Neurological and spinal manifestations of the …...American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:195–211 (2017) RESEARCH REVIEW Neurological and

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 175C:195–211 (2017)

R E S E A R C H R E V I E W

Neurological and Spinal Manifestations of theEhlers–Danlos SyndromesFRASER 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

Fraser CummNeurosurgery,Neurosurgerydiagnosis andEhlers–Danlos

Myles Koby,special clinical

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Richard EllenChiari malform

Candace IreBS in Physical Ethe primary ca

Petra M. KliSchool of Brow

Donlin M. Linfrastructure fin diagnosing

Sunil Patel, Mbase Surgery, Cand neoplastic

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DOI 10.100Article first

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The Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorderscharacterized by joint hypermobility, skin extensibility, and tissue fragility. This communication briefly reportsupon the neurological manifestations that arise including the weakness of the ligaments of the craniocervicaljunction and spine, early disc degeneration, and the weakness of the epineurium and perineurium surroundingperipheral nerves. Entrapment, deformation, and biophysical deformative stresses exerted upon the nervoussystem may alter gene expression, neuronal function and phenotypic expression. This report also discusses

ins Henderson Sr., M.D., was fellowship trained in disorders of the craniocervical junction at the National Hospitals for Neurology andQueens Square London, before returning to complete his commitment to the U.S. Navy. He was then Professor and Director ofof the Spine and Craniocervical Junction at Georgetown University before entering private practice. He has concentrated on thetreatment of hypermobility connective tissue disorders and other rare diseases of the spine. He serves on the Executive Boards of theSociety, the Chiari Syringomyelia Foundation, the ILC, and the TCAPP Foundations.M.D. is a neuroradiologist, formerly at the National Institutes of Health and now at Doctors Community Hospital, Lanham, MD. He hasinterest in the use of dynamic imaging in the investigation of spinal instability disorders.tin, M.D., is an internist at Doctors Community Hospital in Lanham, MD, with special interest in pharmacology and physiology. Hereating complex EDS patients, including those with movement disorders, adult PANDAS, and severe autonomic dysfunction.mano, M.D., is a clinical geneticist with a long interest in the hereditary disorders of connective tissue. Her professional work in the lastentered on Ehlers–Danlos Syndrome. She is Director of Adult Genetics and of the Ehlers-Danlos Society Center for Clinical Care andHarvey Institute for Human Genetics, and Associate Professor of Medicine at Johns Hopkins University School of Medicine. She serves

ve Board and the Medical and Scientific Board of the Ehlers-Danlos Society.zel, M.D., Ph.D., is a neurosurgeonwhowas Professor Chairman of Neurosurgery at the Cleveland pathophysiology treatment of spinal

nese, M.D., is a neurosurgeon in New Hyde Park, New York, and is affiliated with North Shore University Hospital. He received hisfrom University of Torino Faculty of Medicine and has been in practice for more than 20 years. He specializes in Chiari I malformation,and related disorders.bogen, M.D., is Professor Chairman of the Department of Neurological adult brain tumors trauma surgery craniofacial abnormalitiesations congenital conditions. He also conducts research on molecular imaging nanoparticles on traumatic brain injury.ton,M.D., is a BoardCertified Family Physicianwith special interest in caring for Ehlers–Danlos syndromepatients. Dr. Ireton received herducation with Exercise Physiology emphasis from the University of California at Davis. She is currently piloting a group visit program forre of EDS patients in Asheville, NC and has been in practice for more than 20 years.nge, M.D., Ph.D., is a neurosurgeon who completed training in Germany and is currently Professor of Neurosurgery at the Medicaln University. She specializes in hydrocephalus, tethered cord andChiari malformation, and developmental cerebrospinal fluid disorders.ong, M.D., Ph.D., was Professor Chairman of Neurosurgery at The Johns where he took special interest in the development ofor patient care while developing new insights into pathophysiology of pain, spinal disorders, and brain tumors. He presently specializesthe various comorbid conditions of EDS..D., is Professor and Chairman of Neurosurgery at the Medical University of South Carolina. He completed fellowship training in Skullerebrovascular Surgery, and Microneurosurgery, and is presently focused on developing the understanding and treatment of vascularbrain disorders, complex spine disorders, and the treatment of craniocervical and spinal manifestations of EDS.an, M.D., Ph.D., is Professor of Ophthalmology and Director of the Wilmer Eye Institute at The Johns Hopkins Hospital. His clinical

des diagnosis of visual dysfunction after brain injury. Dr. Singman also has a particular interest in teaching health-care providers tovisual sequelae of complex disorders such as traumatic brain injury, Lyme disease, and EDS.ermans is a neurologist the Neuromuscular Centre of Radboud University Medical Center, Nijmegen, The Netherlands. Her main researched myopathies, in particular congenital myopathies, fascioscapulohumeral muscular dystrophy, and the neuromuscular features ofective tissue disorders. She completed a doctoral dissertation on neuromuscular features in Ehlers–Danlos and Marfan syndromes.interest: The senior author is a consultant to LifeSpine, Inc., and is developing technology to improve craniocervical stabilization. Theolds patents on finite element analysis methodology that could be used to assess stress in the brainstem and upper spinal cord. Thedeclare they have no conflict of interest.dence to: Fraser Cummins Henderson Sr., M.D., Ehlers–Danlos Society Center for Clinical Care and Research, Greater Baltimorer, The Metropolitan Neurosurgery Group, 8401 Connecticut Avenue, Suite 220, Chevy Chase, Baltimore, MD 20815. E-mail:aserhendersonMD.com2/ajmg.c.31549published online 21 February 2017 in Wiley Online Library (wileyonlinelibrary.com).

ey Periodicals, Inc.

196 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

increased prevalence ofmigraine, idiopathic intracranial hypertension, Tarlov cysts, tethered cord syndrome, anddystonia, where associations with EDS have been anecdotally reported, but where epidemiological evidence isnot yet available. Chiari Malformation Type I (CMI) has been reported to be a comorbid condition to EDS, andmay be complicated by craniocervical instability or basilar invagination. Motor delay, headache, andquadriparesis have been attributed to ligamentous laxity and instability at the atlanto-occipital and atlantoaxialjoints, which may complicate all forms of EDS. Discopathy and early degenerative spondylotic disease manifestby 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 manifestssymptomatically with weakness, myalgia, easy fatigability, limited walking, reduction of vibration sense, andmild impairment of mobility and daily activities. Consensus criteria and clinical practice guidelines, based uponstronger epidemiological and pathophysiological evidence, are needed to refine diagnosis and treatment of thevarious neurological and spinal manifestations of EDS. © 2017 Wiley Periodicals, Inc.

KEYWORDS: Ehlers–Danlos 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 spinalmanifestations of the Ehlers–Danlos syndromes. Am JMedGenet Part C SeminMedGenet 175C:195–211.

INTRODUCTION

The Ehlers–Danlos syndromes (EDS)are a heterogeneous group of herita-ble connective tissue disorders char-acterized by joint hypermobility, skinextensibility, and tissue fragility. Thesignificance of neurological findingsof EDS have been recently proposedand reviewed [Voermans et al., 2009a;Savasta et al., 2011; Castori andVoermans, 2014]. The followingarticle discusses the etiology andclinical findings related to neurologi-cal and spinal manifestations com-monly observed, yet often poorlyrecognized, in EDS patients, andproposes treatment options and areasof research needed.

METHODS

On the basis of a large shared experiencein the treatment of EDS, the authorswere solicited to contribute a review ofthe neurological and spinal manifesta-tions of EDS. The authors represent aworking group within the InternationalConsortium on the Ehlers–Danlos Syn-dromes. In preparation for the EDSInternational Symposium 2016, theauthors formed subcommittees to re-search individual topics relating to EDSand its neurological presentations, andhere present those findings in synthe-sized, topic-based fashion designed toassist a wider audience of medicalpractitioners in caring for EDS patients,and in advancing research needs for thispopulation.

HEADACHE INEHLERS–DANLOSSYNDROME

EDS patients commonly suffer avariety of headache types [Jacome,1999; Martin and Neilson, 2014;Castori et al., 2015]. These includeheadaches due to migraines, muscletension, intracranial hypertension,craniocervical instability, and cervicalspine disorders, temporomandibularjoint disease, carotid dissection, andother physical conditions. Though apatient may suffer status migrainosis,constant pain is less likely to representa migrainous headache [HeadacheClassification Committee of the In-ternational Headache Society (IHS),2013].

EDS patients commonlysuffer a variety of headache

types. These includeheadaches due to migraines,muscle tension, intracranialhypertension, craniocervicalinstability, and cervical spinedisorders, temporomandibular

joint disease, carotiddissection, and other physical

conditions.

Migraine in EDS

EpidemiologyMigraine, common in the generalpopulation, is more prevalent in women[Nappi and Nappi, 2012]. Migraine isalso more prevalent among EDS whichalso has a female predilection [Bendiket al., 2011; Castori and Voermans,2014; Castori et al., 2015]. Therefore,EDS may be considered a risk factor formigraine.

EtiologyMigraine often presents as a comorbiddisorder with many other medicalconditions [Schurks et al., 2009; Casucciet al., 2012; Pierangeli et al., 2012;Gelfand et al., 2013; van Hemert et al.,2014]. The final common pathwayappears to be abnormal regulation ofcerebral vasculature following a spreadof depression of cortical electricalactivity [Burstein et al., 2015; Ferrariet al., 2015].

Clinical and diagnostic findingsDefined as a primary headache disorder,with recurrent attacks of moderate orsevere intensity, lasting 4–72 hr, mi-graine headaches are more often unilat-eral, pulsating, associated with nausea,photophobia, and phonophobia, whichare disabling and worse with physicalactivity [Headache Classification Com-mittee of the International HeadacheSociety (IHS), 2013]. Migraine is usu-ally preceded by a prodrome andfollowed by fatigue, nausea, and dizzi-ness (postdrome). A careful history may

RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 197

elucidate triggers such as foods, stress,weather changes, sleep changes, menses,seasonal allergies, and caffeine. Physicalfindings may include vertigo, hypersen-sitivity to pressure on certain musclesand tendons, elevated blood pressure,and heart murmur. Migraines may causea benign episodic mydriasis. Findingsmay be suggestive of a stroke. Diagnostictesting should exclude sleep disorders[Kothari et al., 2000], menstrual cycledysfunction including menopause[Nappi and Nappi, 2012; Ripa et al.,2015], and patent foramen ovale [Vol-man et al., 2013].

TreatmentMigraine therapies (e.g., botulinumtoxin, triptans, caffeine, acupuncture,meditation) are legion, and testify to thediverse causes of migraine. Recognitionthat migraine patients suffer multiplepain disorders should prompt a holistictreatment strategy or combination ther-apies [Estemalik and Tepper, 2013; Kresset al., 2015].

Areas needing investigation

(1)
Connection between migraine, EDSand mast cell activation syndrome(MCAS), and cardiac functional/structural defects, such as posturalorthostatic tachycardia syndrome(POTS) and patent foramen ovale.
(2)
Connection between migraine anddiet in EDS.
(3)
Prevalence and impact of migraine inall types of EDS.
(4)
Treatment of migraine in EDS. (5) Effect of other co-morbidities, med-
ications, and nutrition in EDS relatedto migraine prevalence, severity, ortreatment.

IDIOPATHICINTRACRANIALHYPERTENSION (IIH)

Epidemiology

IIH, or pseudotumor cerebri, is a poorlyunderstood entity characterized by anincreased intracranial pressure (ICP),headaches, visual disturbances and pho-tophobia, and occasionally tinnitus,

nausea, and vomiting. Affected patientsmay have objective changes in visionwith 10% developing blindness [Corbettet al., 1982]. Female to male ratios rangefrom 4:1 to 15:1, and obesity is an addedrisk factor [Radhakrishnan et al., 1993].Anecdotal reports from large case serieshave suggested an association betweenEDS and IIH, but no such associationhas been formally reported in thebiomedical literature.

Etiology

Hypotheses proposed for the etiology ofIIH include excess cerebrospinal fluid(CSF) production, reduced CSF absorp-tion, excessive brain water content, andincreased cerebral venous pressure lead-ing to reduced CSF reabsorption [Balland Clarke, 2006]. Recent studies dem-onstrate that up to 93% of patients withIIH have focal venous sinus stenosis onMR venography, most commonly prox-imal to the transverse sigmoid sinusesjunction, 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 symptomsof increased ICP. The visual disturbancesare often associated with the finding ofpapilledema or visual field defects. Thediagnosis is supported by increased ICP:>25 cm of H2O in the obese popula-tion, or >20 cm H2O in the non-obesepopulation. There should be normalcomposition of CSF, thus, excludinginflammatory conditions, absence onMRI, or contrast-enhanced CT ofhydrocephalus and of mass, structural,or vascular lesions, and no other cause ofintracranial hypertension.

Treatment

Treatments include lifestyle modifica-tions targeting weight loss includingbariatric surgery, decreasing CSF pro-duction with acetazolamide, or seriallumbar punctures, CSF diversion with aventriculo-peritoneal or lumbo-perito-neal shunt, optic nerve sheath fenestra-tion, or subtemporal decompression.

Stenting has emerged as an effectivetreatment for IIH in select patients withradiographic cerebral sinus stenosis andevidence of pressure gradients [Sattiet al., 2015].

Areas Needing Investigation

(1)
The epidemiology and etiology ofpseudotumor cerebri in EDS.
(2)
Longitudinal studies to assess the efficacyand risks of medical therapy, shunting,and stenting in the EDS population.
CHIARI I MALFORMATION(CMI)

Epidemiology

Chiari malformation Type I (CMI) hasbeen reported as a comorbid conditionin hypermobile EDS (hEDS) [Milhoratet al., 2007]. The precise incidence ofthe CMI and EDS association is un-known, but the female to male ratio ishigher (9:1) in the CMI and EDSsubgroup than in the general CMIpopulation (3:1). The average age ofonset tends to be younger in the CMIand EDS subgroup, when compared tothe general CMI population.

Chiari malformation Type I(CMI) has been reported as a

comorbid condition inhypermobile EDS (hEDS).The precise incidence of theCMI and EDS association isunknown, but the female tomale ratio is higher (9:1) inthe CMI and EDS subgroupthan in the general CMI

population (3:1).

Etiology

CMI is a mesenchymal disorder affectingthe hindbrain, in which a developmentally


small posterior fossa results in downwardmigration of the brainstem and cerebellartonsils through the foramen magnum intothe spinal canal [Batzdorf et al., 2015]. Theherniation causes obstruction to thenormal regional circulation of the cerebro-spinal fluid (CSF) and compartmentaliza-tion of CSF circulation [Ellenbogen et al.,2000], which may result in suboccipitalpressure headaches. Obstruction of theCSF circulation may result in empty sellasyndrome, with flattening of the pituitarygland and resulting hormonal changes. Asyrinxmay form,which exerts amass effecton the spinal cord, and rarely the brainstem[Kahn et al., 2015]. There is increasingrecognition of CMI variants [Milhoratet al., 1999]. Some have suggested anassociation of tethered cord syndrome andCMI [Royo-Salvador, 1996].

The incidence, prevalence, andetiology of CMI and EDS occurringtogether are not fully understood.However, Milhorat et al. [2007,2010] found a high prevalence ofpatients with hereditary disorders ofconnective tissue in their retrospective

Figure 1. CMI with syrinx in the cervi

series of CMI post-decompression fail-ures that needed further intervention,including craniocervical fusion and/ortethered cord release. While this mayindicate a co-existence of these con-ditions, it does not provide evidence of acausal relationship, but suggests thatEDS and other disorders of connectivetissue should not be overlooked in CMI.


The CMI is traditionally defined radio-logically by 5mm of tonsillar herniationthrough the foramen magnum, thoughothers have suggested a herniation of3mm, or 7mm. The behavior of CMI isoften unrelated to the size of theherniation, and CMI can beasymptomatic.

CM is best characterized by atussive headache (worse with cough,strain, or yelling), dizziness, cerebellarfindings—dysarthria, incoordination,imbalance, and unsteady gait—hearingand vestibular deficits. Romberg’ssign, and deficits of cranial nerves.

cal spinal cord (sagittal view, T1 weighted MRI

There is sometimes trigeminal neuralgia[Milhorat et al., 1999; Tubbs et al.,2011a; Yarbrough et al., 2011]. Brain-stem findings, such as sleep apnea anddysautonomia, are often found in CMthat are complicated by craniocervicalinstability or basilar invagination, the so-called “complex Chiari.”

Treatment

There is no universally agreed uponsurgical threshold for CMI, but surgeryshould be urgently performed in thepresence of progressive neurologicaldeficits, and expanding syringomyelia(Fig. 1) [Yarbrough et al., 2011].

The association of CMI and EDS isburdened by distinct management chal-lenges, including craniocervical insta-bility, and possibly an increased risk ofCSF leaks. CMI may be asymptomatic(incidence unknown), or mildly symp-tomatic, so that surgical interventionmay not be required [Novegno et al.,2008; Strahle et al., 2011]. Sporadiccases of spontaneous resolution of CMI

of the cervical spine).


have beendescribed [Castillo andWilson,1995].


(1)
The incidence, prevalence, and etiol-ogy of CMI and its variants CM0 andCM 1.5 in the EDS populationremains unclear and needs larger dataregistry
(2)
The Complex Chiari malformation,though well described in the literature(see section on craniocervical instabil-ity), is not universally recognizedamong those who perform Chiarisurgery. Prospective studies in EDSpatients with Complex Chiari malfor-mation are needed to compare out-comes following decompression aloneversus those undergoing decompres-sion with fusion/stabilization.
ATLANTOAXIALINSTABILITY

Epidemiology

Atlantoaxial instability (AAI) is a poten-tial complication of all forms of EDS.Motor delay [Jelsma et al., 2013],headache associated with “connectivetissue pathological relaxation” andquadri-paresis have all been attributedto ligamentous laxity and instability atthe atlantooccipital, and atlantoaxialjoints [Nagashima et al., 1981; Halkoet al., 1995].

Epidemiology

The epidemiology of AAI in hEDS isunknown. AAI was seen in two ofthree patients with vascular EDS[Halko et al., 1995]. A high risk ofAAI is apparent in other disordersaffecting connective tissue, includingDown syndrome, Marfan syndrome,and rheumatoid arthritis [MacKenzieand Rankin, 2003; Hankinson andAnderson, 2010].

Etiology

Aproclivity to ligamentous incompetencerenders the atlanto-axial joint a higher risk

for instability. The atlantoaxial junction(AAJ) is themostmobile joint of the body.The AAJ mechanical properties aredetermined by ligamentous structures,most prominent of which are the trans-verse and alar ligaments [Tubbs et al.,2011b].

Hypermobility of the AAJ is com-mon in children, and over 40° ofrotation may be observed in eachdirection, but in the adult there issubstantially less than 40° of rotation[Zhang and Bai, 2007; Martin et al.,2010]. At 35° of rotation of C1 uponC2, there is stretching and kinkingof the contralateral vertebral artery[Selecki, 1969]. At 45°, both vertebralarteries become occluded [Menezes andTraynelis, 2008].


The diagnosis of AAI is predicated upondisabling neck pain or suboccipital pain,and

(1)
history and clinical findings of cervicalmedullary syndrome, or syncopal (orpre-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 acommon occurrence in EDS patients[Castori and Voermans, 2014]. Theremay be symptoms referable to thevertebral artery blood flow, includingvisual changes, as well as headacheresulting from vertebral artery torsion.Syncopal and pre-syncopal events arefrequent. Other symptoms include diz-ziness, nausea, sometimes facial pain,dysphagia, choking, and respiratoryissues. Symptoms usually improve witha neck brace.

Neurological examination dem-onstrates tenderness over spinous pro-cess of C1 and C2, altered mechanicsof neck rotation, hyperreflexia, dysdia-dochokinesia, and hypoesthesia topinprick. Weakness is not a constantfeature of AAI.

A number of radiological featureshave been described, including rotation

of C1 upon C2> 41° (as assessed by CTscan of C1-2) and retro-odontoidpannus on MRI [Fielding et al., 1978;Taniguchi et al., 2008]. The difficultyof recognizing rotary instability onstandard X-ray, CT, and MRI imageshas resulted in failure to diagnose[Kothari et al., 2000].

Treatment

The first line of treatment should be neckbrace, physical therapy, and avoidance ofactivities that provoke exacerbation ofthe AAI symptoms. If the non-operativetreatment fails, fusion stabilization ofC1/C2 is required. Incompetence of the alarligament requires dorsal surgical fusion[Menendez and Wright, 2007]. Occiputto C1/C2 fusion should be considered inthe presence of craniocervical instability,basilar invagination, or complex Chiarimalformation.


(1)
The prevalence and natural history ofAAI in the EDS population.
(2)
The importance of dynamic imag-ing studies (such as CT with rota-tion of the cervical spine to extremeleft and right, requires furthervalidation to promote a generalizedadoption of these studies to diag-nose AAI, and to prompt greateravailability of dynamic imagingfacilities).
(3)
Surgical outcomes for treatment ofrotational instability and the long-term outcome in EDS.
CRANIOCERVICALINSTABILITY

Epidemiology

Craniocervical instability (CCI) isrecognized as a manifestation ofligamentous laxity in EDS [Naga-shima et al., 1981; Milhorat et al.,2010]. Ligamentous laxity has beenshown to result in neuraxial injury[Lindenburg and Freytag, 1970; Hen-derson et al., 1993; Menezes andTraynelis, 2008].


Etiology

CCI is a pathological condition inwhich ligamentous connections fromthe 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 dyslexiaand dyspraxia in the EDS populationmerit investigation as possible conse-quences of early onset degenerativechanges resulting from ligamentouslaxity upon the central nervous system[Nagashima et al., 1981; Adib et al.,2005]. The most prominent movementof the atlanto-occipital joint is flexion-extension; axial rotation is normallylimited to <5 degrees of rotation[Dvorak et al., 1987].

There is increased recognition ofmechanisms of neuronal injury thatresult from stretching, or deformativestress [Jafari et al., 1997; Maxwell et al.,1999; Shi and Whitebone, 2006]. Theconsequent formation of axon retrac-tion balls is similar to that seen in diffuseaxonal injury of the brain (Fig. 2)[Geddes et al., 2000; Henderson et al.,2005]. Stretching of neurons causespathological calcium influx [Wolfet al., 2001], altered gene expression

Figure 2. Axon retraction bulbs in the uphotograph (�500), axial section of the dors

[Arundine et al., 2004], and apoptosis[Liu et al., 1997; Arundine et al., 2004].


CCI-related symptoms result from de-formation of the brainstem and upperspinal cord, traction on the vertebralartery, and possibly from the consequen-ces of altered venous or CSF outflowfrom the cranium.CCI often occurswithbasilar invagination or ventral brainstemcompression, the findings of which aredominated by pyramidal and sensorychanges: weakness of the limbs hyper-reflexia and pathological reflexes (e.g.,Babinski, Hoffman’s sign, absence of theabdominal reflex), paresthesias, and aplethora of other symptoms—includingsphincter problems, headache, neck pain,dizziness, vertigo, dyspnea, dysphonia,altered vision, and hearing, syncope,emesis, altered sexual function, alteredmenses, and gait changes [Caetano deBarros et al., 1968]. These signs, inaggregate, constitute the cervical medul-lary syndrome [Batzdorf et al., 2015],elements of which are commonlyrecorded among EDS patients [Cellettiet al., 2012].

Three metrics may be useful inthe identification of CCI and basilar

pper spinal cord, from cadaveric studies of subjecal column at the C2 level. Silver stain).

invagination: the clivo-axial angle, theHarris measurement, and the Grabb,Mapstone, Oakes method [Batzdorfet al., 2015; NINDS Common DataElements, 2016]. The Clivo-axial angle(CXA) is the angle formed between theposterior aspect of the lower clivus and theposterior axial line.TheCXAhas a normalrange of 145° to 160°, but an angle of lessthan 135° is pathological [Henderson et al.,1993; Henderson et al., 2010a; Batzdorfet al., 2015]. Increasing kyphosis of clivo-axial angle (i.e., amore acuteCXA) createsa fulcrum by which the odontoid deformsthe brainstem [Menezes, 2012]. Themedulla becomes kinked as the CXAbecomes more kyphotic.

The second radiologic metric, thehorizontal Harris measurement, is thedistance from the basion to the posterioraxial line (PAL) [Harris et al., 1994].Instability is present when the basion tothe PAL exceeds 12mm. This measure-ment, used in conjunction with dy-namic flexion and extension images ofthe cervical spine, can also be used tomeasure the dynamic translation be-tween the basion and the odontoid[Batzdorf et al., 2015; NINDS Com-mon Data Elements, 2016]. In thenormal individual, there should beno measurable translatory movement

ts with basilar invagination (Microscopic


(sliding movement). Translation ofgreater than 1mm between the basionand odontoid reflects craniovertebralinstability, and may warrant stabilization(Fig. 3) [Wiesel and Rothman, 1979;White and Panjabi, 1990].

The third metric, the Grabb, Map-stone, and Oakes measurement predictsrisk of ventral brainstem compression,and has been statistically correlated withclinical outcome [Grabb et al., 1999;Henderson et al., 2010b]. A measure-ment >9mm suggests high risk of

Figure 3. a: The craniocervical junctionT2 weighted MRI of the cervical spine in fldemonstrating a translation of 6mm from fle

ventral brainstem compression [Grabbet al., 1999].

There is a relatively nascent recog-nition of the importance of dynamicimaging of the CCJ. For example, thebrainstem may appear normal on rou-tine magnetic resonance imaging in thesupine position, but show pathologicalventral brainstem compression in theflexion view sitting upright [Klimo Jret al., 2008; Henderson et al., 2010b;Milhorat et al., 2010]. “Functional”dynamic studies in flexion and extension

in flexion, showing a forward slide of the basion wexion). b: In extension, the basion lies along thexion to extension (Sagittal view, T2 weighted M

are important to determine whetherthere is pathological hypermobility atthe craniocervical junction [Klekamp,2012].

Treatment

Indications for surgery include severeheadache, symptoms which constitutethe cervical medullary syndrome,neurological deficits referable to thebrainstem and upper spinal cord,radiological findings of CCI, and

ith respect to the odontoid (Sagittal view,posterior edge of the odontoid process,RI cervical spine).


failure of a reasonable course of non-operative therapy. Though there areno established criteria for treatment ofCCI in EDS, there is abundantliterature addressing the diagnosis ofCCI [White and Panjabi, 1990; Harriset al., 1994; Batzdorf et al., 2015], andthe treatment of CCI with craniocer-vical stabilization in various congenitalor degenerative connective tissue dis-orders [Nagashima et al., 1981; Goeland Sharma, 2005; Henderson et al.,2010b; Milhorat et al., 2010; Tubbset al., 2011a; Klekamp, 2012; Yoshi-zumi et al., 2014].


(1)
Prevalence and natural history of axialligamentous instability in EDS.
(2)
Validation of radiological metrics fordetermining CCI in the EDSpopulation.
(3)
Development of an internationaldata registry using the NINDSCommon Data Elements [2016] tofacilitate therapeutic trials for CCIin EDS.
SEGMENTAL KYPHOSISAND INSTABILITY

Epidemiology

The prevalence of cervical and tho-racic segmental instability in thepopulation of patients with hyper-mobility syndromes has not been wellestablished. However, discopathy andearly degenerative spondylotic diseasein hEDS and classical type EDS is wellestablished. EDS is characterized bysegmental instability, kyphosis, andscoliosis. Spondylosis, defined by thepresence of non-inflammatory discdegeneration, is usually preceded bymild segmental instability [Shedidand Benzel, 2007]. As a consequenceof cervical and thoracic instability,and discopathy in EDS, there is loss ofthe normal cervical lordosis and anincreasing kyphosis, rendering EDSpatients prone to progressive myelop-athy, and mechanical neck and chestpain.

The prevalence of cervical andthoracic segmental instabilityin the population of patientswith hypermobility syndromeshas not been well established.However, discopathy and

early degenerative spondyloticdisease in hEDS and classicaltype EDS is well established.

EDS is characterized bysegmental instability,kyphosis, and scoliosis.

Etiology

Ligamentous laxity is an importantdeterminant in the development ofspinal instability other connective dis-orders such as rheumatoid arthritis,Down syndrome and osteogenesis im-perfecta, but there have been no series todemonstrate this linkage in EDS. Theimportance of ligamentous laxity isincreasingly appreciated among clini-cians [Tredwell et al., 1990; Steilen et al.,2014].

The pathophysiology of segmentalinstability is well described: duringflexion, there is deformation of thelateral and ventral columns of the spinalcord, directly related to the strain on thecord [Henderson et al., 2005; Shedidand Benzel, 2007]. Extension moreoften results in compression of thecord by buckling of the ligamentumflavum, resulting in myelopathic symp-toms [Muhle et al., 1998]. The cervicalspinal cord can be physiologically teth-ered in the sagittal plane, such thatnormal cord elongation in flexion isexaggerated by the kyphosis; this resultsin increased deformity and anatomicstretching of the cord. This “sagittalbowstring effect” underlies a physiolog-ical tethering effect, with resultingneurological deficits [Shedid and Ben-zel, 2007]. Others have recognized the

importance of the dentate ligaments inapplying stressors to the spinal cord,with the subsequent result of focalmyelopathy [Cusick et al., 1977].


Clinical findings include pain anddisability, as well as sensory, motor,and reflex changes. Radiculo-myelop-athy may manifest in an acute, sub-acute, or chronic manner as radicularand dermatomal or non-radicularmyelopathic hypoesthesia, hyperes-thesia, or paresthesia, and less oftenweakness. Over time, there may beascending numbness, spasticity, Lher-mitte’s sign, and eventually leg weak-ness, altered gait, clumsiness, and longtract findings. There is often markedtenderness to palpation over unstablemotion segments.

Clinical differential diagnoses in theEDS population should be kept in mind:instability at the atlanto-occipital andatlantoaxial joints, shoulder, clavicularand rib subluxations, brachial plexop-athy, vascular anomalies, dissection orvenous insufficiency, peripheral neurop-athy, multiple sclerosis, amyotrophiclateral sclerosis, myasthenia gravis, mye-lopathy due to drugs—such as statins,colchicine, steroids- vitamin deficiency,especially B12 and B3, mitochondrialdysfunction, stroke, and psychologicaldisorders.

Though CT scans andMRI remainthe standard for most practitioners,radiological findings do not alwayscorrelate well with clinical findings orsurgical outcome [Arnasson et al.,1987]. Dynamic instability is unlikelyto be demonstrated in a resting supinesubject, and pathological instability willoften become manifest only when theligaments are placed under stress.Though not yet validated, dynamicMRI in the upright position subjectsthe vertebral spine to physiologicalloading, and can be performed in theflexed and extended positions to dem-onstrate instability (Fig. 4) [Milhoratet al., 2010; Klekamp, 2012].

White and Panjabi [1990] havedefined the reference ranges for flex-ion, extension, lateral tilt, and rotation


at each level of the spine. Radiologicalfindings of segmental instability mayinclude evidence of spinal cord com-pression or deformity, hyper-angula-tion at one or more segmental levels(>11.5° angulation between adjacentvertebra, subluxation >3mm), and thepresence of pathological longitudinalstretching.

Figure 4. a: Segmental cervical instabilitycompression on neutral view (Sagittal view, Tupon extension of the neck, showing posterospine, T2 weighted).

Treatment

Initial management includes neck brac-ing and physical therapy with therapistswho are knowledgeable regarding liga-mentous laxity including EDS, attain-ment of a good sagittal balance, andavoidance of certain activities. Rest willoften improve symptoms. If symptoms

, showing widespread degenerative disc disease ch2 weightedMRI of the cervical spine in the neutra-listhesis of C4 on C5, causing spinal cord comp

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 increaseddegeneration of discs adjacent to fusedmotion segments) has not been deter-mined in the EDSpopulation, but shouldbe considered in surgical planning;

aracteristic of EDS-HT, but no spinal cordl position). b: Dynamic instability evidentression (MRI sagittal view of the cervical


motion-sparing technology may be animportant option in this population,though there is yet no published litera-ture in the EDS population.

Areas Needing FurtherInvestigation

(1)
Definition, prevalence and naturalhistory of segmental instability in theEDS population.
(2)
Clinical history of segmental instabil-ity after stabilization, including rates ofadjacent segment degeneration indifferent types of EDS.
(3)
Studies to improve diagnostic efficacyof segmental instability utilizing up-right MRI.
TETHERED CORDSYNDROME

Tethered cord syndrome (TCS) in EDSis most often associated with a structur-ally abnormal filum terminale, andusually characterized by low back painand the clinical triad of neurogenicbladder, lower extremity weaknessand sensory loss, and musculoskeletalabnormalities.

Epidemiology

The incidence of the specific diagnosisof TCS is unclear, both within thegeneral and EDS populations in theUnited States [Bui et al., 2007]. Theprevalence of TCS in a diverse sample ofTurkish school children was 0.1%[Bademci et al., 2006]. In a cohort of2,987 consecutively evaluated patientswith diagnoses of CMI or “low lying”cerebellar tonsils (LLCT, tonsillar de-scent 0–4mm), Milhorat et al.[2009] found TCS, using a definitionthat allowed for normal position of theconus medullaris on MRI (i.e., at orabove, the L1 vertebra), in 14% of theCMI 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 atthe S2 level. The filum contains neural,glial, and ependymal remnants that stemfrom embryonic spinal cord whichbegin to regress at 9–10 weeks ofgestation [Jang et al., 2016]. Thepresence of fatty tissue, “nerve twigs”(dysplastic axons), fat and vascularlacunes, and suspicion of “congested”veins, are usually seen in the abnormalfila specimens obtained from patientswith TCS [Thompson et al.,2014] Stretching of the spinal cord bythe structurally abnormal filum is thepresumed mechanism of TCS. Symp-toms may become more apparent as achild grows. Forcible flexion andstretching is often deemed responsiblefor adult onset of TCS [Aufschnaiteret al., 2008]. Poor blood flow andoxidative stress in the spinal cord havealso been implicated in animal models asmechanisms of neuronal injury [Yamadaet al., 2007].


TCS is characterized by aching/burningpain in the low back, legs and feet, andsensori-motor findings in lower extrem-ities: weakness is common, with heavi-ness, stiffness, and tightness of legs andcramps; paresthesias in the pelvic area orlegs and hypoesthesia to pinprick in thelumbar and sacral dermatomes is oftenobserved. Findings are often asymmet-ric. A history of toe-walking may beelicited. Urological findings includeurinary hesitancy, frequency, urgency,retention/incomplete emptying, noctu-ria, irregular urinary stream, sensory lossof the bladder, frequent urinary tractinfections, and incontinence.

There is often enuresis into latechildhood. There may be fecal inconti-nence, constipation, or sexual dysfunc-tion. As TCS results in a combination ofupper and lower motor neuron injury,there is often hyperreflexia in the lowerextremities, but normal reflexes in thearms. The legs are usually weak, withnormal upper extremity strength. Sen-sory loss is usually prominent in thelumbar and sacral dermatomes, butnormal in the arms and trunk. Ortho-pedic deformities include scoliosis,

kyphosis, functional ankle and footdeformities (ankle pronation with phys-ical strain), and pes planus or pes cavus[Hoffman et al., 1976; Pang andWilberger, 1982].

Urodynamic testing is important inthe diagnosis of TCS. Neurogenicbladder manifestations may range fromurinary retention and detrusor under-activity to urinary incontinence, over-activity of the detrusor, and sphincterdysfunction [Tu and Steinbok, 2013].While formal urodynamic criteria havenot been established for TCS, detrusorsphincter dysynergia, large post voidresidual, and very large bladder capacity(>800ml) are good urodynamic indi-cators of a neurogenic bladder. Urody-namics can help to differentiate theneurogenic bladder of TCS from thatdue to diabetes or bladder obstructionfrom prostatic hypertrophy.

MRI of the cervical, thoracic, andlumbar spine is required to rule outother causes of leg weakness and lowback pain, such as disc herniation,spondylolisthesis, stenosis, neoplasm,or intrinsic lesions of the spinal cord—such as multiple sclerosis or signs oftrauma. The MRI may show low lyingconus (below the mid L2 level), fattyinfiltration, a stretched or thickenedfilum, a syrinx in the lower spinal cord,scoliosis or spina bifida occulta. Theterm “occult tethered cord” (OTCS)refers towhere theMRI shows a normalposition of the conus [Tu and Steinbok,2013]. A large diameter of the filumterminale in axial T2 studies is a positiveindicator that favors untethering in thepresence of TCS [Fabiano et al., 2009].

Controversy exists over whether itis necessary to radiologically demon-strate a “low lying conus medullaris,”that is, a conus ending at the lower L2level or below. There has been theintuitive presumption that a low-lyingconus represents a spinal cord undertension. However, this presumption hasnot been verified, and indeed, there areno epidemiological studies which allowthe definition of a specific imagingfinding to establish the diagnosis ofTCS. Nor are there epidemiologicalstudies in the normal population thatdemonstrate specific findings that


exclude TCS. On the other hand, thereis a growing body of evidence thatsupports the clinical diagnosis of TCSwith or without the radiologicaldemonstration of a low-lying conusmedullaris, which justifies surgical in-tervention when the clinical criteria aremet [Tu and Steinbok, 2013].

Treatment of TCS

There is no standard technique in thesurgical treatment of TCS. Generally,the lamina is removed, anywherefrom L2 to S1, a durotomy is made,and electrical stimulation is used toconfirm the absence of any nerveroots which may be associated withthe filum. Finally, a microsurgicalresection of the filum terminale(usually a 10 mm segment for pathol-ogy) is performed (Fig. 5). The filumtends to be taut, and to briskly retractupon sectioning. However, findingsare variable, and there is no evidenceto suggest that the intraoperativefindings predict or correlate withthe surgical outcome and severity ofthe TCS [Pang and Wilberger, 1982;Milhorat et al., 2009]. In some cases,it may be necessary to perform alumbar stabilization across themotion segment in which the filumwas sectioned. The resected filumshould be sent for histopathologicalevaluation.

Figure 5. a: Tethered cord syndrome: columbar spine, T1 weighted MRI). b: Tethe(Intraoperative photograph of the lumbar spi

Areas Needing Research

(1)

nusredne th

Prospectively and retrospectively eval-uate specific clinical features andradiological metrics for predictiveaccuracy, to establish validated inclu-sion and exclusion criteria for futurestudies regarding TCS.

(2)
Determine the incidence of TCS inEDS patients.
(3)
Determine epidemiologically whetherTCS is a co-morbid feature of CMIin EDS.
(4)
Validate outcome measures by whichto determine the surgical outcomes.
(5)
Establish complication rates for TCSsurgery in the EDS population.
DYSTONIAS AND OTHERMOVEMENT DISORDERS

Epidemiology

Movement disorders can be broadlydivided into hyperkinetic disorders(too much movement) or hypokineticmovement occurring in the consciousstate. The hyperkinetic movement dis-orders—including dystonia, tremor,chorea, myoclonus, and tic disorders—are observed in the EDS populationaccording to anecdotal reports fromlarge series of patients, but have notbeen documented in the peer-reviewedliterature.

at the normal level (L1), fatty filum suggestivecord syndrome: the thickened filum terminecal sac and the durotomy).

Etiology

Pain and trauma are frequent compo-nents of EDS, and there is a significantbody of literature suggesting movementdisorders may arise from extracranialtrauma. Post-traumatic dystonia maydevelop in a limb following trauma tothat limb [van Rooijen et al., 2011].This may be one mechanism thatestablishes a link between EDS andmovement disorders. However, whileseveral of the authors have strong clinicalsuspicion of a connection, there are nopublished studies that confirm thatmovement disorders are a co-morbidityof hEDS [Rubio-Agusti et al., 2012].

While dystonia in joint hypermo-bility syndromes (JHS) have beenobserved, causality has not been demon-strated. In one large series, one third ofpatients with “fixed dystonia” werefound to have JHS [Kassavetis et al.,2012]. The authors suggested that move-ment avoidance may have been adoptedto avoidpain, and in time resulted in fixeddystonia. The etiology of the fixeddystonia has also been variously attrib-uted to peripheral injury [van Rooijenet al., 2011], and psychogenicmovementdisorder [Hallett, 2016].


Neurological evaluation and EEG torule out seizure should be performed.

of tethered cord syndrome (Sagittal viewale at the L2 level, just before division.


The diagnosis of psychogenic move-ment disorder has been met with someskepticism [Palmer et al., 2016], but isdistinguished from malingering, andthought to result from psychologicalcauses [Hallett, 2016]; it is characterizedby involuntary, disabling movements,abrupt in onset, a waxing/waningcourse, changes in the nature of themovement over time, worsening withstress, anxiety or depression, and im-provement with distraction; they aredifficult to diagnose and treat. Prognosisfor improvement is better in patientswith a shorter duration of illness [Lang,2006].

Treatment

There is no established treatment algo-rithm for movement disorders in pa-tients with EDS.


(1)
Establish studies to determine theepidemiology and etiology of move-ment disorders in EDS, and todemonstrate whether there is a co-morbid relationship.
(2)
Develop evidence-based treatmentstrategies for movement disorders inthe EDS population.
NEUROMUSCULARFEATURES OF EHLERS-DANLOS SYNDROME

Epidemiology

EDS, especially hEDS, is associated withhigh prevalence of myalgia, nocturnalmuscle cramps involving the calves,hypotonia, progressive muscle weak-ness, poorly developed musculature,and scapular winging, which to someextent may be the result of avoidance ofexercise due to hypermobility andinstability of joints [Banerjee et al.,1988; Palmeri et al., 2003].

Musculoskeletal pain starts early, ischronic and debilitating [Voermanset al., 2010]. Neuromuscular diseasemanifests symptomatically with muscleweakness, myalgia, easy fatigability, and

limited walking distance; physical find-ings include muscle weakness, reductionof vibration sense, and mild impairmentof mobility and daily activities [Voer-mans et al., 2009b].

Musculoskeletal pain startsearly, is chronic and

debilitating. Neuromusculardisease manifests

symptomatically with muscleweakness, myalgia, easyfatigability, and limitedwalking distance; physicalfindings include muscleweakness, reduction of

vibration sense, and mildimpairment of mobility and

daily activities.

Brachial and/or lumbosacral plexusneuropathies and other compressionmono-neuropathies are not uncommonin EDS [Voermans et al., 2006; vanRooijen et al., 2011]. The presence ofradiculopathy or small-fiber neuropathyprobably explains a higher prevalence ofneuropathic symptoms (paresthesias/numbness in hands or feet) than regis-tered on neurophysiological or ultra-sound testing. There is a high prevalenceof ulnar nerve luxation at the elbowdetected 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 andneuromuscular complications. Humanand murine studies suggest a correlationbetween TNX levels and degree ofneuromuscular involvement, and a cor-responding role of the extracellularmatrix defect in muscle and peripheralnerve dysfunction in EDS [Huijinget al., 2010; Voermans et al., 2011].

However, TNX deficiency accounts foronly a very small percentage of patientswith hEDS. Reduced quantitative mus-cle function appears to be secondary tomuscle dysfunction rather than reducedmuscle mass [Rombaut et al., 2012].Abnormal myo-tendinous junctions inthemuscle belly [Penisson-Besnier et al.,2013], mild to moderate myopathy and/or neuropathy, and defects of theextracellular matrix of the connectivetissue investing muscle and peripheralnerve may increase muscle dysfunction[Voermans et al., 2009b, 2012; Syx et al.,2015].

The pathophysiological mechanismof peripheral neuropathy in hEDSappears, in part, to result from abnormalstretching and pressure upon peripheralnerves that results from joint subluxa-tion. The connective tissue of peripheralnerves might fail to resist excessivemechanical stress: increased vulnerabil-ity is linked to underlying geneticdefects in TNXB, collagens I, III,or V deficient epi-, peri-, and endo-neurium [Voermans et al., 2009b;Granata et al., 2013]. This defect mightalso relate to the occurrence of axonalpolyneuropathy in various types of EDS[Muellbacher et al., 1998].

Abnormal extracellular matrix ingeneralized connective tissue structuresuggests molecular overlap betweeninherited connective tissue disordersand certain congenital myopathies,awareness of which may be helpful inrecognition of these rare disorders[Voermans et al., 2008; Donkervoortet al., 2015].

Clinical and Diagnostic Features

The approach to neuromuscular symp-toms and signs, and helpful ancillaryinvestigations has been thoroughlyreviewed [Merrison and Hanna,2009], and supplemented by theWUSTL database on neuromusculardisorders.

Treatment

A recent study on medical consumptionand outcome reported the impact ofpain upon daily functioning in hEDS.


Most patients (92%) used pain medi-cations; 52% underwent physicaltherapy—including neuromuscular ex-ercises, massage, and electrotherapy—ofwhom two thirds reported a positiveoutcome. The study concluded that theimpaired functional status of hEDSpatients strongly determined the highrate of treatment consumption, whichunderscores the importance of develop-ment of evidence-based guidelines fortreatment [Rombaut et al., 2011]. Thereis increasing evidence that treatmentshould consist of a multidisciplinaryprogram. One study demonstrated suc-cess combining physical therapy, cogni-tive behavioral therapy, and grouptherapy, followed by individual homeexercises and weekly guidance by phys-iotherapist for three months, thenreadmission for reevaluation and furthertraining advice. Patients reported im-proved performance of daily activities,muscle strength and endurance, reducedkinesiophobia, and increased participa-tion in daily life [Bathen et al., 2013].


(1)
The contributions of the variouscausative factors to muscle dysfunctionin EDS, including increased compli-ance of the series-elastic component ofmuscle tissue, failure of maximalvoluntary muscle activation, and im-paired proprioception.
(2)
Clinical trials of physical training andcognitive behavioral therapy on mus-cle strength and endurance in EDSpatients.
(3)
The development of evidence-basedguidelines to improve muscle strength.
TARLOV CYST SYNDROME

Epidemiology

Tarlov cysts are perineurial cysts thatmay impose pressure upon adjacentneural structures. Numerous small sur-gical series describe the spectrum ofpathology, but there is significant con-fusion in the reported literature withother cystic structures: the sacral me-ningocele and dural ectasia. The sacral

meningocele principally affects males,fills the sacrum, and typically involvesall of the sacral roots. Dural ectasia maypresent with large intra-abdominalcysts associated with connective dis-orders [Nabors et al., 1988; Stern,1988].

There is a general presumption thatthese cystic abnormalities, includingTarlov cysts, are incidental findings.However, the belief that all Tarlov cystsare asymptomatic has no support in theliterature. An unpublished review atJohns Hopkins on 756 patients withsymptomatic spinal cysts, found 18 withlarge sacral internal meningoceles withdramatic associated sacral erosion, ofwhom 16 were women with Marfandisease or EDS. The remainder hadtypical Tarlov cysts, with a female tomale ratio of seven to one, usually onsacral nerve roots. A small numberexisted on the lumbar, thoracic orcervical roots. Delay in treatment re-sulted because most patients had beentold that the cysts were asymptomaticand did not need to be treated, or that nosatisfactory treatment existed, or thattreatment was too dangerous to con-template. Rarely, there may be massivedilatation of the lumbar and sacral thecalsac, with extensions of the subarachnoidspace along nerve roots and into abdo-men and pelvis.

Etiology

The finding of inflammatory cells inthe walls of symptomatic Tarlov cysts[Voyadzis et al., 2001] begs comparisonwith the recent findings inflammatorycells in the fila terminale of EDS patientswith TCS [Klinge, 2015].


Tarlov cysts are a radiological diagnosis.The Tarlov cysts appear primarily in thesacrum, at the level of the root ganglia,causing erosion of the surrounding bone(Fig. 6). Cervical and thoracic Tarlov cystsmay produce pain and neurologicalsymptoms or deficits in the distributionof the involvednerve root, or myelopathicfrom an extradural or subarachnoid cyst inthe high thoracic region, or symptomatic

fromamediastinal cystic extensionbehindthe trachea.

The most common syndrome,occurring in approximately 70% ofsymptomatic patients, is comprised ofsacral pain, worse when sitting andstanding, and improved when lyingdown; pain in the S2–S5 dermatomesin the pelvis and perineum, sciatica inthe Sl and S2 dermatomes, and lesscommonly L5 root dermatome. Boweland bladder dysfunction are common.One third of patients have bowel andbladder dysfunction, and sensory com-plaints related to nerve roots S2, S3, S4without sciatica. A small group ofpatients have bowel and bladder dys-function and sacral root sensory losswithout pain.

Treatment

Of patients undergoing surgical obliter-ation of the Tarlov cysts, successfuloutcomes are reported in 80–88% ofpatients, with few complications [Voy-adzis et al., 2001; Feigenbaum andHenderson, 2006]. Alternatively, pa-tients may undergo aspiration of thecyst and injection of the cysts with fibringlue, although the results are lesssatisfactory [Patel et al., 1997].


(1)
Determine the prevalence of Tarlovcysts in the general population and thehEDS and classic type EDSpopulations.
(2)
Define the ratio of symptomatic versusasymptomatic patients, and the factorsthat appear to trigger pain.
(3)
Compare the pathophysiology of Tar-lov cysts in the general populationversus the EDS population.
(4)
A prospective randomized trial tocompare treatments: surgical resectionversus aspiration and injection of fibringlue.
(5)
Longitudinal studies of natural andclinical history of Tarlov cysts in EDS.
(6)
Utility of urodynamic studies as op-posed to patient report for symptomsof neurogenic bladder.

Figure 6. a: Tarlov cyst, with substantial bone erosion and compression of the right S2 nerve to the wall of the cyst in 9 o’clockposition (T2 weightedMRI, axial view through sacrum). b: Large S2/S3 Tarlov cyst, T1 weighted view, Tarlov cyst on T2 weighted view(Sagittal MRI views through the sacrum).


CONCLUSION

Incompetent connective tissue results inlax ligaments within the axial skeleton,peripheral nerve sheaths, and possiblythe architecture of the myoneural andmuscular endplates. Ligamentous laxityof the axial skeleton in particular,subjects the central and radicular ner-vous system to entrapment, deforma-tion, and biophysical deformativestresses. Biophysical stress is increasinglyrecognized in the alteration of geneexpression, cellular function, and ulti-mately phenotypic expression. Clinicalpractice guidelines, based upon strongerepidemiological and pathophysiologicalevidence, are needed for the diagnosisand treatment of the various neurologi-cal and spinal manifestations of EDS.

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