Francomano EDS2011 what we know 2slides

EDNF 2011 Conference 7/28/11

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Ehlers-‐Danlos Syndrome Update 2011 What We Know –

And What We Don’t Know

Clair A. Francomano, M.D.

Overview •  ClassificaMon •  Pain •  Neurologic ComplicaMons

– Autonomic dysfuncMon –  Chiari malformaMon – Occult tethered cord –  Increased intracranial pressure

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



ClassificaMon – Types of Ehlers Danlos Syndrome

•  Classical type –  Joint hypermobility – Skin involvement (soV, stretchy, translucent)

•  Hypermobile type –  Joint hypermobility – Minimal skin involvement

•  Vascular type – Aneurysms (typically medium-‐sized arteries in the abdominal cavity)

EDS ClassificaMon, 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 ClassificaMon, conMnued

•  Arthrochalasia type (VII A and B) –  severe generalized joint hypermobility with recurrent subluxaMons

–  congenital, bilateral hip dislocaMon –  Mssue fragility with widened atrophic scars –  kyphoscoliosis –  stretchy skin –  caused by defects in type I collagen processing

•  Dermatosporaxis type (VIIC)

ClassificaMon -‐ QuesMons

•  Is there a beaer 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 subjecMve. Is there a good way to quanMtate skin involvement?

•  How does the joint and skin involvement change with age?



ClassificaMon -‐ QuesMons •  From a clinical perspecMve, there appear to be addiMonal subtypes of EDS. –  EDS with Marfan-‐like habitus (tall, thin, difficulty pufng 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 connecMve Mssue condiMons such as osteogenesis imperfecta, SMckler 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%)



QuesMons

•  We know that about half the people with Classical EDS have alteraMons 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 quesMons. Gene idenMficaMon will help us understand the fundamental biology underpinning these disorders, and may lead to raMonal 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, mulMdisciplinary approach is needed for management

•  We need much more informaMon about opMmal strategies for pain

Autonomic DysfuncMon In EDS

•  Postural OrthostaMc Tachycardia syndrome (POTS)

•  Neurally Mediated Hypotension •  GastrointesMnal moMlity issues •  Temperature instability •  Sleep disturbances



Autonomic DysfuncMon in EDS Open QuesMons

•  Is this a primary neurologic problem? •  Is autonomic dysfuncMon always secondary to impingement of the brainstem or upper cervical spinal cord?

•  Does stabilizaMon of the craniocervical juncMon improve autonomic dysfuncMon?

•  How can we improve the GI moMlity issues?

Anatomy of the Spine








Anatomy of the Craniocervical JuncMon



Anatomy of the Craniocervical JuncMon

Pathology of the Spine



Tendons and Ligaments

•  Ligaments and tendons are made of connecMve Mssue

•  Ligaments connect bone to bone •  Tendons connect muscle to bone •  Tendons are an extension of the strong connecMve Mssue that surrounds all muscles – the fascia

Tendons and Ligaments



Chiari MalformaMon

Classical EDS – 16 year old female

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



§  MulMple Schmorl’s nodes in the T-‐spine §  Disc desiccaMon in mulMple levels §  Tonsillar ectopia without crowding of the posterior fossa §  Pannus around the odontoid §  Cervical degeneraMve disc disease

Hypermobile EDS – 21 year old man

Classical EDS – 50 year old woman

High grade mulM-‐level cervical stenosis Spondylolisthesis Retroflexed odontoid Pannus formaMon



Normal Cord Tethered Cord

Upright MRI in 27 year old female with EDS/CMI



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

52 year old Woman Classical EDS

LeV: §  mulM level herniaMons §  disc desiccaMon §  neural foramina narrowing §  facet arthrosis

Right top: §  Severe degeneraMve disc

disease §  Herniated discs

§  Spondylolisthesis

Boaom: §  Spinal canal stenosis

§  Dural ectasia §  DegeneraMve disc disease

54 yo F

56 yo M

39 yo M



Unilateral facet arthrosis, L4 level T1 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 mulM level disc bulges

32 year old woman with classical EDS

§  MulM-‐level disc herniaMons §  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 Woman Normal

PaMents with hereditary connecMve Mssue disorders may present with varying degrees of occipitoatlantoaxial hypermobility, resulMng in •  Symptoms referable to basilar impression •  Retro-‐odontoid pannus formaMon •  FuncMonal cranial sealing •  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 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

•  DegeneraMve 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 malformaMon is associated with EDS in a significant minority of paMents

•  Pannus formaMon around the odontoid-‐ thought to be related to craniocervical instability

•  Retroflexed or misshaped odontoid •  No age or subtype correlaMon observed with craniocervical juncMon abnormaliMes



Summary and RecommendaMons

•  Spinal pathology is a major cause of morbidity in Classical and Hypermobile EDS

•  Low threshold for MRI invesMgaMons is appropriate for EDS paMents with complaint of back and neck pain

•  AnMcipatory guidance is appropriate for avoidance of acMviMes that are known to accelerate disc disease

Spine in EDS – What We Don’t Know

•  Why do some paMents develop disabling symptoms while others never do? •  Why does seemingly minor trauma induce severe, someMmes life-‐changing symptoms? •  What is the long-‐term prognosis for stabilizaMon surgeries of the craniocervical juncMon and spine? •  What is the long-‐term prognosis of detethering procedures for tethered cord?



Immune Issues

•  We have seen mulMple paMents with disorders of the immune system, including both humoral and cellular immunity

•  Is there an associaMon, or merely a chance occurrence of two disorders

•  Are these related to autonomic dysfuncMon? Or is there another mechanism at play?

•  Why do paMents with hereditary disorders of connecMve Mssue seem to be at increased risk of autoimmune condiMons?

Mast Cell Disease

•  There is a subset of EDS paMents who develop symptoms of mast cell disease (flushing, hives, anaphylaxis)

•  Is this a chance associaMon or another manifestaMon of the phenotype?



Drug Metabolism

•  Many EDS paMents do not metabolize drugs as expected.

•  Many paMents have reported that they are slow to respond to the “caine” derivaMves in the dental office – need mulMple injecMons; wears off very slowly

•  Metabolism of many drugs either prolonged or accelerated

•  What can we learn from these observaMons about the underlying disorder(s)?

Thanks to

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

Documents

Francomano EDS2011 what we know 2slides