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Neurological and spinal manifestations of the Ehlers-Danlos syndromes

Authors:
  • The Metroplitan Neurosurgery Group

Abstract and Figures

The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterized by joint hypermobility, skin extensibility, and tissue fragility. This communication briefly reports upon the neurological manifestations that arise including the weakness of the ligaments of the craniocervical junction and spine, early disc degeneration, and the weakness of the epineurium and perineurium surrounding peripheral nerves. Entrapment, deformation, and biophysical deformative stresses exerted upon the nervous system may alter gene expression, neuronal function and phenotypic expression. This report also discusses increased prevalence of migraine, idiopathic intracranial hypertension, Tarlov cysts, tethered cord syndrome, and dystonia, where associations with EDS have been anecdotally reported, but where epidemiological evidence is not yet available. Chiari Malformation Type I (CMI) has been reported to be a comorbid condition to EDS, and may be complicated by craniocervical instability or basilar invagination. Motor delay, headache, and quadriparesis have been attributed to ligamentous laxity and instability at the atlanto-occipital and atlantoaxial joints, which may complicate all forms of EDS. Discopathy and early degenerative spondylotic disease manifest by spinal segmental instability and kyphosis, rendering EDS patients prone to mechanical pain, and myelopathy. Musculoskeletal pain starts early, is chronic and debilitating, and the neuromuscular disease of EDS manifests symptomatically with weakness, myalgia, easy fatigability, limited walking, reduction of vibration sense, and mild impairment of mobility and daily activities. Consensus criteria and clinical practice guidelines, based upon stronger epidemiological and pathophysiological evidence, are needed to refine diagnosis and treatment of the various neurological and spinal manifestations of EDS. © 2017 Wiley Periodicals, Inc.
Content may be subject to copyright.
American Journal of Medical Genetics Part C (Seminars in Medical Genetics)
RESEARCH REVIEW
Neurological and Spinal Manifestations of the
EhlersDanlos Syndromes
FRASER C. HENDERSON SR.,* CLAUDIU AUSTIN, EDWARD BENZEL,
PAOLO BOLOGNESE, RICHARD ELLENBOGEN, CLAIR A. FRANCOMANO, CANDACE IRETON,
PETRA KLINGE, MYLES KOBY, DONLIN LONG, SUNIL PATEL, ERIC L. SINGMAN,
AND NICOL C. VOERMANS
The EhlersDanlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders
characterized by joint hypermobility, skin extensibility, and tissue fragility. This communication briey reports
upon the neurological manifestations that arise including the weakness of the ligaments of the craniocervical
junction and spine, early disc degeneration, and the weakness of the epineurium and perineurium surrounding
peripheral nerves. Entrapment, deformation, and biophysical deformative stresses exerted upon the nervous
system may alter gene expression, neuronal function and phenotypic expression. This report also discusses
Fraser Cummins Henderson Sr., M.D., was fellowship trained in disorders of the craniocervical junction at the National Hospitals for Neurology and
Neurosurgery, Queens Square London, before returning to complete his commitment to the U.S. Navy. He was then Professor and Director of
Neurosurgery of the Spine and Craniocervical Junction at Georgetown University before entering private practice. He has concentrated on the
diagnosis and treatment of hypermobility connective tissue disorders and other rare diseases of the spine. He serves on the Executive Boards of the
EhlersDanlos Society, the Chiari Syringomyelia Foundation, the ILC, and the TCAPP Foundations.
Myles Koby, M.D. is a neuroradiologist, formerly at the National Institutes of Health and now at Doctors Community Hospital, Lanham, MD. He has
special clinical interest in the use of dynamic imaging in the investigation of spinal instability disorders.
Claudiu Austin, M.D., is an internist at Doctors Community Hospital in Lanham, MD, with special interest in pharmacology and physiology. He
specializes in treating complex EDS patients, including those with movement disorders, adult PANDAS, and severe autonomic dysfunction.
Clair Francomano, M.D., is a clinical geneticist with a long interest in the hereditary disorders of connective tissue. Her professional work in the last
10 years has centered on EhlersDanlos Syndrome. She is Director of Adult Genetics and of the Ehlers-Danlos Society Center for Clinical Care and
Research at the Harvey Institute for Human Genetics, and Associate Professor of Medicine at Johns Hopkins University School of Medicine. She serves
on the Executive Board and the Medical and Scientic Board of the Ehlers-Danlos Society.
Edward Benzel, M.D., Ph.D., is a neurosurgeon who was Professor Chairman of Neurosurgery at the Cleveland pathophysiology treatment of spinal
disorders.
Paolo Bolognese, M.D., is a neurosurgeon in New Hyde Park, New York, and is afliated with North Shore University Hospital. He received his
medical degree from University of Torino Faculty of Medicine and has been in practice for more than 20 years. He specializes in Chiari I malformation,
syringomyelia, and related disorders.
Richard Ellenbogen, M.D., is Professor Chairman of the Department of Neurological adult brain tumors trauma surgery craniofacial abnormalities
Chiari malformations congenital conditions. He also conducts research on molecular imaging nanoparticles on traumatic brain injury.
Candace Ireton, M.D., is a Board Certied Family Physician with special interest in caring for EhlersDanlos syndrome patients. Dr. Ireton received her
BS in Physical Education with Exercise Physiology emphasis from the University of California at Davis. She is currently piloting a group visit program for
the primary care of EDS patients in Asheville, NC and has been in practice for more than 20 years.
Petra M. Klinge, M.D., Ph.D., is a neurosurgeon who completed training in Germany and is currently Professor of Neurosurgery at the Medical
School of Brown University. She specializes in hydrocephalus, tethered cord and Chiari malformation, and developmental cerebrospinal uid disorders.
Donlin M. Long, M.D., Ph.D., was Professor Chairman of Neurosurgery at The Johns where he took special interest in the development of
infrastructure for patient care while developing new insights into pathophysiology of pain, spinal disorders, and brain tumors. He presently specializes
in diagnosing the various comorbid conditions of EDS.
Sunil Patel, M.D., is Professor and Chairman of Neurosurgery at the Medical University of South Carolina. He completed fellowship training in Skull
base Surgery, Cerebrovascular Surgery, and Microneurosurgery, and is presently focused on developing the understanding and treatment of vascular
and neoplastic brain disorders, complex spine disorders, and the treatment of craniocervical and spinal manifestations of EDS.
Eric L. Singman, M.D., Ph.D., is Professor of Ophthalmology and Director of the Wilmer Eye Institute at The Johns Hopkins Hospital. His clinical
expertise includes diagnosis of visual dysfunction after brain injury. Dr. Singman also has a particular interest in teaching health-care providersto
recognize the visual sequelae of complex disorders such as traumatic brain injury, Lyme disease, and EDS.
Dr. Nicol Voermans is a neurologist the Neuromuscular Centre of Radboud University Medical Center, Nijmegen, The Netherlands. Her main research
focus is inherited myopathies, in particular congenital myopathies, fascioscapulohumeral muscular dystrophy, and the neuromuscular features of
inherited connective tissue disorders. She completed a doctoral dissertation on neuromuscular features in EhlersDanlos and Marfan syndromes.
Conicts of interest: The senior author is a consultant to LifeSpine, Inc., and is developing technology to improve craniocervical stabilization. The
senior author holds patents on nite element analysis methodology that could be used to assess stress in the brainstem and upper spinal cord. The
other authors declare they have no conict of interest.
*Correspondence to: Fraser Cummins Henderson Sr., M.D., EhlersDanlos Society Center for Clinical Care and Research, Greater Baltimore
Medical Center, The Metropolitan Neurosurgery Group, 8401 Connecticut Avenue, Suite 220, Chevy Chase, Baltimore, MD 20815. E-mail:
henderson@fraserhendersonMD.com
DOI 10.1002/ajmg.c.31549
Article rst published online in Wiley Online Library (wileyonlinelibrary.com).
ß2017 Wiley Periodicals, Inc.
increased prevalence of migraine, idiopathic intracranial hypertension, Tarlov cysts, tethered cord syndrome, and
dystonia, where associations with EDS have been anecdotally reported, but where epidemiological evidence is
not yet available. Chiari Malformation Type I (CMI) has been reported to be a comorbid condition to EDS, and
may be complicated by craniocervical instability or basilar invagination. Motor delay, headache, and
quadriparesis have been attributed to ligamentous laxity and instability at the atlanto-occipital and atlantoaxial
joints, which may complicate all forms of EDS. Discopathy and early degenerative spondylotic disease manifest
by spinal segmental instability and kyphosis, rendering EDS patients prone to mechanical pain, and myelopathy.
Musculoskeletal pain starts early, is chronic and debilitating, and the neuromuscular disease of EDS manifests
symptomatically with weakness, myalgia, easy fatigability, limited walking, reduction of vibration sense, and
mild impairment of mobility and daily activities. Consensus criteria and clinical practice guidelines, based upon
stronger epidemiological and pathophysiological evidence, are needed to rene diagnosis and treatment of the
various neurological and spinal manifestations of EDS. © 2017 Wiley Periodicals, Inc.
KEY WORDS: EhlersDanlos syndrome; headache; craniocervical instability; atlantoaxial instability; tethered cord syndrome
How to cite this article: Henderson Sr. FC, Austin C, Benzel E, Bolognese P, Ellenbogen R, Francomano CA,
Ireton C, Klinge P, Koby M, Long D, Patel S, Singman EL, Voermans NC. 2017. Neurological and spinal
manifestations of the EhlersDanlos syndromes. Am J Med Genet Part C Semin Med Genet 9999C:117.
INTRODUCTION
The EhlersDanlos syndromes (EDS)
are a heterogeneous group of herita-
ble connective tissue disorders char-
acterized by joint hypermobility, skin
extensibility, and tissue fragility. The
significance of neurological findings
of EDS have been recently proposed
and reviewed [Voermans et al., 2009a;
Savasta et al., 2011; Castori and
Voermans, 2014]. The following
article discusses the etiology and
clinical findings related to neurologi-
cal and spinal manifestations com-
monly observed, yet often poorly
recognized, in EDS patients, and
proposes treatment options and areas
of research needed.
METHODS
On the basis of a large shared experience
in the treatment of EDS, the authors
were solicited to contribute a review of
the neurological and spinal manifesta-
tions of EDS. The authors represent a
working group within the International
Consortium on the EhlersDanlos Syn-
dromes. In preparation for the EDS
International Symposium 2016, the
authors formed subcommittees to re-
search individual topics relating to EDS
and its neurological presentations, and
here present those findings in synthe-
sized, topic-based fashion designed to
assist a wider audience of medical
practitioners in caring for EDS patients,
and in advancing research needs for this
population.
HEADACHE IN
EHLERSDANLOS
SYNDROME
EDS patients commonly suffer a
variety of headache types [Jacome,
1999; Martin and Neilson, 2014;
Castori et al., 2015]. These include
headaches due to migraines, muscle
tension, intracranial hypertension,
craniocervical instability, and cervical
spine disorders, temporomandibular
joint disease, carotid dissection, and
other physical conditions. Though a
patient may suffer status migrainosis,
constant pain is less likely to represent
a migrainous headache [Headache
Classification Committee of the In-
ternational Headache Society (IHS),
2013].
EDS patients commonly
suffer a variety of headache
types. These include
headaches due to migraines,
muscle tension, intracranial
hypertension, craniocervical
instability, and cervical spine
disorders, temporomandibular
joint disease, carotid
dissection, and other physical
conditions.
Migraine in EDS
Epidemiology
Migraine, common in the general
population, is more prevalent in women
[Nappi and Nappi, 2012]. Migraine is
also more prevalent among EDS which
also has a female predilection [Bendik
et al., 2011; Castori and Voermans,
2014; Castori et al., 2015]. Therefore,
EDS may be considered a risk factor for
migraine.
Etiology
Migraine often presents as a comorbid
disorder with many other medical
conditions [Schurks et al., 2009; Casucci
et al., 2012; Pierangeli et al., 2012;
Gelfand et al., 2013; van Hemert et al.,
2014]. The final common pathway
appears to be abnormal regulation of
cerebral vasculature following a spread
of depression of cortical electrical
activity [Burstein et al., 2015; Ferrari
et al., 2015].
Clinical and diagnostic findings
Defined as a primary headache disorder,
with recurrent attacks of moderate or
severe intensity, lasting 472 hr, mi-
graine headaches are more often unilat-
eral, pulsating, associated with nausea,
photophobia, and phonophobia, which
are disabling and worse with physical
activity [Headache Classification Com-
mittee of the International Headache
Society (IHS), 2013]. Migraine is usu-
ally preceded by a prodrome and
followed by fatigue, nausea, and dizzi-
ness (postdrome). A careful history may
2 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW
elucidate triggers such as foods, stress,
weather changes, sleep changes, menses,
seasonal allergies, and caffeine. Physical
findings may include vertigo, hypersen-
sitivity to pressure on certain muscles
and tendons, elevated blood pressure,
and heart murmur. Migraines may cause
a benign episodic mydriasis. Findings
may be suggestive of a stroke. Diagnostic
testing should exclude sleep disorders
[Kothari et al., 2000], menstrual cycle
dysfunction including menopause
[Nappi and Nappi, 2012; Ripa et al.,
2015], and patent foramen ovale [Vol-
man et al., 2013].
Treatment
Migraine therapies (e.g., botulinum
toxin, triptans, caffeine, acupuncture,
meditation) are legion, and testify to the
diverse causes of migraine. Recognition
that migraine patients suffer multiple
pain disorders should prompt a holistic
treatment strategy or combination ther-
apies [Estemalik and Tepper, 2013; Kress
et al., 2015].
Areas needing investigation
(1) Connection between migraine, EDS
and mast cell activation syndrome
(MCAS), and cardiac functional/
structural defects, such as postural
orthostatic tachycardia syndrome
(POTS) and patent foramen ovale.
(2) Connection between migraine and
diet in EDS.
(3) Prevalence and impact of migraine in
all types of EDS.
(4) Treatment of migraine in EDS.
(5) Effect of other co-morbidities, med-
ications, and nutrition in EDS related
to migraine prevalence, severity, or
treatment.
IDIOPATHIC
INTRACRANIAL
HYPERTENSION (IIH)
Epidemiology
IIH, or pseudotumor cerebri, is a poorly
understood entity characterized by an
increased intracranial pressure (ICP),
headaches, visual disturbances and pho-
tophobia, and occasionally tinnitus,
nausea, and vomiting. Affected patients
may have objective changes in vision
with 10% developing blindness [Corbett
et al., 1982]. Female to male ratios range
from 4:1 to 15:1, and obesity is an added
risk factor [Radhakr ishnan et al., 1993].
Anecdotal reports from large case series
have suggested an association between
EDS and IIH, but no such association
has been formally reported in the
biomedical literature.
Etiology
Hypotheses proposed for the etiology of
IIH include excess cerebrospinal fluid
(CSF) production, reduced CSF absorp-
tion, excessive brain water content, and
increased cerebral venous pressure lead-
ing to reduced CSF reabsorption [Ball
and Clarke, 2006]. Recent studies dem-
onstrate that up to 93% of patients with
IIH have focal venous sinus stenosis on
MR venography, most commonly prox-
imal to the transverse sigmoid sinuses
junction, suggesting that venous abnor-
malities may play a role in the patho-
physiology of IIH [Farb et al., 2003].
Clinical and Diagnostic Findings
The diagnosis of IIH requires symptoms
of increased ICP. The visual disturbances
are often associated with the finding of
papilledema or visual field defects. The
diagnosis is supported by increased ICP:
>25 cm of H
2
O in the obese popula-
tion, or >20 cm H
2
O in the non-obese
population. There should be normal
composition of CSF, thus, excluding
inflammatory conditions, absence on
MRI, or contrast-enhanced CT of
hydrocephalus and of mass, structural,
or vascular lesions, and no other cause of
intracranial hypertension.
Treatment
Treatments include lifestyle modifica-
tions targeting weight loss including
bariatric surgery, decreasing CSF pro-
duction with acetazolamide, or serial
lumbar punctures, CSF diversion with a
ventriculo-peritoneal or lumbo-per ito-
neal shunt, optic nerve sheath fenestra-
tion, or subtemporal decompression.
Stenting has emerged as an effective
treatment for IIH in select patients with
radiographic cerebral sinus stenosis and
evidence of pressure gradients [Satti
et al., 2015].
Areas Needing Investigation
(1) The epidemiology and etiology of
pseudotumor cerebri in EDS.
(2) Longitudinal studies to assess the efficacy
and risks of medical therapy, shunting,
and stenting in the EDS population.
CHIARI I MALFORMATION
(CMI)
Epidemiology
Chiari malformation Type I (CMI) has
been reported as a comorbid condition
in hypermobile EDS (hEDS) [Milhorat
et al., 2007]. The precise incidence of
the CMI and EDS association is un-
known, but the female to male ratio is
higher (9:1) in the CMI and EDS
subgroup than in the general CMI
population (3:1). The average age of
onset tends to be younger in the CMI
and EDS subgroup, when compared to
the general CMI population.
Chiari malformation Type I
(CMI) has been reported as a
comorbid condition in
hypermobile EDS (hEDS).
The precise incidence of the
CMI and EDS association is
unknown, but the female to
male ratio is higher (9:1) in
the CMI and EDS subgroup
than in the general CMI
population (3:1).
Etiology
CMI is a mesenchymal disorder affecting
thehindbrain,inwhichadevelopmentally
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 3
small posterior fossa results in downward
migration of the brainstem and cerebellar
tonsils through the foramen magnum into
the spinal canal [Batzdorf et al., 2015]. The
herniation causes obstruction to the
normal regional circulation of the cerebro-
spinal fluid (CSF) and compartmentaliza-
tion of CSF circulation [Ellenbogen et al.,
2000], which may result in suboccipital
pressure headaches. Obstruction of the
CSF circulation may result in empty sella
syndrome, with flattening of the pituitary
gland and resulting hormonal changes. A
syrinx may form, which exerts a mass effect
on the spinal cord, and rarely the brainstem
[Kahn et al., 2015]. There is increasing
recognition of CMI variants [Milhorat
et al., 1999]. Some have suggested an
association of tethered cord syndrome and
CMI [Royo-Salvador, 1996].
The incidence, prevalence, and
etiology of CMI and EDS occurring
together are not fully understood.
However, Milhorat et al. [2007,
2010] found a high prevalence of
patients with hereditary disorders of
connective tissue in their retrospective
series of CMI post-decompression fail-
ures that needed further intervention,
including craniocervical fusion and/or
tethered cord release. While this may
indicate a co-existence of these con-
ditions, it does not provide evidence of a
causal relationship, but suggests that
EDS and other disorders of connective
tissue should not be overlooked in CMI.
Clinical and Diagnostic Findings
The CMI is traditionally defined radio-
logically by 5 mm of tonsillar herniation
through the foramen magnum, though
others have suggested a herniation of
3 mm, or 7 mm. The behavior of CMI is
often unrelated to the size of the
herniation, and CMI can be
asymptomatic.
CM is best characterized by a
tussive headache (worse with cough,
strain, or yelling), dizziness, cerebellar
findingsdysarthria, incoordination,
imbalance, and unsteady gaithearing
and vestibular deficits. Rombergs
sign, and deficits of cranial nerves.
There is sometimes trigeminal neuralgia
[Milhorat et al., 1999; Tubbs et al.,
2011a; Yarbrough et al., 2011]. Brain-
stem findings, such as sleep apnea and
dysautonomia, are often found in CM
that are complicated by craniocervical
instability or basilar invagination, the so-
called complex Chiari.
Treatment
There is no universally agreed upon
surgical threshold for CMI, but surgery
should be urgently performed in the
presence of progressive neurological
deficits, and expanding syringomyelia
(Fig. 1) [Yarbrough et al., 2011].
The association of CMI and EDS is
burdened by distinct management chal-
lenges, including craniocervical insta-
bility, and possibly an increased risk of
CSF leaks. CMI may be asymptomatic
(incidence unknown), or mildly symp-
tomatic, so that surgical intervention
may not be required [Novegno et al.,
2008; Strahle et al., 2011]. Sporadic
cases of spontaneous resolution of CMI
Figure 1. CMI with syrinx in the cervical spinal cord (sagittal view, T1 weighted MRI of the cervical spine).
4 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW
have been described [Castillo and Wilson,
1995].
Areas Needing Investigation
(1) The incidence, prevalence, and etiol-
ogy of CMI and its variants CM0 and
CM 1.5 in the EDS population
remains unclear and needs larger data
registry
(2) The Complex Chiari malformation,
though well described in the literature
(see section on craniocervical instabil-
ity), is not universally recognized
among those who perform Chiari
surgery. Prospective studies in EDS
patients with Complex Chiari malfor-
mation are needed to compare out-
comes following decompression alone
versus those undergoing decompres-
sion with fusion/stabilization.
ATLANTOAXIAL
INSTABILITY
Epidemiology
Atlantoaxial instability (AAI) is a poten-
tial complication of all forms of EDS.
Motor delay [Jelsma et al., 2013],
headache associated with connective
tissue pathological relaxationand
quadri-paresis have all been attributed
to ligamentous laxity and instability at
the atlantooccipital, and atlantoaxial
joints [Nagashima et al., 1981; Halko
et al., 1995].
Epidemiology
The epidemiology of AAI in hEDS is
unknown. AAI was seen in two of
three patients with vascular EDS
[Halko et al., 1995]. A high risk of
AAI is apparent in other disorders
affecting connective tissue, including
Down syndrome, Marfan syndrome,
and rheumatoid arthritis [MacKenzie
and Rankin, 2003; Hankinson and
Anderson, 2010].
Etiology
A proclivity to ligamentous incompetence
renders the atlanto-axial joint a higher risk
for instability. The atlantoaxial junction
(AAJ)isthemostmobilejointofthebody.
The AAJ mechanical properties are
determined by ligamentous structures,
most prominent of which are the trans-
verseandalarligaments[Tubbsetal.,
2011b].
Hypermobility of the AAJ is com-
mon in children, and over 40° of
rotation may be observed in each
direction, but in the adult there is
substantially less than 40° of rotation
[Zhang and Bai, 2007; Martin et al.,
2010]. At 35° of rotation of C1 upon
C2, there is stretching and kinking
of the contralateral vertebral artery
[Selecki, 1969]. At 45°, both vertebral
arteries become occluded [Menezes and
Traynelis, 2008].
Clinical and Diagnostic Findings
The diagnosis of AAI is predicated upon
disabling neck pain or suboccipital pain,
and
(1) history and clinical findings of cervical
medullary syndrome, or syncopal (or
pre-syncopal) episodes,
(2) demonstrable neurological findings, and
(3) radiological evidence of instability or
compression of the neuroaxis.
Neck pain and suboccipital head-
ache are the most common findings,
with the caveats that headache is a
common occurrence in EDS patients
[Castori and Voermans, 2014]. There
may be symptoms referable to the
vertebral artery blood flow, including
visual changes, as well as headache
resulting from vertebral artery torsion.
Syncopal and pre-syncopal events are
frequent. Other symptoms include diz-
ziness, nausea, sometimes facial pain,
dysphagia, choking, and respiratory
issues. Symptoms usually improve with
a neck brace.
Neurological examination dem-
onstrates tenderness over spinous pro-
cess of C1 and C2, altered mechanics
of neck rotation, hyperreflexia, dysdia-
dochokinesia, and hypoesthesia to
pinprick. Weakness is not a constant
feature of AAI.
A number of radiological features
have been described, including rotation
of C1 upon C2 >41° (as assessed by CT
scan of C1-2) and retro-odontoid
pannus on MRI [Fielding et al., 1978;
Taniguchi et al., 2008]. The difficulty
of recognizing rotary instability on
standard X-ray, CT, and MRI images
has resulted in failure to diagnose
[Kothari et al., 2000].
Treatment
The first line of treatment should be neck
brace, physical therapy, and avoidance of
activities that provoke exacerbation of
the AAI symptoms. If the non-operative
treatment fails, fusion stabilization of C1/
C2 is required. Incompetence of the alar
ligament requires dorsal surgical fusion
[Menendez and Wright, 2007]. Occiput
to C1/C2 fusion should be considered in
the presence of craniocervical instability,
basilar invagination, or complex Chiari
malformation.
Areas Needing Investigation
(1) The prevalence and natural history of
AAI in the EDS population.
(2) Theimportanceofdynamicimag-
ing studies (such as CT with rota-
tion of the cervical spine to extreme
left and right, requires further
validation to promote a generalized
adoption of these studies to diag-
nose AAI, and to prompt greater
availability of dynamic imaging
facilities).
(3) Surgical outcomes for treatment of
rotational instability and the long-
term outcome in EDS.
CRANIOCERVICAL
INSTABILITY
Epidemiology
Craniocervical instability (CCI) is
recognized as a manifestation of
ligamentous laxity in EDS [Naga-
shima et al., 1981; Milhorat et al.,
2010]. Ligamentous laxity has been
showntoresultinneuraxialinjury
[Lindenburg and Freytag, 1970; Hen-
derson et al., 1993; Menezes and
Traynelis, 2008].
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 5
Etiology
CCI is a pathological condition in
which ligamentous connections from
the skull to the spine are incompetent.
Motor delay, developmental co-
ordination disorder, headaches second-
ary to spinal compression, clumsiness,
and the relatively high rate of dyslexia
and dyspraxia in the EDS population
merit investigation as possible conse-
quences of early onset degenerative
changes resulting from ligamentous
laxity upon the central nervous system
[Nagashima et al., 1981; Adib et al.,
2005]. The most prominent movement
of the atlanto-occipital joint is flexion-
extension; axial rotation is normally
limited to <5 degrees of rotation
[Dvorak et al., 1987].
There is increased recognition of
mechanisms of neuronal injury that
result from stretching, or deformative
stress [Jafari et al., 1997; Maxwell et al.,
1999; Shi and Whitebone, 2006]. The
consequent formation of axon retrac-
tion balls is similar to that seen in diffuse
axonal injury of the brain (Fig. 2)
[Geddes et al., 2000; Henderson et al.,
2005]. Stretching of neurons causes
pathological calcium influx [Wolf
et al., 2001], altered gene expression
[Arundine et al., 2004], and apoptosis
[Liu et al., 1997; Arundine et al., 2004].
Clinical and Diagnostic Findings
CCI-related symptoms result from de-
formation of the brainstem and upper
spinal cord, traction on the vertebral
artery, and possibly from the consequen-
ces of altered venous or CSF outflow
from the cranium. CCI often occurs with
basilar invagination or ventral brainstem
compression, the findings of which are
dominated by pyramidal and sensory
changes: weakness of the limbs hyper-
reflexia and pathological reflexes (e.g.,
Babinski, Hoffmans sign, absence of the
abdominal reflex), paresthesias, and a
plethora of other symptomsincluding
sphincter problems,headache, neck pain,
dizziness, vertigo, dyspnea, dysphonia,
altered vision, and hearing, syncope,
emesis, altered sexual function, altered
menses, and gait changes [Caetano de
Barros et al., 1968]. These signs, in
aggregate, constitute the cervical medul-
lary syndrome [Batzdorf et al., 2015],
elements of which are commonly
recorded among EDS patients [Celletti
et al., 2012].
Threemetricsmaybeusefulin
the identification of CCI and basilar
invagination: the clivo-axial angle, the
Harris measurement, and the Grabb,
Mapstone, Oakes method [Batzdorf
et al., 2015; NINDS Common Data
Elements, 2016]. The Clivo-axial angle
(CXA) is the angle formed between the
posterior aspect of the lower clivus and the
posterior axial line. The CXA has a normal
range of 145° to 160°, but an angle of less
than 135° is pathological [Henderson et al.,
1993; Henderson et al., 2010a; Batzdorf
et al., 2015]. Increasing kyphosis of clivo-
axial angle (i.e., a more acute CXA) creates
a fulcrum by which the odontoid deforms
the brainstem [Menezes, 2012]. The
medulla becomes kinked as the CXA
becomes more kyphotic.
The second radiologic metric, the
horizontal Harris measurement, is the
distance from the basion to the posterior
axial line (PAL) [Harris et al., 1994].
Instability is present when the basion to
the PAL exceeds 12 mm. This measure-
ment, used in conjunction with dy-
namic flexion and extension images of
the cervical spine, can also be used to
measure the dynamic translation be-
tween the basion and the odontoid
[Batzdorf et al., 2015; NINDS Com-
mon Data Elements, 2016]. In the
normal individual, there should be
no measurable translatory movement
Figure 2. Axon retraction bulbs in the upper spinal cord, from cadaveric studies of subjects with basilar invagination (Microscopic
photograph (500), axial section of the dorsal column at the C2 level. Silver stain).
6 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW
(sliding movement). Translation of
greater than 1 mm between the basion
and odontoid reflects craniovertebral
instability, and may warrant stabilization
(Fig. 3) [Wiesel and Rothman, 1979;
White and Panjabi, 1990].
The third metric, the Grabb, Map-
stone, and Oakes measurement predicts
risk of ventral brainstem compression,
and has been statistically correlated with
clinical outcome [Grabb et al., 1999;
Henderson et al., 2010b]. A measure-
ment >9 mm suggests high risk of
ventral brainstem compression [Grabb
et al., 1999].
There is a relatively nascent recog-
nition of the importance of dynamic
imaging of the CCJ. For example, the
brainstem may appear normal on rou-
tine magnetic resonance imaging in the
supine position, but show pathological
ventral brainstem compression in the
flexion view sitting upright [Klimo Jr
et al., 2008; Henderson et al., 2010b;
Milhorat et al., 2010]. Functional
dynamic studies in flexion and extension
are important to determine whether
there is pathological hypermobility at
the craniocervical junction [Klekamp,
2012].
Treatment
Indications for surgery include severe
headache, symptoms which constitute
the cervical medullary syndrome,
neurological deficits referable to the
brainstem and upper spinal cord,
radiological findings of CCI, and
Figure 3. a: The craniocervical junction in flexion, showing a forward slide of the basion with respect to the odontoid (Sagittal view,
T2 weighted MRI of the cervical spine in flexion). b: In extension, the basion lies along the posterior edge of the odontoid process,
demonstrating a translation of 6 mm from flexion to extension (Sagittal view, T2 weighted MRI cervical spine).
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 7
failure of a reasonable course of non-
operative therapy. Though there are
no established criteria for treatment of
CCI in EDS, there is abundant
literature addressing the diagnosis of
CCI [White and Panjabi, 1990; Harris
et al., 1994; Batzdorf et al., 2015], and
the treatment of CCI with craniocer-
vical stabilization in various congenital
or degenerative connective tissue dis-
orders [Nagashima et al., 1981; Goel
and Sharma, 2005; Henderson et al.,
2010b; Milhorat et al., 2010; Tubbs
et al., 2011a; Klekamp, 2012; Yoshi-
zumi et al., 2014].
Areas Needing Investigation
(1) Prevalence and natural history of axial
ligamentous instability in EDS.
(2) Validation of radiological metrics for
determining CCI in the EDS
population.
(3) Development of an international
data registry using the NINDS
Common Data Elements [2016] to
facilitate therapeutic trials for CCI
in EDS.
SEGMENTAL KYPHOSIS
AND INSTABILITY
Epidemiology
Theprevalenceofcervicalandtho-
racic segmental instability in the
population of patients with hyper-
mobility syndromes has not been well
established. However, discopathy and
early degenerative spondylotic disease
in hEDS and classical type EDS is well
established. EDS is characterized by
segmental instability, kyphosis, and
scoliosis. Spondylosis, defined by the
presence of non-inflammatory disc
degeneration, is usually preceded by
mild segmental instability [Shedid
and Benzel, 2007]. As a consequence
of cervical and thoracic instability,
anddiscopathyinEDS,thereislossof
thenormalcervicallordosisandan
increasing kyphosis, rendering EDS
patients prone to progressive myelop-
athy, and mechanical neck and chest
pain.
The prevalence of cervical and
thoracic segmental instability
in the population of patients
with hypermobility syndromes
has not been well established.
However, discopathy and
early degenerative spondylotic
disease in hEDS and classical
type EDS is well established.
EDS is characterized by
segmental instability,
kyphosis, and scoliosis.
Etiology
Ligamentous laxity is an important
determinant in the development of
spinal instability other connective dis-
orders such as rheumatoid arthritis,
Down syndrome and osteogenesis im-
perfecta, but there have been no series to
demonstrate this linkage in EDS. The
importance of ligamentous laxity is
increasingly appreciated among clini-
cians [Tredwell et al., 1990; Steilenet al.,
2014].
The pathophysiology of segmental
instability is well described: during
flexion, there is deformation of the
lateral and ventral columns of the spinal
cord, directly related to the strain on the
cord [Henderson et al., 2005; Shedid
and Benzel, 2007]. Extension more
often results in compression of the
cord by buckling of the ligamentum
flavum, resulting in myelopathic symp-
toms [Muhle et al., 1998]. The cervical
spinal cord can be physiologically teth-
ered in the sagittal plane, such that
normal cord elongation in flexion is
exaggerated by the kyphosis; this results
in increased deformity and anatomic
stretching of the cord. This sagittal
bowstring effectunderlies a physiolog-
ical tethering effect, with resulting
neurological deficits [Shedid and Ben-
zel, 2007]. Others have recognized the
importance of the dentate ligaments in
applying stressors to the spinal cord,
with the subsequent result of focal
myelopathy [Cusick et al., 1977].
Clinical and Diagnostic Findings
Clinical findings include pain and
disability, as well as sensory, motor,
and reflex changes. Radiculo-myelop-
athy may manifest in an acute, sub-
acute, or chronic manner as radicular
and dermatomal or non-radicular
myelopathic hypoesthesia, hyperes-
thesia, or paresthesia, and less often
weakness. Over time, there may be
ascending numbness, spasticity, Lher-
mittes sign, and eventually leg weak-
ness, altered gait, clumsiness, and long
tract findings. There is often marked
tenderness to palpation over unstable
motion segments.
Clinical differential diagnoses in the
EDS population should be kept in mind:
instability at the atlanto-occipital and
atlantoaxial joints, shoulder, clavicular
and rib subluxations, brachial plexop-
athy, vascular anomalies, dissection or
venous insufficiency, peripheral neurop-
athy, multiple sclerosis, amyotrophic
lateral sclerosis, myasthenia gravis, mye-
lopathy due to drugssuch as statins,
colchicine, steroids- vitamin deficiency,
especially B12 and B3, mitochondrial
dysfunction, stroke, and psychological
disorders.
Though CT scans and MRI remain
the standard for most practitioners,
radiological findings do not always
correlate well with clinical findings or
surgical outcome [Arnasson et al.,
1987]. Dynamic instability is unlikely
to be demonstrated in a resting supine
subject, and pathological instability will
often become manifest only when the
ligaments are placed under stress.
Though not yet validated, dynamic
MRI in the upright position subjects
the vertebral spine to physiological
loading, and can be performed in the
flexed and extended positions to dem-
onstrate instability (Fig. 4) [Milhorat
et al., 2010; Klekamp, 2012].
White and Panjabi [1990] have
defined the reference ranges for flex-
ion, extension, lateral tilt, and rotation
8 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW
at each level of the spine. Radiological
findings of segmental instability may
include evidence of spinal cord com-
pression or defor mity, hyper-angula-
tion at one or more segmental levels
(>11.5° angulation between adjacent
vertebra, subluxation >3 mm), and the
presence of pathological longitudinal
stretching.
Treatment
Initial management includes neck brac-
ing and physical therapy with therapists
who are knowledgeable regarding liga-
mentous laxity including EDS, attain-
ment of a good sagittal balance, and
avoidance of certain activities. Rest will
often improve symptoms. If symptoms
are refractory to conservative manage-
ment, fusion, and stabilization of unsta-
ble levels may be indicated.
The rate of adjacent segment de-
generation (the tendency for increased
degeneration of discs adjacent to fused
motion segments) has not been deter-
mined in the EDS population, but should
be considered in surgical planning;
Figure 4. a: Segmental cervical instability, showing widespread degenerative disc disease characteristic of EDS-HT, but no spinal cord
compression on neutral view (Sagittal view, T2 weighted MRI of the cervical spine in the neutral position). b: Dynamic instability evident
upon extension of the neck, showing postero-listhesis of C4 on C5, causing spinal cord compression (MRI sagittal view of the cervical
spine, T2 weighted).
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 9
motion-sparing technology may be an
important option in this population,
though there is yet no published litera-
ture in the EDS population.
Areas Needing Further
Investigation
(1) Definition, prevalence and natural
history of segmental instability in the
EDS population.
(2) Clinical history of segmental instabil-
ity after stabilization, including rates of
adjacent segment degeneration in
different types of EDS.
(3) Studies to improve diagnostic efficacy
of segmental instability utilizing up-
right MRI.
TETHERED CORD
SYNDROME
Tethered cord syndrome (TCS) in EDS
is most often associated with a structur-
ally abnormal filum terminale, and
usually characterized by low back pain
and the clinical triad of neurogenic
bladder, lower extremity weakness
and sensory loss, and musculoskeletal
abnormalities.
Epidemiology
The incidence of the specific diagnosis
of TCS is unclear, both within the
general and EDS populations in the
United States [Bui et al., 2007]. The
prevalence of TCS in a diverse sample of
Turkish school children was 0.1%
[Bademci et al., 2006]. In a cohort of
2,987 consecutively evaluated patients
with diagnoses of CMI or low lying
cerebellar tonsils (LLCT, tonsillar de-
scent 04 mm), Milhorat et al.
[2009] found TCS, using a definition
that allowed for normal position of the
conus medullaris on MRI (i.e., at or
above, the L1 vertebra), in 14% of the
CMI patients they examined and in 63%
of the LLCT cohort.
Etiology
The filum comprises a fibrous, collage-
nous, and elastic band that connects the
conus medullaris with the dural sac at
the S2 level. The filum contains neural,
glial, and ependymal remnants that stem
from embryonic spinal cord which
begin to regress at 910 weeks of
gestation [Jang et al., 2016]. The
presence of fatty tissue, nerve twigs
(dysplastic axons), fat and vascular
lacunes, and suspicion of congested
veins, are usually seen in the abnormal
fila specimens obtained from patients
with TCS [Thompson et al.,
2014] Stretching of the spinal cord by
the structurally abnormal filum is the
presumed mechanism of TCS. Symp-
toms may become more apparent as a
child grows. Forcible flexion and
stretching is often deemed responsible
for adult onset of TCS [Aufschnaiter
et al., 2008]. Poor blood flow and
oxidative stress in the spinal cord have
also been implicated in animal models as
mechanisms of neuronal injury [Yamada
et al., 2007].
Clinical and Diagnostic Findings
TCS is characterized by aching/burning
pain in the low back, legs and feet, and
sensori-motor findings in lower extrem-
ities: weakness is common, with heavi-
ness, stiffness, and tightness of legs and
cramps; paresthesias in the pelvic area or
legs and hypoesthesia to pinprick in the
lumbar and sacral dermatomes is often
observed. Findings are often asymmet-
ric. A history of toe-walking may be
elicited. Urological findings include
urinary hesitancy, frequency, urgency,
retention/incomplete emptying, noctu-
ria, irregular urinary stream, sensory loss
of the bladder, frequent urinary tract
infections, and incontinence.
There is often enuresis into late
childhood. There may be fecal inconti-
nence, constipation, or sexual dysfunc-
tion. As TCS results in a combination of
upper and lower motor neuron injury,
there is often hyperreflexia in the lower
extremities, but normal reflexes in the
arms. The legs are usually weak, with
normal upper extremity strength. Sen-
sory loss is usually prominent in the
lumbar and sacral dermatomes, but
normal in the arms and trunk. Ortho-
pedic deformities include scoliosis,
kyphosis, functional ankle and foot
deformities (ankle pronation with phys-
ical strain), and pes planus or pes cavus
[Hoffman et al., 1976; Pang and
Wilberger, 1982].
Urodynamic testing is important in
the diagnosis of TCS. Neurogenic
bladder manifestations may range from
urinary retention and detrusor under-
activity to urinary incontinence, over-
activity of the detrusor, and sphincter
dysfunction [Tu and Steinbok, 2013].
While formal urodynamic criteria have
not been established for TCS, detrusor
sphincter dysynergia, large post void
residual, and very large bladder capacity
(>800 ml) are good urodynamic indi-
cators of a neurogenic bladder. Urody-
namics can help to differentiate the
neurogenic bladder of TCS from that
due to diabetes or bladder obstruction
from prostatic hypertrophy.
MRI of the cervical, thoracic, and
lumbar spine is required to rule out
other causes of leg weakness and low
back pain, such as disc herniation,
spondylolisthesis, stenosis, neoplasm,
or intrinsic lesions of the spinal cord
such as multiple sclerosis or signs of
trauma. The MRI may show low lying
conus (below the mid L2 level), fatty
infiltration, a stretched or thickened
filum, a syrinx in the lower spinal cord,
scoliosis or spina bifida occulta. The
term occult tethered cord(OTCS)
refers to where the MRI shows a normal
position of the conus [Tu and Steinbok,
2013]. A large diameter of the filum
terminale in axial T2 studies is a positive
indicator that favors untethering in the
presence of TCS [Fabiano et al., 2009].
Controversy exists over whether it
is necessary to radiologically demon-
strate a low lying conus medullaris,
that is, a conus ending at the lower L2
level or below. There has been the
intuitive presumption that a low-lying
conus represents a spinal cord under
tension. However, this presumption has
not been verified, and indeed, there are
no epidemiological studies which allow
the definition of a specific imaging
finding to establish the diagnosis of
TCS. Nor are there epidemiological
studies in the normal population that
demonstrate specific findings that
10 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW
exclude TCS. On the other hand, there
is a growing body of evidence that
supports the clinical diagnosis of TCS
with or without the radiological
demonstration of a low-lying conus
medullaris, which justifies surgical in-
tervention when the clinical criteria are
met [Tu and Steinbok, 2013].
Treatment of TCS
There is no standard technique in the
surgical treatment of TCS. Generally,
the lamina is removed, anywhere
from L2 to S1, a durotomy is made,
and electrical stimulation is used to
confirm the absence of any nerve
roots which may be associated with
the filum. Finally, a microsurgical
resection of the filum terminale
(usually a 10 mm segment for pathol-
ogy) is performed (Fig. 5). The filum
tends to be taut, and to briskly retract
upon sectioning. However, findings
are variable, and there is no evidence
to suggest that the intraoperative
findings predict or correlate with
the surgical outcome and severity of
the TCS [Pang and Wilberger, 1982;
Milhorat et al., 2009]. In some cases,
it may be necessary to perform a
lumbar stabilization across the
motion segment in which the filum
was sectioned. The resected filum
should be sent for histopathological
evaluation.
Areas Needing Research
(1) Prospectively and retrospectively eval-
uate specific clinical features and
radiological metrics for predictive
accuracy, to establish validated inclu-
sion and exclusion criteria for future
studies regarding TCS.
(2) Determine the incidence of TCS in
EDS patients.
(3) Determine epidemiologically whether
TCS is a co-morbid feature of CMI
in EDS.
(4) Validate outcome measures by which
to determine the surgical outcomes.
(5) Establish complication rates for TCS
surgery in the EDS population.
DYSTONIAS AND OTHER
MOVEMENT DISORDERS
Epidemiology
Movement disorders can be broadly
divided into hyperkinetic disorders
(too much movement) or hypokinetic
movement occurring in the conscious
state. The hyperkinetic movement dis-
ordersincluding dystonia, tremor,
chorea, myoclonus, and tic disorders
are observed in the EDS population
according to anecdotal reports from
large series of patients, but have not
been documented in the peer-reviewed
literature.
Etiology
Pain and trauma are frequent compo-
nents of EDS, and there is a significant
body of literature suggesting movement
disorders may arise from extracranial
trauma. Post-traumatic dystonia may
develop in a limb following trauma to
that limb [van Rooijen et al., 2011].
This may be one mechanism that
establishes a link between EDS and
movement disorders. However, while
several of the authors have strong clinical
suspicion of a connection, there are no
published studies that confirm that
movement disorders are a co-morbidity
of hEDS [Rubio-Agusti et al., 2012].
While dystonia in joint hypermo-
bility syndromes (JHS) have been
observed, causality has not been demon-
strated. In one large series, one third of
patients with fixed dystoniawere
found to have JHS [Kassavetis et al.,
2012]. The authors suggested that move-
ment avoidance may have been adopted
to avoid pain, and in time resulted in fixed
dystonia. The etiology of the fixed
dystonia has also been variously attrib-
uted to peripheral injury [van Rooijen
et al., 2011], and psychogenic movement
disorder [Hallett, 2016].
Clinical and Diagnostic Findings
Neurological evaluation and EEG to
rule out seizure should be performed.
Figure 5. a: Tethered cord syndrome: conus at the normal level (L1), fatty filum suggestive of tethered cord syndrome (Sagittal view
lumbar spine, T1 weighted MRI). b: Tethered cord syndrome: the thickened filum terminale at the L2 level, just before division.
(Intraoperative photograph of the lumbar spine thecal sac and the durotomy).
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 11
The diagnosis of psychogenic move-
ment disorder has been met with some
skepticism [Palmer et al., 2016], but is
distinguished from malingering, and
thought to result from psychological
causes [Hallett, 2016]; it is characterized
by involuntary, disabling movements,
abrupt in onset, a waxing/waning
course, changes in the nature of the
movement over time, worsening with
stress, anxiety or depression, and im-
provement with distraction; they are
difficult to diagnose and treat. Prognosis
for improvement is better in patients
with a shorter duration of illness [Lang,
2006].
Treatment
There is no established treatment algo-
rithm for movement disorders in pa-
tients with EDS.
Areas Needing Research
(1) Establish studies to determine the
epidemiology and etiology of move-
ment disorders in EDS, and to
demonstrate whether there is a co-
morbid relationship.
(2) Develop evidence-based treatment
strategies for movement disorders in
the EDS population.
NEUROMUSCULAR
FEATURES OF EHLERS-
DANLOS SYNDROME
Epidemiology
EDS, especially hEDS, is associated with
high prevalence of myalgia, nocturnal
muscle cramps involving the calves,
hypotonia, progressive muscle weak-
ness, poorly developed musculature,
and scapular winging, which to some
extent may be the result of avoidance of
exercise due to hypermobility and
instability of joints [Banerjee et al.,
1988; Palmeri et al., 2003].
Musculoskeletal pain starts early, is
chronic and debilitating [Voermans
et al., 2010]. Neuromuscular disease
manifests symptomatically with muscle
weakness, myalgia, easy fatigability, and
limited walking distance; physical find-
ings include muscle weakness, reduction
of vibration sense, and mild impairment
of mobility and daily activities [Voer-
mans et al., 2009b].
Musculoskeletal pain starts
early, is chronic and
debilitating. Neuromuscular
disease manifests
symptomatically with muscle
weakness, myalgia, easy
fatigability, and limited
walking distance; physical
findings include muscle
weakness, reduction of
vibration sense, and mild
impairment of mobility and
daily activities.
Brachial and/or lumbosacral plexus
neuropathies and other compression
mono-neuropathies are not uncommon
in EDS [Voermans et al., 2006; van
Rooijen et al., 2011]. The presence of
radiculopathy or small-fiber neuropathy
probably explains a higher prevalence of
neuropathic symptoms (paresthesias/
numbness in hands or feet) than regis-
tered on neurophysiological or ultra-
sound testing. There is a high prevalence
of ulnar nerve luxation at the elbow
detected on dynamic ultrasound [Gran-
ata et al., 2013].
Etiology
Some pathophysiologic studies are avail-
able on the relationship between tenas-
cin-x(TNX) deficient EDS and
neuromuscular complications. Human
and murine studies suggest a correlation
between TNX levels and degree of
neuromuscular involvement, and a cor-
responding role of the extracellular
matrix defect in muscle and peripheral
nerve dysfunction in EDS [Huijing
et al., 2010; Voermans et al., 2011].
However, TNX deficiency accounts for
only a very small percentage of patients
with hEDS. Reduced quantitative mus-
cle function appears to be secondary to
muscle dysfunction rather than reduced
muscle mass [Rombaut et al., 2012].
Abnormal myo-tendinous junctions in
the muscle belly [Penisson-Besnier et al.,
2013], mild to moderate myopathy and/
or neuropathy, and defects of the
extracellular matrix of the connective
tissue investing muscle and peripheral
nerve may increase muscle dysfunction
[Voermans et al., 2009b, 2012; Syxet al.,
2015].
The pathophysiological mechanism
of peripheral neuropathy in hEDS
appears, in part, to result from abnormal
stretching and pressure upon peripheral
nerves that results from joint subluxa-
tion. The connective tissue of peripheral
nerves might fail to resist excessive
mechanical stress: increased vulnerabil-
ity is linked to underlying genetic
defects in TNXB, collagens I, III,
or V deficient epi-, peri-, and endo-
neurium [Voermans et al., 2009b;
Granata et al., 2013]. This defect might
also relate to the occurrence of axonal
polyneuropathy in various types of EDS
[Muellbacher et al., 1998].
Abnormal extracellular matrix in
generalized connective tissue structure
suggests molecular overlap between
inherited connective tissue disorders
and certain congenital myopathies,
awareness of which may be helpful in
recognition of these rare disorders
[Voermans et al., 2008; Donkervoort
et al., 2015].
Clinical and Diagnostic Features
The approach to neuromuscular symp-
toms and signs, and helpful ancillary
investigations has been thoroughly
reviewed [Merrison and Hanna,
2009], and supplemented by the
WUSTL database on neuromuscular
disorders.
Treatment
A recent study on medical consumption
and outcome reported the impact of
pain upon daily functioning in hEDS.
12 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW
Most patients (92%) used pain medi-
cations; 52% underwent physical
therapyincluding neuromuscular ex-
ercises, massage, and electrotherapyof
whom two thirds reported a positive
outcome. The study concluded that the
impaired functional status of hEDS
patients strongly determined the high
rate of treatment consumption, which
underscores the importance of develop-
ment of evidence-based guidelines for
treatment [Rombaut et al., 2011]. There
is increasing evidence that treatment
should consist of a multidisciplinary
program. One study demonstrated suc-
cess combining physical therapy, cogni-
tive behavioral therapy, and group
therapy, followed by individual home
exercises and weekly guidance by phys-
iotherapist for three months, then
readmission for reevaluation and further
training advice. Patients reported im-
proved performance of daily activities,
muscle strength and endurance, reduced
kinesiophobia, and increased participa-
tion in daily life [Bathen et al., 2013].
Areas Needing Research
(1) The contributions of the various
causative factors to muscle dysfunction
in EDS, including increased compli-
ance of the series-elastic component of
muscle tissue, failure of maximal
voluntary muscle activation, and im-
paired proprioception.
(2) Clinical trials of physical training and
cognitive behavioral therapy on mus-
cle strength and endurance in EDS
patients.
(3) The development of evidence-based
guidelines to improve muscle strength.
TARLOV CYST SYNDROME
Epidemiology
Tarlov cysts are perineurial cysts that
may impose pressure upon adjacent
neural structures. Numerous small sur-
gical series descr ibe the spectrum of
pathology, but there is significant con-
fusion in the reported literature with
other cystic structures: the sacral me-
ningocele and dural ectasia. The sacral
meningocele principally affects males,
fills the sacrum, and typically involves
all of the sacral roots. Dural ectasia may
present with large intra-abdominal
cysts associated with connective dis-
orders [Nabors et al., 1988; Stern,
1988].
There is a general presumption that
these cystic abnormalities, including
Tarlov cysts, are incidental findings.
However, the belief that all Tarlov cysts
are asymptomatic has no support in the
literature. An unpublished review at
Johns Hopkins on 756 patients with
symptomatic spinal cysts, found 18 with
large sacral internal meningoceles with
dramatic associated sacral erosion, of
whom 16 were women with Marfan
disease or EDS. The remainder had
typical Tarlov cysts, with a female to
male ratio of seven to one, usually on
sacral nerve roots. A small number
existed on the lumbar, thoracic or
cervical roots. Delay in treatment re-
sulted because most patients had been
told that the cysts were asymptomatic
and did not need to be treated, or that no
satisfactory treatment existed, or that
treatment was too dangerous to con-
template. Rarely, there may be massive
dilatation of the lumbar and sacral thecal
sac, with extensions of the subarachnoid
space along nerve roots and into abdo-
men and pelvis.
Etiology
The finding of inflammatory cells in
the walls of symptomatic Tarlov cysts
[Voyadzis et al., 2001] begs comparison
with the recent findings inflammatory
cells in the fila terminale of EDS patients
with TCS [Klinge, 2015].
Clinical and Diagnostic Findings
Tarlov cysts are a radiological diagnosis.
The Tarlov cysts appear primarily in the
sacrum, at the level of the root ganglia,
causing erosion of the surrounding bone
(Fig. 6). Cervical and thoracic Tarlov cysts
may produce pain and neurological
symptoms or deficits in the distribution
of the involved nerve root, or myelopathic
from an extradural or subarachnoid cyst in
the high thoracic region, or symptomatic
from a mediastinal cystic extension behind
the trachea.
The most common syndrome,
occurring in approximately 70% of
symptomatic patients, is comprised of
sacral pain, worse when sitting and
standing, and improved when lying
down; pain in the S2S5 dermatomes
in the pelvis and perineum, sciatica in
the Sl and S2 dermatomes, and less
commonly L5 root dermatome. Bowel
and bladder dysfunction are common.
One third of patients have bowel and
bladder dysfunction, and sensory com-
plaints related to nerve roots S2, S3, S4
without sciatica. A small group of
patients have bowel and bladder dys-
function and sacral root sensory loss
without pain.
Treatment
Of patients undergoing surgical obliter-
ation of the Tarlov cysts, successful
outcomes are reported in 8088% of
patients, with few complications [Voy-
adzis et al., 2001; Feigenbaum and
Henderson, 2006]. Alternatively, pa-
tients may undergo aspiration of the
cyst and injection of the cysts with fibrin
glue, although the results are less
satisfactory [Patel et al., 1997].
Areas Needing Research
(1) Determine the prevalence of Tarlov
cysts in the general population and the
hEDS and classic type EDS
populations.
(2) Define the ratio of symptomatic versus
asymptomatic patients, and the factors
that appear to trigger pain.
(3) Compare the pathophysiology of Tar-
lov cysts in the general population
versus the EDS population.
(4) A prospective randomized trial to
compare treatments: surgical resection
versus aspiration and injection of fibrin
glue.
(5) Longitudinal studies of natural and
clinical history of Tarlov cysts in EDS.
(6) Utility of urodynamic studies as op-
posed to patient report for symptoms
of neurogenic bladder.
RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 13
CONCLUSION
Incompetent connective tissue results in
lax ligaments within the axial skeleton,
peripheral nerve sheaths, and possibly
the architecture of the myoneural and
muscular endplates. Ligamentous laxity
of the axial skeleton in particular,
subjects the central and radicular ner-
vous system to entrapment, deforma-
tion, and biophysical deformative
stresses. Biophysical stress is increasingly
recognized in the alteration of gene
expression, cellular function, and ulti-
mately phenotypic expression. Clinical
practice guidelines, based upon stronger
epidemiological and pathophysiological
evidence, are needed for the diagnosis
and treatment of the various neurologi-
cal and spinal manifestations of EDS.
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RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 17
... Thus, the clinical manifestations, pathogenesis, diagnosis, management, and complications are different due to the diversity in the presentations of this disease. In some patients, neurological and spinal manifestations have been reported [7]. Furthermore, anxious symptomatology, anxiety disorders [8], depressive symptoms, and anxious obsessive/compulsive personality disorder [9] have also been found in a few patients. ...
... Lumbar spondylosis is also noted in these patients [79]. This results in mechanical pain in the patient [7]. In this patient, on MRI, incipient spondylosis was noted in L4, because of which the patient has been currently using a walking stick. ...
... Research to establish that movement disorders are collateral of hEDS is not available yet [86]. However, it now is suggested that movement evasion might have developed to avoid pain, resulting in fixed dystonia [7], which was also present in our patient. Migraine could also be a clinical manifestation [87]. ...
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Ehlers-Danlos syndromes (EDS) are a heterogeneous group of genetically transmitted connective tissue disorders that directly affect collagen synthesis, with a broad range of symptoms. Case presentation: This study presents a clinical case of a Colombian woman with myopathic EDS and multiple comorbidities taking 40 years of medical history to make the right diagnosis. This article also presents a review of the current literature on EDS, not only to remind the syndrome but also to help the clinician correctly identify symptoms of this diverse syndrome. Conclusion: A multidisciplinary approach to the diagnosis of the patient, including clinical and molecular analysis, and neuropsychological and psychological assessment, is important to improve the treatment choice and the outcome prediction of the patients.
... Thus, the clinical manifestations, pathogenesis, diagnosis, management, and complications are different due to the diversity in the presentations of this disease. In some patients, neurological and spinal manifestations have been reported [7]. Furthermore, anxious symptomatology, anxiety disorders [8], depressive symptoms, and anxious obsessive/compulsive personality disorder [9] have also been found in a few patients. ...
... Lumbar spondylosis is also noted in these patients [79]. This results in mechanical pain in the patient [7]. In this patient, on MRI, incipient spondylosis was noted in L4, because of which the patient has been currently using a walking stick. ...
... Research to establish that movement disorders are collateral of hEDS is not available yet [86]. However, it now is suggested that movement evasion might have developed to avoid pain, resulting in fixed dystonia [7], which was also present in our patient. Migraine could also be a clinical manifestation [87]. ...
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Full-text available
Ehlers-Danlos syndromes (EDS) are a heterogeneous group of genetically transmitted connective tissue disorders that directly affect collagen synthesis, with a broad range of symptoms. Case presentation: This study presents a clinical case of a Colombian woman with myopathic EDS and multiple comorbidities taking 40 years of medical history to make the right diagnosis. This article also presents a review of the current literature on EDS, not only to remind the syndrome but also to help the clinician correctly identify symptoms of this diverse syndrome. Conclusion: A multidisciplinary approach to the diagnosis of the patient, including clinical and molecular analysis, and neuropsychological and psychological assessment, is important to improve the treatment choice and the outcome prediction of the patients.
... Neurologic complications of hEDS are protean (53). Migraine is more common in patients with hEDS and that can be not only associated with reduced vision from aura but postdromal effects such as glare sensitivity and possibly convergence insufficiency (54). ...
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Ehlers-Danlos syndrome (EDS) is a rare, genetically variable, heterogenous group of (currently recognized) thirteen connective tissue disorders characterized by skin hyperextensibility, tissue fragility, and generalized joint hypermobility. In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS. In this review, we comprehensively gather and discuss the ocular manifestations of EDS and its thirteen subtypes in the clinical setting.
... Definitive diagnosis relies on molecular confirmation with all subtypes except for hypermobile EDS (hEDS), which is a clinical diagnosis , though a genetic basis is also suspected for hEDS (Hakim et al., 2004). Comorbid symptoms are common for patients with EDS and include multiple body systems marked by neurologic (Henderson Sr. et al., 2017;Tinkle et al., 2017), cardiovascular , gastrointestinal (Fikree et al., 2017), dermatologic , gynecologic , and musculoskeletal issues . Other co-morbid symptoms, such as chronic pain (Engelbert et al., 2017), deficits with proprioception (Rombaut et al., 2010), headaches (Martin & Neilson, 2014), anxiety and depression (Martin & Neilson, 2014) commonly occur in hEDS. ...
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Background: Ehlers-Danlos syndrome (EDS) represents a family of heritable connective tissue disorders with overlapping phenotypic features, frequently including joint hypermobility, tissue fragility, and skin hyperextensibility. Comorbid symptoms are common for patients with EDS and include multiple body systems marked by neurologic, cardiovascular, gastrointestinal, musculoskeletal issues, chronic pain, headaches, and anxiety and depression. The many comorbidities lead to high disease burden, which requires greater healthcare utilization. Methods: This survey of families examines healthcare utilization, of adults and minors, through evaluation of subspecialty care appointments across many healthcare systems in one region. Results: There were 155 adults and 83 minors with a diagnosis of EDS with a total of 693 unique visits across 27 different specialties at over 20 different hospitals or clinics in the surveyed area. Cardiology, neurology, and gastroenterology were the most utilized subspecialties for adults, while rheumatology, cardiology, and neurology were most utilized by minors. Many respondents (67%) reported their medical care needs are not being met, and 87% reported interest in a multidisciplinary clinic for EDS with the most interest in pain management, physical and occupational therapy, and rheumatology. Conclusion: Understanding healthcare utilization and needs of those with EDS can provide the foundation for improved care for those with EDS through a coordinated multidisciplinary care model.
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Experts in symptomatic generalized joint hypermobility (S-GJH) agree that upper cervical instability (UCI) needs to be better recognized in S-GJH, which commonly presents in the clinic as generalized hypermobility spectrum disorder and hypermobile Ehlers-Danlos syndrome. While mild UCI may be common, it can still be impactful; though considerably less common, severe UCI can potentially be debilitating. UCI includes both atlanto-occipital and atlantoaxial instability. In the absence of research or published literature describing validated tests or prediction rules, it is not clear what signs and symptoms are most important for diagnosis of UCI. Similarly, healthcare providers lack agreed-upon ways to screen and classify different types or severity of UCI and how to manage UCI in this population. Consequently, recognition and management of UCI in this population has likely been inconsistent and not based on the knowledge and skills of the most experienced clinicians. The current work represents efforts of an international team of physical/physiotherapy clinicians and a S-GJH expert rheumatologist to develop expert consensus recommendations for screening, assessing, and managing patients with UCI associated with S-GJH. Hopefully these recommendations can improve overall recognition and care for this population by combining expertise from physical/physiotherapy clinicians and researchers spanning three continents. These recommendations may also stimulate more research into recognition and conservative care for this complex condition.
Article
Study Design Retrospective database analysis. Objectives To study postoperative complication rates following anterior cervical discectomy and fusion (ACDF) in patients with Ehlers-Danlos syndrome (EDS) compared with patients without EDS. Methods The Mariner database was utilized to identify patients with EDS undergoing one or two level anterior cervical discectomy and fusion (ACDF). Postoperative short-term outcomes assessed included medical complications, readmissions, and ED-visits within 90 days of surgery. Additionally, surgical complications including wound complications, surgical site infection, one- and two-year anterior revision along with posterior revision, pseudarthrosis, and hardware failure within 2 years were assessed. Multivariate logistic regression was used to adjust for demographic variables, comorbidities and number of levels operated on. Results The present study identified 533 patients in the EDS group and 2634 patients in the matched control group. EDS patients undergoing ACDF are at an increased risk for 90-day major medical complications (OR 3.31; P < .001). EDS patients were also found to be associated with surgical complications including wound complications (OR 2.94; P < .001), surgical site infection (OR 8.60; P < .001) within 90 days, pseudarthrosis (OR 2.33; P < .001), instrument failure (OR 4.03; P < .001), anterior revision (OR 22.87; P < .001), and posterior revision (OR 3.17; P < .001) within 2 years. Conclusions EDS is associated with higher rates of both medical and surgical complications following ACDF. Spine surgeons should be cognizant of the increased risks in this population to provide appropriate preoperative counseling and enhanced perioperative medical management.
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In this article the author, the eightieth President of the Medical Women’s Federation and a clinical academic, reflects on disability, gender, and leadership. She draws on lessons from her sixteen-year NHS career in HIV Medicine in East London, UK. She explores her experiences and challenges as a Consultant Physician who became invisibly disabled and reflects on how her chosen leadership style has evolved in parallel. Readers are encouraged to reflect on invisible disability, ‘ableism’ and how to navigate conversations with colleagues.
Chapter
Kap. 1 dieses Fachbuchs widmet sich der Entstehung der Ehlers-Danlos-Syndrome, der aktuellen Klassifikation, der Diagnostik und den Verdachtsmomenten. In diesem Kapitel wird Schritt für Schritt erklärt, wie das Bindegewebe, das als „Kleber“ den ganzen Körper zusammenhält, aufgebaut ist und wie sich genetische Erkrankungen entwickeln: von der DNA, über die Aminosäuren bis hin zum Protein. Anschließend wird anhand der alten und neuen Klassifikationen gezeigt, wie die verschiedenen Typen der EDS entstehen, wie weitläufig die Symptome sein können und welche Verdachtsmomente schon frühzeitig in den verschiedenen medizinischen Fachrichtungen in Richtung EDS denken lassen sollten. Zum Ende des Kapitels wird die Diagnostik der EDS näher erläutert, von der ersten Anamnese, über die klinische Untersuchung bis hin zu den angewandten Kriterien.
Chapter
In Kap. 3 werden viele der bekannten komorbiden Erkrankungen, deren Management und aktuelle Forschungslage näher beleuchtet. Darunter z. B. Osteoporose, Arthrose, Skoliose, Gastroparese und andere gastrointestinale Komplikationen, Blutungs- und Hämatomneigung, neurologische und muskuläre Beschwerden, die verschiedenen Schmerzarten, Müdigkeit und Erschöpfung, Herz- und Gefäßkomplikationen, Augenprobleme, Temporomandibuläre Dysfunktion, Hernien und Prolapse, psychiatrische und psychologische Aspekte, gynäkologische Probleme und zusätzliche Erkrankungen wie Fibromyalgie. Außerdem werden die Entstehungsmechanismen der häufigsten Komorbiditäten sowie deren Zusammenhang mit den EDS diskutiert. Hier wird vor allem dem Mastzellaktivierungssyndrom, den autonomen Neuropathien, der Chiari-Malformation, dem Tethered Cord Syndrome sowie der kraniozervikalen Instabilität besonders viel Platz eingeräumt.
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Evidence suggests that migraine activity is influenced by hormonal factors, and particularly by estrogen levels, but relatively few studies have investigated the prevalence and characteristics of migraine according to the menopausal status. Overall, population-based studies have shown an improvement of migraine after menopause, with a possible increase in perimenopause. On the contrary, the studies performed on patients referring to headache centers have shown no improvement or even worsening of migraine. Menopause etiology may play a role in migraine evolution during the menopausal period, with migraine improvement more likely occurring after spontaneous rather than after surgical menopause. Postmenopausal hormone replacement therapy has been found to be associated with migraine worsening in observational population-based studies. The effects of several therapeutic regimens on migraine has also been investigated, leading to nonconclusive results. To date, no specific preventive measures are recommended for menopausal women with migraine. There is a need for further research in order to clarify the relationship between migraine and hormonal changes in women, and to quantify the real burden of migraine after the menopause. Hormonal manipulation for the treatment of refractory postmenopausal migraine is still a matter of debate.
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In medically refractory idiopathic intracranial hypertension, optic nerve sheath fenestration or CSF shunting is considered the next line of management. Venous sinus stenosis has been increasingly recognized as a treatable cause of elevated intracranial pressure in a subset of patients. In this article, we present the results of the largest meta-analysis of optic nerve sheath fenestration, CSF shunting, and dural venous sinus stenting. This is the only article that compares these procedures, to our knowledge. We performed a PubMed search of all peer-reviewed articles from 1988 to 2014 for patients who underwent a procedure for medically refractory idiopathic intracranial hypertension. Optic nerve sheath fenestration analysis included 712 patients. Postprocedure, there was improvement of vision in 59%, headache in 44%, and papilledema in 80%; 14.8% of patients required a repeat procedure with major and minor complication rates of 1.5% and 16.4%, respectively. The CSF diversion procedure analysis included 435 patients. Postprocedure, there was improvement of vision in 54%, headache in 80%, and papilledema in 70%; 43% of patients required at least 1 additional surgery. The major and minor complication rates were 7.6% and 32.9%, respectively. The dural venous sinus stenting analysis included 136 patients. After intervention, there was improvement of vision in 78%, headache in 83%, and papilledema in 97% of patients. The major and minor complication rates were 2.9% and 4.4%, respectively. Fourteen additional procedures were performed with a repeat procedure rate of 10.3%. Three patients had contralateral stent placement, while 8 had ipsilateral stent placement within or adjacent to the original stent. Only 3 patients required conversion to CSF diversion or 2.2% of patients with stents. Patients with medically refractory idiopathic intracranial hypertension have traditionally undergone a CSF diversion procedure as the first intervention. This paradigm may need to be re-examined, given the high technical and clinical success and low complication rates with dural venous sinus stenting. © 2015 American Society of Neuroradiology.
Book
Combining orthopedic surgery with biomechanical engineering, this reference and teaching text reviews and analyzes the clinical and scientific data on the mechanics of the human spine. This edition adds new material on vibration (i.e. road driving) and its effect on the spine; anatomy and kinematics
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The authors determine the dynamic changes of the spinal canal during flexion and extension in patients with cervical spondylosis. Forty-six patients were studied inside a whole-body magnetic resonance (MR) scanner with between 50 degrees of flexion and 30 degrees of extension, using a positioning device. At neutral position (0 degree) and maximum flexion and extension sagittal T2-weighted turbo spin echo sequences were acquired. A significant (P < or = 0.05) increase of spinal stenosis was found at extension (48%, 22 of 46 patients) when compared with flexion (24%, 11 of 46). Cervical cord compression was diagnosed at flexion in 5 patients (11%) and at extension in 9 patients (20%). Concerning the number of patients with cervical cord compression at flexion and extension, significant differences (P < or = 0.05) were found in patients with degenerative changes at four segments compared with patients with one segment involvement. Magnetic resonance imaging identified a significant percentage of increased spinal stenosis at flexion and, especially, at extension, which was not observed at neutral position (0 degree). Flexion and extension MR imaging demonstrates additional information using a noninvasive technique concerning the dynamic factors in the pathogenesis of cervical spondylotic myelopathy.
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Previous studies have suggested that secondary neurulation provides no functional neurons but only the filum terminale. However, no studies have confirmed that the coccygeal and lower sacral nerves do not originate from the secondary neural tube but only from the primary tube. To obtain a better understanding of these relationships, we examined sagittal or frontal sections from 20 embryonic and fetal specimens ranging from 6 to 14 weeks of gestation. During the growth of the vertebral column as well as the subsequent upward migration of the caudal end of the dural sac, the secondary neural tube was stretched to maintain the original attachment to the coccyx or the lower sacral vertebra. The filum-like structure showed much individual variability but in all cases appeared to be derived from the stretched neural tube. Intermediate age morphology revealed that the secondary neural tube itself provided an initial filum terminale before the ascent of the dural sac. Given that the coccygeal and lower sacral nerves are likely to originate from the secondary neural tube, these parts of the tube persisted and differentiated into spinal neurons to form the anococcygeal nerves. Likewise, the filum terminale was also most likely to contain some neurons that persisted postnatally. Depending on the timing and site of degeneration of the secondary neural tube, individual variations could occur in proportion to the amount of sensory and motor elements in the anococcygeal nerve supply.
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Chiari I malformation (CM) is a common neurosurgical diagnosis, and spinal cord syrinx is frequently found in patients with CM. Asymptomatic CM is a common imaging finding. Symptomatic CM is less common. Variation in prevalence estimates may be attributed to differences in sensitivity of CM detection between studies as well as differences in the populations being analyzed. The prevalence of low tonsil position and CM on MRI is higher in children and young adults compared with older adults. Studies that include a large number of older adults find a lower prevalence compared with analyses of children.
Article
Functional or psychogenic movement disorders are common and disabling, and sometime difficult to diagnose. The history and physical exam can give positive features that will support the diagnosis, which should not be based solely on exclusion. Some clues in the history are sudden onset, intermittent time course, variability of manifestation over time, childhood trauma, history of other somatic symptom and secondary gain. Anxiety and depression are common, but not necessarily more than the general population. On examination, distraction and suggestibility may be present. There are specific signs that should be looked for with different types of movements. For example, with tremor, change in frequency over time and entrainment are common features. With myoclonus, the movements might be complex in type with long latencies to stimulus induced jerks. Gait disorders show good balance despite claims to the contrary. Functional dystonia still remains a challenging diagnosis in many circumstances, although fixed dystonia is one sign more likely to be functional.