Ehlers-Danlos Syndrome Update 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 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 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%)

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 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?

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

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

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

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

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

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

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

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 Normal 19 year old Man 18 year old Woman

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

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

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%

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 stabilization surgeries of the craniocervical junction and spine? What is the long-term prognosis of detethering procedures 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