Ehlers-Danlos SyndromeUpdate 2011

What We Know – And What We Don’t Know

Clair A. Francomano, M.D.

Overview

• Classification• Pain• Neurologic Complications

– Autonomic dysfunction– Chiari malformation– Occult tethered cord– Increased intracranial pressure

• Immune Function, including autoimmunity• Mast Cell Disease• Drug Metabolism

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)

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

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)

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?

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

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%)

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

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

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

Autonomic Dysfunction In EDS

• Postural Orthostatic Tachycardia syndrome (POTS)

• Neurally Mediated Hypotension• Gastrointestinal motility issues• Temperature instability• Sleep disturbances

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?

Anatomy of the Spine

Anatomy of the Spine

Anatomy of the Spine

Anatomy of the Spine

                                                                    

       

Anatomy of the Craniocervical Junction

Anatomy of the Craniocervical Junction

Pathology of the Spine

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

Tendons and Ligaments

Chiari Malformation

Classical EDS – 16 year old female

Tonsillar ectopia Posterior fossa crowding Abnormal long odontoid Pannus formation Loss of height of cervical discs

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

Hypermobile EDS – 21 year old man

Classical EDS –50 year old woman

High grade multi-level cervical stenosis

Spondylolisthesis

Retroflexed odontoid

Pannus formation

Normal Cord Tethered Cord

Upright MRI in 27 year old female with EDS/CMI

Dural ectasia Degenerative and desiccated discs Herniated discs Type 2 Modic changes Spinal stenosis Spondylolisthesis

52 year old Woman Classical EDS

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

54 yo F

56 yo M

39 yo M

Unilateral facet arthrosis, L4 levelT1 MRI image

16- year old girl with hypermobile EDS

48 yo woman with hypermobile EDS

Annular tears at L4-L5 and L5-S1

Spondylolisthesis at L4-L5 and multi level disc bulges

32 year old woman with classical EDS

Multi-level disc herniations Spinal canal stenosis Neural foramina narrowing Severe facet arthrosis

18-year old man with hypermobile EDS

Eccentric Nucleus Pulposus

19 year old Man 18 year old WomanNormal

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

Atrophy of the thoracic spinal cord

Hypermobile EDS – 49 year old woman

Findings on Lumbar Spine MRIs (N=58)Degenerative disc diseasemultiple 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 pulposusyounger age group (<25)

12 21%Dural “cysts” 3 5%Type II Modic changesolder age group (>40)

9 16%Spondylolisthesis 4 7%Annular tears 7 12%

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.

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

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

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 stabilizationsurgeries of the craniocervical junction and spine?

• What is the long-term prognosis of detetheringprocedures for tethered cord?

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?

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?

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)?

Thanks to

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