Download Ehlers-Danlos Syndrome

Ehlers-Danlos Syndrome
Update 2011
What We Know –
And What We Don’t Know
Clair A. Francomano, M.D.
Overview
• Classification
• Pain
• Neurologic Complications
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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 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
54 yo F
Right top:
 Severe degenerative disc
disease
 Herniated discs
 Spondylolisthesis
56 yo M
Bottom:
 Spinal canal stenosis
 Dural ectasia
 Degenerative disc disease
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
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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
Herniation and expulsion of discs
Spinal canal stenosis
Facet arthrosis
Dural ectasia
Eccentric nucleus pulposus
younger age group (<25)
Dural “cysts”
Type II Modic changes
older age group (>40)
Spondylolisthesis
Annular tears
45
78%
30
10
48
15
12
52%
17%
83%
26%
21%
3
9
5%
16%
4
7
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 odontoidthought 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
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Dr Nazli McDonnell
Dr. Fraser Henderson
Dr. Alan Pocinki
Dr. Robert Gerwin
Ms. Jessica Adcock
All my patients and their families