • Arthrochalasia type • Dermatosporaxis type

5. EDS Classification, continued • Arthrochalasiatype (VII A and B) • severe generalized joint hypermobility with recurrent subluxations • congenital, bilateral hip dislocation • tissue fragility with widened atrophic scars • kyphoscoliosis • stretchy skin • caused by defects in type I collagen processing • Dermatosporaxistype (VIIC)

6. Classification - Questions • Is there a better way to classify the various types of EDS? • Skin involvement is extremely variable, even within families (some members of a family may appear to have classical, others hypermobile type). As of now the assessment is highly subjective. Is there a good way to quantitate skin involvement? • How does the joint and skin involvement change with age?

7. Classification - Questions • From a clinical perspective, there appear to be additional subtypes of EDS. • EDS with Marfan-like habitus (tall, thin, difficulty putting on weight). This subgroup resembles MASS phenotype. Is there a biological basis for this resemblance? • Classical type “with vascular features” – persons with EDS who have cerebral aneurysms, cardiovascular features such as septal aneurysm, and others • Families with overlap between EDS and other connective tissue conditions such as osteogenesisimperfecta, Stickler syndrome and Marfan syndrome

8. Genes • Classical type • Type V collagen, alpha 1 or alpha 2 genes (50%) • Unknown (50%) • Hypermobile type • Unknown • Vascular type • Type III collagen, alpha 1 gene (100%)

9. Questions • We know that about half the people with Classical EDS have alterations in one of the two type V collagen genes. What are the other genes causing the classical type? • What genes cause the hypermobile type of EDS? These are not strictly academic questions. Gene identification will help us understand the fundamental biology underpinning these disorders, and may lead to rational approaches to treatment

10. Help is On the Way – Whole Genome Sequencing • The cost of DNA sequencing has been cut by about 6 orders of magnitude over the past 10 years (from $1 billion to $10-15,000 per genome) • NIH is about to fund Centers for whole genome sequencing, specifically to find unknown genes causing Mendelian disorders

11. Pain in EDS • Myopathic • Neuropathic • Single most common cause for referral • Comprehensive, multidisciplinary approach is needed for management • We need much more information about optimal strategies for pain

12. Autonomic Dysfunction In EDS • Postural Orthostatic Tachycardia syndrome (POTS) • Neurally Mediated Hypotension • Gastrointestinal motility issues • Temperature instability • Sleep disturbances

13. Autonomic Dysfunction in EDSOpen Questions • Is this a primary neurologic problem? • Is autonomic dysfunction always secondary to impingement of the brainstem or upper cervical spinal cord? • Does stabilization of the craniocervical junction improve autonomic dysfunction? • How can we improve the GI motility issues?

14. Anatomy of the Spine

15. Anatomy of the Spine

16. Anatomy of the Spine

17. Anatomy of the Spine

18. Anatomy of the Craniocervical Junction

19. Anatomy of the Craniocervical Junction

20. Pathology of the Spine

21. Tendons and Ligaments • Ligaments and tendons are made of connective tissue • Ligaments connect bone to bone • Tendons connect muscle to bone • Tendons are an extension of the strong connective tissue that surrounds all muscles – the fascia

22. Tendons and Ligaments

23. Chiari Malformation

24. Classical EDS – 16 year old female • Tonsillar ectopia • Posterior fossa crowding • Abnormal long odontoid • Pannus formation • Loss of height of cervical discs

25. Hypermobile EDS – 21 year old man • Multiple Schmorl’s nodes in the T-spine • Disc desiccation in multiple levels • Tonsillar ectopia without crowding of the posterior fossa • Pannus around the odontoid • Cervical degenerative disc disease

26. Classical EDS –50 year old woman High grade multi-level cervical stenosis Spondylolisthesis Retroflexed odontoid Pannus formation

27. Normal Cord Tethered Cord

28. Upright MRI in 27 year old female with EDS/CMI

29. 52 year old Woman Classical EDS • Dural ectasia • Degenerative and desiccated discs • Herniated discs • Type 2 Modic changes • Spinal stenosis • Spondylolisthesis

30. Left: • multi level herniations • disc desiccation • neural foramina narrowing • facet arthrosis • Right top: • Severe degenerative disc disease • Herniated discs • Spondylolisthesis • Bottom: • Spinal canal stenosis • Dural ectasia • Degenerative disc disease 56 yo M 54 yo F 39 yo M

31. Unilateral facet arthrosis, L4 level T1 MRI image 16- year old girl with hypermobile EDS

32. Annular tears at L4-L5 and L5-S1 48 yo woman with hypermobile EDS

33. Spondylolisthesis at L4-L5 and multi level disc bulges 32 year old woman with classical EDS

34. Multi-level disc herniations • Spinal canal stenosis • Neural foramina narrowing • Severe facet arthrosis 18-year old man with hypermobile EDS

35. Eccentric Nucleus Pulposus 19 year old Man 18 year old Woman Normal

36. Patients with hereditary connective tissue disorders may present with varying degrees of occipitoatlantoaxial hypermobility, resulting in • Symptoms referable to basilar impression • Retro-odontoid pannus formation • Functional cranial settling • Caudal displacement of the cerebellar tonsils

37. Hypermobile EDS – 49 year old woman Atrophy of the thoracic spinal cord

38. Findings on Lumbar Spine MRIs (N=58)

39. Spine In EDS – What We Know • Degenerative disc disease is extremely common in classical and hypermobile EDS • Spinal stenosis at the cervical level is seen in about 1/3 of women over the age of 40 • Scoliosis may progress in adults with EDS • Spinal disease causing significant morbidity, back pain, and neurological symptoms is nearly ubiquitous and frequently causes disability.

40. Spine in EDS, Cont. • Chiari malformation is associated with EDS in a significant minority of patients • Pannusformation around the odontoid- thought to be related to craniocervical instability • Retroflexed or misshaped odontoid • No age or subtype correlation observed with craniocervical junction abnormalities

41. Summary and Recommendations • Spinal pathology is a major cause of morbidity in Classical and Hypermobile EDS • Low threshold for MRI investigations is appropriate for EDS patients with complaint of back and neck pain • Anticipatory guidance is appropriate for avoidance of activities that are known to accelerate disc disease

42. Spine in EDS –What We Don’t Know • Why do some patients develop disabling symptoms • while others never do? • Why does seemingly minor trauma induce severe, • sometimes life-changing symptoms? • What is the long-term prognosis for stabilization • surgeries of the craniocervical junction and spine? • What is the long-term prognosis of detethering • procedures for tethered cord?

43. Immune Issues • We have seen multiple patients with disorders of the immune system, including both humoral and cellular immunity • Is there an association, or merely a chance occurrence of two disorders • Are these related to autonomic dysfunction? Or is there another mechanism at play? • Why do patients with hereditary disorders of connective tissue seem to be at increased risk of autoimmune conditions?

44. Mast Cell Disease • There is a subset of EDS patients who develop symptoms of mast cell disease (flushing, hives, anaphylaxis) • Is this a chance association or another manifestation of the phenotype?

45. Drug Metabolism • Many EDS patients do not metabolize drugs as expected. • Many patients have reported that they are slow to respond to the “caine” derivatives in the dental office – need multiple injections; wears off very slowly • Metabolism of many drugs either prolonged or accelerated • What can we learn from these observations about the underlying disorder(s)?

46. Thanks to • DrNazli McDonnell • Dr. Fraser Henderson • Dr. Alan Pocinki • Dr. Robert Gerwin • Ms. Jessica Adcock • All my patients and their families