1. Ehlers-Danlos Syndrome Update 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
Minimal skin involvement
Vascular type
Aneurysms (typically medium-sized arteries in the abdominal cavity)

4. EDS Classification, cont.
Kyphoscoliosis type
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
Arthrochalasia type (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
Dermatosporaxis type (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 osteogenesis imperfecta, Stickler syndrome and Marfan syndrome

8. Genes Classical type Hypermobile type Vascular 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 EDS Open 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
Normal
19 year old Man
18 year old Woman

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)
Degenerative disc disease
multiple levels; narrowing of neural foramina 45
78%
Herniation and expulsion of discs 30
52%
Spinal canal stenosis 10
17%
Facet arthrosis 48
83%
Dural ectasia 15
26%
Eccentric nucleus pulposus
younger age group (<25) 12
21%
Dural “cysts” 3 5%
Type II Modic changes
older age group (>40) 9
16%
Spondylolisthesis 4 7%
Annular tears 7
12%

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
Pannus formation 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 Dr Nazli McDonnell Dr. Fraser Henderson Dr. Alan Pocinki
Dr. Robert Gerwin
Ms. Jessica Adcock
All my patients and their families