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

Neurological and Spinal Manifestations of the Ehlers–Danlos 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 Ehlers–Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders characterized by joint , 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 . Entrapment, deformation, and biophysical deformative stresses exerted upon the 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 , 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 Ehlers–Danlos Society, the Chiari 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 Ehlers–Danlos 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 Scientific 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 affiliated 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 Certified Family Physician with special interest in caring for Ehlers–Danlos 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 , tethered cord and , and developmental cerebrospinal fluid 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 , 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 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 Ehlers–Danlos and Marfan syndromes. Conflicts 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 finite element analysis methodology that could be used to assess stress in the and upper . The other authors declare they have no conflict of interest. *Correspondence to: Fraser Cummins Henderson Sr., M.D., Ehlers–Danlos 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: [email protected] DOI 10.1002/ajmg.c.31549 Article first published online 21 February 2017 in Wiley Online Library (wileyonlinelibrary.com).

ß 2017 Wiley Periodicals, Inc. 196 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

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 , rendering EDS patients prone to mechanical pain, and . 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.

KEY WORDS: 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 spinal manifestations of the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet 175C:195–211.

INTRODUCTION HEADACHE IN Migraine in EDS EHLERS–DANLOS The Ehlers–Danlos syndromes (EDS) Epidemiology SYNDROME are a heterogeneous group of herita- Migraine, common in the general ble connective tissue disorders char- EDS patients commonly suffer a population, is more prevalent in women acterized by joint hypermobility, skin variety of headache types [Jacome, [Nappi and Nappi, 2012]. Migraine is extensibility, and tissue fragility. The 1999; Martin and Neilson, 2014; also more prevalent among EDS which significance of neurological findings Castori et al., 2015]. These include also has a female predilection [Bendik of EDS have been recently proposed headaches due to migraines, muscle et al., 2011; Castori and Voermans, and reviewed [Voermans et al., 2009a; tension, intracranial hypertension, 2014; Castori et al., 2015]. Therefore, Savasta et al., 2011; Castori and craniocervical instability, and cervical EDS may be considered a risk factor for Voermans, 2014]. The following spine disorders, temporomandibular migraine. article discusses the etiology and joint disease, carotid dissection, and clinical findings related to neurologi- other physical conditions. Though a Etiology cal and spinal manifestations com- patient may suffer status migrainosis, Migraine often presents as a comorbid monly observed, yet often poorly constant pain is less likely to represent disorder with many other medical recognized, in EDS patients, and a migrainous headache [Headache conditions [Schurks et al., 2009; Casucci proposes treatment options and areas Classification Committee of the In- et al., 2012; Pierangeli et al., 2012; of research needed. ternational Headache Society (IHS), Gelfand et al., 2013; van Hemert et al., 2013]. 2014]. The final common pathway appears to be abnormal regulation of METHODS cerebral vasculature following a spread On the basis of a large shared experience of depression of cortical electrical in the treatment of EDS, the authors EDS patients commonly activity [Burstein et al., 2015; Ferrari were solicited to contribute a review of et al., 2015]. the neurological and spinal manifesta- suffer a variety of headache tions of EDS. The authors represent a types. These include Clinical and diagnostic findings working group within the International Defined as a primary headache disorder, Consortium on the Ehlers–Danlos Syn- headaches due to migraines, with recurrent attacks of moderate or dromes. In preparation for the EDS muscle tension, intracranial severe intensity, lasting 4–72 hr, mi- International Symposium 2016, the hypertension, craniocervical graine headaches are more often unilat- authors formed subcommittees to re- eral, pulsating, associated with nausea, search individual topics relating to EDS instability, and cervical spine photophobia, and phonophobia, which and its neurological presentations, and disorders, temporomandibular are disabling and worse with physical here present those findings in synthe- activity [Headache Classification Com- sized, topic-based fashion designed to joint disease, carotid mittee of the International Headache assist a wider audience of medical dissection, and other physical Society (IHS), 2013]. Migraine is usu- practitioners in caring for EDS patients, conditions. ally preceded by a prodrome and and in advancing research needs for this followed by fatigue, nausea, and dizzi- population. 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, nausea, and vomiting. Affected patients Stenting has emerged as an effective weather changes, sleep changes, menses, may have objective changes in vision treatment for IIH in select patients with seasonal allergies, and caffeine. Physical with 10% developing blindness [Corbett radiographic cerebral sinus stenosis and findings may include , hypersen- et al., 1982]. Female to male ratios range evidence of pressure gradients [Satti sitivity to pressure on certain muscles from 4:1 to 15:1, and obesity is an added et al., 2015]. and tendons, elevated blood pressure, risk factor [Radhakrishnan et al., 1993]. and heart murmur. Migraines may cause Anecdotal reports from large case series Areas Needing Investigation a benign episodic mydriasis. Findings have suggested an association between may be suggestive of a stroke. Diagnostic EDS and IIH, but no such association testing should exclude sleep disorders has been formally reported in the (1) The epidemiology and etiology of [Kothari et al., 2000], menstrual cycle biomedical literature. pseudotumor cerebri in EDS. dysfunction including menopause (2) Longitudinal studies to assess the efficacy [Nappi and Nappi, 2012; Ripa et al., and risks of medical therapy, shunting, Etiology 2015], and patent foramen ovale [Vol- and stenting in the EDS population. man et al., 2013]. Hypotheses proposed for the etiology of IIH include excess CHIARI I MALFORMATION Treatment (CSF) production, reduced CSF absorp- (CMI) Migraine therapies (e.g., botulinum tion, excessive brain water content, and toxin, triptans, caffeine, acupuncture, increased cerebral venous pressure lead- Epidemiology meditation) are legion, and testify to the ing to reduced CSF reabsorption [Ball diverse causes of migraine. Recognition and Clarke, 2006]. Recent studies dem- Chiari malformation Type I (CMI) has that migraine patients suffer multiple onstrate that up to 93% of patients with been reported as a comorbid condition pain disorders should prompt a holistic IIH have focal venous sinus stenosis on in hypermobile EDS (hEDS) [Milhorat treatment strategy or combination ther- MR venography, most commonly prox- et al., 2007]. The precise incidence of apies [Estemalik and Tepper, 2013; Kress imal to the transverse sigmoid sinuses the CMI and EDS association is un- et al., 2015]. junction, suggesting that venous abnor- known, but the female to male ratio is malities may play a role in the patho- higher (9:1) in the CMI and EDS Areas needing investigation physiology of IIH [Farb et al., 2003]. subgroup than in the general CMI population (3:1). The average age of (1) Connection between migraine, EDS onset tends to be younger in the CMI Clinical and Diagnostic Findings and mast cell activation syndrome and EDS subgroup, when compared to (MCAS), and cardiac functional/ The diagnosis of IIH requires symptoms the general CMI population. structural defects, such as postural of increased ICP.The visual disturbances orthostatic tachycardia syndrome are often associated with the finding of (POTS) and patent foramen ovale. papilledema or visual field defects. The (2) Connection between migraine and diagnosis is supported by increased ICP: Chiari malformation Type I > diet in EDS. 25 cm of H2O in the obese popula- (CMI) has been reported as a (3) Prevalence and impact of migraine in tion, or >20 cm H2O in the non-obese all types of EDS. population. There should be normal comorbid condition in (4) Treatment of migraine in EDS. composition of CSF, thus, excluding hypermobile EDS (hEDS). (5) Effect of other co-morbidities, med- inflammatory conditions, absence on The precise incidence of the ications, and nutrition in EDS related MRI, or contrast-enhanced CT of to migraine prevalence, severity, or hydrocephalus and of mass, structural, CMI and EDS association is treatment. or vascular lesions, and no other cause of unknown, but the female to intracranial hypertension. male ratio is higher (9:1) in IDIOPATHIC INTRACRANIAL Treatment the CMI and EDS subgroup HYPERTENSION (IIH) Treatments include lifestyle modifica- than in the general CMI tions targeting weight loss including population (3:1). Epidemiology bariatric surgery, decreasing CSF pro- IIH, or pseudotumor cerebri, is a poorly duction with acetazolamide, or serial understood entity characterized by an lumbar punctures, CSF diversion with a Etiology increased intracranial pressure (ICP), ventriculo-peritoneal or lumbo-perito- headaches, visual disturbances and pho- neal shunt, optic sheath fenestra- CMI is a mesenchymal disorder affecting tophobia, and occasionally tinnitus, tion, or subtemporal decompression. thehindbrain,inwhichadevelopmentally 198 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW small posterior fossa results in downward series of CMI post-decompression fail- There is sometimes trigeminal neuralgia migration of the brainstem and cerebellar ures that needed further intervention, [Milhorat et al., 1999; Tubbs et al., tonsils through the into including craniocervical fusion and/or 2011a; Yarbrough et al., 2011]. Brain- the [Batzdorf et al., 2015]. The tethered cord release. While this may stem findings, such as sleep apnea and herniation causes obstruction to the indicate a co-existence of these con- , are often found in CM normal regional circulation of the cerebro- ditions, it does not provide evidence of a that are complicated by craniocervical spinal fluid (CSF) and compartmentaliza- causal relationship, but suggests that instability or basilar invagination, the so- tion of CSF circulation [Ellenbogen et al., EDS and other disorders of connective called “complex Chiari.” 2000], which may result in suboccipital tissue should not be overlooked in CMI. pressure headaches. Obstruction of the Treatment CSF circulation may result in empty sella Clinical and Diagnostic Findings syndrome, with flattening of the pituitary There is no universally agreed upon gland and resulting hormonal changes. A The CMI is traditionally defined radio- surgical threshold for CMI, but surgery syrinx may form, which exerts a mass effect logically by 5 mm of tonsillar herniation should be urgently performed in the on the spinal cord, and rarely the brainstem through the foramen magnum, though presence of progressive neurological [Kahn et al., 2015]. There is increasing others have suggested a herniation of deficits, and expanding syringomyelia recognition of CMI variants [Milhorat 3 mm, or 7 mm. The behavior of CMI is (Fig. 1) [Yarbrough et al., 2011]. et al., 1999]. Some have suggested an often unrelated to the size of the The association of CMI and EDS is association of tethered cord syndrome and herniation, and CMI can be burdened by distinct management chal- CMI [Royo-Salvador, 1996]. asymptomatic. lenges, including craniocervical insta- The incidence, prevalence, and CM is best characterized by a bility, and possibly an increased risk of etiology of CMI and EDS occurring tussive headache (worse with cough, CSF leaks. CMI may be asymptomatic together are not fully understood. strain, or yelling), dizziness, cerebellar (incidence unknown), or mildly symp- However, Milhorat et al. [2007, findings—, incoordination, tomatic, so that surgical intervention 2010] found a high prevalence of imbalance, and unsteady gait—hearing may not be required [Novegno et al., patients with hereditary disorders of and vestibular deficits. Romberg’s 2008; Strahle et al., 2011]. Sporadic connective tissue in their retrospective sign, and deficits of . 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). RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 199 have been described [Castillo and Wilson, for instability. The atlantoaxial junction of C1 upon C2 > 41° (as assessed by CT 1995]. (AAJ)isthemostmobilejointofthebody. scan of C1-2) and retro-odontoid The AAJ mechanical properties are pannus on MRI [Fielding et al., 1978; determined by ligamentous structures, Taniguchi et al., 2008]. The difficulty Areas Needing Investigation most prominent of which are the trans- of recognizing rotary instability on verseandalarligaments[Tubbsetal., standard X-ray, CT, and MRI images (1) The incidence, prevalence, and etiol- 2011b]. has resulted in failure to diagnose ogy of CMI and its variants CM0 and Hypermobility of the AAJ is com- [Kothari et al., 2000]. CM 1.5 in the EDS population mon in children, and over 40° of remains unclear and needs larger data rotation may be observed in each Treatment registry direction, but in the adult there is (2) The Complex Chiari malformation, substantially less than 40° of rotation The first line of treatment should be though well described in the literature [Zhang and Bai, 2007; Martin et al., brace, physical therapy, and avoidance of (see section on craniocervical instabil- 2010]. At 35° of rotation of C1 upon activities that provoke exacerbation of ity), is not universally recognized C2, there is stretching and kinking the AAI symptoms. If the non-operative among those who perform Chiari of the contralateral vertebral artery treatment fails, fusion stabilization of C1/ surgery. Prospective studies in EDS [Selecki, 1969]. At 45°, both vertebral C2 is required. Incompetence of the alar patients with Complex Chiari malfor- arteries become occluded [Menezes and ligament requires dorsal surgical fusion mation are needed to compare out- Traynelis, 2008]. [Menendez and Wright, 2007]. Occiput comes following decompression alone to C1/C2 fusion should be considered in versus those undergoing decompres- the presence of craniocervical instability, Clinical and Diagnostic Findings sion with fusion/stabilization. basilar invagination, or complex Chiari The diagnosis of AAI is predicated upon malformation. disabling or suboccipital pain, ATLANTOAXIAL and INSTABILITY Areas Needing Investigation (1) history and clinical findings of cervical Epidemiology medullary syndrome, or syncopal (or (1) The prevalence and natural history of Atlantoaxial instability (AAI) is a poten- pre-syncopal) episodes, AAI in the EDS population. tial complication of all forms of EDS. (2) demonstrable neurological findings, and (2) Theimportanceofdynamicimag- Motor delay [Jelsma et al., 2013], (3) radiological evidence of instability or ing studies (such as CT with rota- headache associated with “connective compression of the neuroaxis. tion of the cervical spine to extreme tissue pathological relaxation” and Neck pain and suboccipital head- left and right, requires further quadri-paresis have all been attributed ache are the most common findings, validation to promote a generalized to ligamentous laxity and instability at with the caveats that headache is a adoption of these studies to diag- the atlantooccipital, and atlantoaxial common occurrence in EDS patients nose AAI, and to prompt greater joints [Nagashima et al., 1981; Halko [Castori and Voermans, 2014]. There availability of dynamic imaging et al., 1995]. may be symptoms referable to the facilities). vertebral artery blood flow, including (3) Surgical outcomes for treatment of visual changes, as well as headache rotational instability and the long- Epidemiology resulting from vertebral artery torsion. term outcome in EDS. The epidemiology of AAI in hEDS is Syncopal and pre-syncopal events are unknown. AAI was seen in two of frequent. Other symptoms include diz- CRANIOCERVICAL three patients with vascular EDS ziness, nausea, sometimes facial pain, INSTABILITY [Halko et al., 1995]. A high risk of , choking, and respiratory AAI is apparent in other disorders issues. Symptoms usually improve with Epidemiology affecting connective tissue, including a neck brace. Down syndrome, , Neurological examination dem- Craniocervical instability (CCI) is and [MacKenzie onstrates tenderness over spinous pro- recognized as a manifestation of and Rankin, 2003; Hankinson and cess of C1 and C2, altered mechanics ligamentous laxity in EDS [Naga- Anderson, 2010]. of neck rotation, hyperreflexia, dysdia- shima et al., 1981; Milhorat et al., dochokinesia, and hypoesthesia to 2010]. Ligamentous laxity has been pinprick. Weakness is not a constant showntoresultinneuraxialinjury Etiology feature of AAI. [Lindenburg and Freytag, 1970; Hen- A proclivity to ligamentous incompetence A number of radiological features derson et al., 1993; Menezes and renders the atlanto-axial joint a higher risk have been described, including rotation Traynelis, 2008]. 200 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

Etiology [Arundine et al., 2004], and apoptosis invagination: the clivo-axial angle, the [Liu et al., 1997; Arundine et al., 2004]. Harris measurement, and the Grabb, CCI is a pathological condition in Mapstone, Oakes method [Batzdorf which ligamentous connections from et al., 2015; NINDS Common Data Clinical and Diagnostic Findings the skull to the spine are incompetent. Elements, 2016]. The Clivo-axial angle Motor delay, developmental co- CCI-related symptoms result from de- (CXA) is the angle formed between the ordination disorder, headaches second- formation of the brainstem and upper posterior aspect of the lower clivus and the ary to spinal compression, clumsiness, spinal cord, traction on the vertebral posterior axial line. The CXA has a normal and the relatively high rate of dyslexia artery, and possibly from the consequen- range of 145° to 160°, but an angle of less and dyspraxia in the EDS population ces of altered venous or CSF outflow than 135° is pathological [Henderson et al., merit investigation as possible conse- from the cranium. CCI often occurs with 1993; Henderson et al., 2010a; Batzdorf quences of early onset degenerative basilar invagination or ventral brainstem et al., 2015]. Increasing kyphosis of clivo- changes resulting from ligamentous compression, the findings of which are axial angle (i.e., a more acute CXA) creates laxity upon the dominated by pyramidal and sensory a fulcrum by which the odontoid deforms [Nagashima et al., 1981; Adib et al., changes: weakness of the limbs hyper- the brainstem [Menezes, 2012]. The 2005]. The most prominent movement reflexia and pathological reflexes (e.g., medulla becomes kinked as the CXA of the atlanto-occipital joint is flexion- Babinski, Hoffman’s sign, absence of the becomes more kyphotic. extension; axial rotation is normally abdominal reflex), , and a The second radiologic metric, the limited to <5 degrees of rotation plethora of other symptoms—including horizontal Harris measurement, is the [Dvorak et al., 1987]. sphincter problems, headache, neck pain, distance from the basion to the posterior There is increased recognition of dizziness, vertigo, dyspnea, dysphonia, axial line (PAL) [Harris et al., 1994]. mechanisms of neuronal injury that altered vision, and hearing, syncope, Instability is present when the basion to result from stretching, or deformative emesis, altered sexual function, altered the PAL exceeds 12 mm. This measure- stress [Jafari et al., 1997; Maxwell et al., menses, and gait changes [Caetano de ment, used in conjunction with dy- 1999; Shi and Whitebone, 2006]. The Barros et al., 1968]. These signs, in namic flexion and extension images of consequent formation of axon retrac- aggregate, constitute the cervical medul- the cervical spine, can also be used to tion balls is similar to that seen in diffuse lary syndrome [Batzdorf et al., 2015], measure the dynamic translation be- axonal injury of the brain (Fig. 2) elements of which are commonly tween the basion and the odontoid [Geddes et al., 2000; Henderson et al., recorded among EDS patients [Celletti [Batzdorf et al., 2015; NINDS Com- 2005]. Stretching of neurons causes et al., 2012]. mon Data Elements, 2016]. In the pathological calcium influx [Wolf Threemetricsmaybeusefulin normal individual, there should be et al., 2001], altered gene expression the identification of CCI and basilar no measurable translatory movement

Figure 2. Axon retraction bulbs in the upper spinal cord, from cadaveric studies of subjects with basilar invagination (Microscopic photograph (Â500), axial section of the dorsal column at the C2 level. Silver stain). RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 201

(sliding movement). Translation of ventral brainstem compression [Grabb are important to determine whether greater than 1 mm between the basion et al., 1999]. there is pathological hypermobility at and odontoid reflects craniovertebral There is a relatively nascent recog- the craniocervical junction [Klekamp, instability, and may warrant stabilization nition of the importance of dynamic 2012]. (Fig. 3) [Wiesel and Rothman, 1979; imaging of the CCJ. For example, the White and Panjabi, 1990]. brainstem may appear normal on rou- Treatment The third metric, the Grabb, Map- tine magnetic resonance imaging in the stone, and Oakes measurement predicts supine position, but show pathological Indications for surgery include severe risk of ventral brainstem compression, ventral brainstem compression in the headache, symptoms which constitute and has been statistically correlated with flexion view sitting upright [Klimo Jr the cervical medullary syndrome, clinical outcome [Grabb et al., 1999; et al., 2008; Henderson et al., 2010b; neurological deficits referable to the Henderson et al., 2010b]. A measure- Milhorat et al., 2010]. “Functional” brainstem and upper spinal cord, ment >9 mm suggests high risk of dynamic studies in flexion and extension 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). 202 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW failure of a reasonable course of non- importance of the dentate ligaments in operative therapy. Though there are applying stressors to the spinal cord, no established criteria for treatment of with the subsequent result of focal CCI in EDS, there is abundant The prevalence of cervical and myelopathy [Cusick et al., 1977]. literature addressing the diagnosis of thoracic segmental instability CCI [White and Panjabi, 1990; Harris Clinical and Diagnostic Findings et al., 1994; Batzdorf et al., 2015], and in the population of patients the treatment of CCI with craniocer- with hypermobility syndromes Clinical findings include pain and vical stabilization in various congenital has not been well established. disability, as well as sensory, motor, or degenerative connective tissue dis- and reflex changes. Radiculo-myelop- orders [Nagashima et al., 1981; Goel However, discopathy and athy may manifest in an acute, sub- and Sharma, 2005; Henderson et al., early degenerative spondylotic acute, or chronic manner as radicular 2010b; Milhorat et al., 2010; Tubbs and dermatomal or non-radicular et al., 2011a; Klekamp, 2012; Yoshi- disease in hEDS and classical myelopathic hypoesthesia, hyperes- zumi et al., 2014]. type EDS is well established. thesia, or , and less often weakness. Over time, there may be EDS is characterized by ascending numbness, spasticity, Lher- Areas Needing Investigation segmental instability, mitte’s sign, and eventually leg weak- kyphosis, and . ness, altered gait, clumsiness, and long (1) Prevalence and natural history of axial tract findings. There is often marked ligamentous instability in EDS. tenderness to palpation over unstable (2) Validation of radiological metrics for motion segments. determining CCI in the EDS Etiology Clinical differential diagnoses in the population. EDS population should be kept in mind: (3) Development of an international Ligamentous laxity is an important instability at the atlanto-occipital and data registry using the NINDS determinant in the development of atlantoaxial joints, shoulder, clavicular Common Data Elements [2016] to spinal instability other connective dis- and rib subluxations, brachial plexop- facilitate therapeutic trials for CCI orders such as rheumatoid arthritis, athy, vascular anomalies, dissection or in EDS. Down syndrome and osteogenesis im- venous insufficiency, peripheral neurop- perfecta, but there have been no series to athy, multiple sclerosis, amyotrophic demonstrate this linkage in EDS. The lateral sclerosis, myasthenia gravis, mye- SEGMENTAL KYPHOSIS importance of ligamentous laxity is lopathy due to drugs—such as statins, AND INSTABILITY increasingly appreciated among clini- colchicine, steroids- vitamin deficiency, cians [Tredwell et al., 1990; Steilen et al., especially B12 and B3, mitochondrial Epidemiology 2014]. dysfunction, stroke, and psychological Theprevalenceofcervicalandtho- The pathophysiology of segmental disorders. racic segmental instability in the instability is well described: during Though CT scans and MRI remain population of patients with hyper- flexion, there is deformation of the the standard for most practitioners, mobility syndromes has not been well lateral and ventral columns of the spinal radiological findings do not always established. However, discopathy and cord, directly related to the strain on the correlate well with clinical findings or early degenerative spondylotic disease cord [Henderson et al., 2005; Shedid surgical outcome [Arnasson et al., in hEDS and classical type EDS is well and Benzel, 2007]. Extension more 1987]. Dynamic instability is unlikely established. EDS is characterized by often results in compression of the to be demonstrated in a resting supine segmental instability, kyphosis, and cord by buckling of the ligamentum subject, and pathological instability will scoliosis. Spondylosis, defined by the flavum, resulting in myelopathic symp- often become manifest only when the presence of non-inflammatory disc toms [Muhle et al., 1998]. The cervical ligaments are placed under stress. degeneration, is usually preceded by spinal cord can be physiologically teth- Though not yet validated, dynamic mild segmental instability [Shedid ered in the sagittal plane, such that MRI in the upright position subjects and Benzel, 2007]. As a consequence normal cord elongation in flexion is the vertebral spine to physiological of cervical and thoracic instability, exaggerated by the kyphosis; this results loading, and can be performed in the anddiscopathyinEDS,thereislossof in increased deformity and anatomic flexed and extended positions to dem- thenormalcervicallordosisandan stretching of the cord. This “sagittal onstrate instability (Fig. 4) [Milhorat increasing kyphosis, rendering EDS bowstring effect” underlies a physiolog- et al., 2010; Klekamp, 2012]. patients prone to progressive myelop- ical tethering effect, with resulting White and Panjabi [1990] have athy, and mechanical neck and chest neurological deficits [Shedid and Ben- defined the reference ranges for flex- pain. zel, 2007]. Others have recognized the ion, extension, lateral tilt, and rotation RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 203 at each level of the spine. Radiological Treatment are refractory to conservative manage- findings of segmental instability may ment, fusion, and stabilization of unsta- include evidence of spinal cord com- Initial management includes neck brac- ble levels may be indicated. pression or deformity, hyper-angula- ing and physical therapy with therapists The rate of adjacent segment de- tion at one or more segmental levels who are knowledgeable regarding liga- generation (the tendency for increased (>11.5° angulation between adjacent mentous laxity including EDS, attain- degeneration of discs adjacent to fused , subluxation >3 mm), and the ment of a good sagittal balance, and motion segments) has not been deter- presence of pathological longitudinal avoidance of certain activities. Rest will mined in the EDS population, but should stretching. often improve symptoms. If symptoms 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). 204 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW motion-sparing technology may be an with the dural sac at kyphosis, functional ankle and foot important option in this population, the S2 level. The filum contains neural, deformities (ankle pronation with phys- though there is yet no published litera- glial, and ependymal remnants that stem ical strain), and pes planus or pes cavus ture in the EDS population. from embryonic spinal cord which [Hoffman et al., 1976; Pang and begin to regress at 9–10 weeks of Wilberger, 1982]. gestation [Jang et al., 2016]. The Urodynamic testing is important in Areas Needing Further presence of fatty tissue, “nerve twigs” the diagnosis of TCS. Neurogenic Investigation (dysplastic axons), fat and vascular bladder manifestations may range from lacunes, and suspicion of “congested” urinary retention and detrusor under- (1) Definition, prevalence and natural veins, are usually seen in the abnormal activity to urinary incontinence, over- history of segmental instability in the fila specimens obtained from patients activity of the detrusor, and sphincter EDS population. with TCS [Thompson et al., dysfunction [Tu and Steinbok, 2013]. (2) Clinical history of segmental instabil- 2014] Stretching of the spinal cord by While formal urodynamic criteria have ity after stabilization, including rates of the structurally abnormal filum is the not been established for TCS, detrusor adjacent segment degeneration in presumed mechanism of TCS. Symp- sphincter dysynergia, large post void different types of EDS. toms may become more apparent as a residual, and very large bladder capacity (3) Studies to improve diagnostic efficacy child grows. Forcible flexion and (>800 ml) are good urodynamic indi- of segmental instability utilizing up- stretching is often deemed responsible cators of a neurogenic bladder. Urody- right MRI. for adult onset of TCS [Aufschnaiter namics can help to differentiate the et al., 2008]. Poor blood flow and neurogenic bladder of TCS from that oxidative stress in the spinal cord have due to diabetes or bladder obstruction TETHERED CORD also been implicated in animal models as from prostatic hypertrophy. SYNDROME mechanisms of neuronal injury [Yamada MRI of the cervical, thoracic, and Tethered cord syndrome (TCS) in EDS et al., 2007]. lumbar spine is required to rule out is most often associated with a structur- other causes of leg weakness and low ally abnormal , and , such as disc herniation, Clinical and Diagnostic Findings usually characterized by , stenosis, neoplasm, and the clinical triad of neurogenic TCS is characterized by aching/burning or intrinsic lesions of the spinal cord— bladder, lower extremity weakness pain in the low back, legs and feet, and such as multiple sclerosis or signs of and sensory loss, and musculoskeletal sensori-motor findings in lower extrem- trauma. The MRI may show low lying abnormalities. ities: weakness is common, with heavi- conus (below the mid L2 level), fatty ness, stiffness, and tightness of legs and infiltration, a stretched or thickened cramps; paresthesias in the pelvic area or filum, a syrinx in the lower spinal cord, Epidemiology legs and hypoesthesia to pinprick in the scoliosis or occulta. The The incidence of the specific diagnosis lumbar and sacral dermatomes is often term “occult tethered cord” (OTCS) of TCS is unclear, both within the observed. Findings are often asymmet- refers to where the MRI shows a normal general and EDS populations in the ric. A history of toe-walking may be position of the conus [Tu and Steinbok, United States [Bui et al., 2007]. The elicited. Urological findings include 2013]. A large diameter of the filum prevalence of TCS in a diverse sample of urinary hesitancy, frequency, urgency, terminale in axial T2 studies is a positive Turkish school children was 0.1% retention/incomplete emptying, noctu- indicator that favors untethering in the [Bademci et al., 2006]. In a cohort of ria, irregular urinary stream, sensory loss presence of TCS [Fabiano et al., 2009]. 2,987 consecutively evaluated patients of the bladder, frequent urinary tract Controversy exists over whether it with diagnoses of CMI or “low lying” infections, and incontinence. is necessary to radiologically demon- cerebellar tonsils (LLCT, tonsillar de- There is often enuresis into late strate a “low lying conus medullaris,” scent 0–4 mm), Milhorat et al. childhood. There may be fecal inconti- that is, a conus ending at the lower L2 [2009] found TCS, using a definition nence, constipation, or sexual dysfunc- level or below. There has been the that allowed for normal position of the tion. As TCS results in a combination of intuitive presumption that a low-lying conus medullaris on MRI (i.e., at or upper and lower motor neuron injury, conus represents a spinal cord under above, the L1 vertebra), in 14% of the there is often hyperreflexia in the lower tension. However, this presumption has CMI patients they examined and in 63% extremities, but normal reflexes in the not been verified, and indeed, there are of the LLCT cohort. arms. The legs are usually weak, with no epidemiological studies which allow normal upper extremity strength. Sen- the definition of a specific imaging sory loss is usually prominent in the finding to establish the diagnosis of Etiology lumbar and sacral dermatomes, but TCS. Nor are there epidemiological The filum comprises a fibrous, collage- normal in the arms and trunk. Ortho- studies in the normal population that nous, and elastic band that connects the pedic deformities include scoliosis, demonstrate specific findings that RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 205 exclude TCS. On the other hand, there Areas Needing Research Etiology is a growing body of evidence that Pain and trauma are frequent compo- supports the clinical diagnosis of TCS nents of EDS, and there is a significant with or without the radiological (1) Prospectively and retrospectively eval- body of literature suggesting movement demonstration of a low-lying conus uate specific clinical features and disorders may arise from extracranial medullaris, which justifies surgical in- radiological metrics for predictive trauma. Post-traumatic dystonia may tervention when the clinical criteria are accuracy, to establish validated inclu- develop in a limb following trauma to met [Tu and Steinbok, 2013]. sion and exclusion criteria for future that limb [van Rooijen et al., 2011]. studies regarding TCS. This may be one mechanism that (2) Determine the incidence of TCS in Treatment of TCS establishes a link between EDS and EDS patients. movement disorders. However, while There is no standard technique in the (3) Determine epidemiologically whether several of the authors have strong clinical surgical treatment of TCS. Generally, TCS is a co-morbid feature of CMI suspicion of a connection, there are no the lamina is removed, anywhere in EDS. published studies that confirm that from L2 to S1, a durotomy is made, (4) Validate outcome measures by which movement disorders are a co-morbidity and electrical stimulation is used to to determine the surgical outcomes. of hEDS [Rubio-Agusti et al., 2012]. confirm the absence of any nerve (5) Establish complication rates for TCS While dystonia in joint hypermo- roots which may be associated with surgery in the EDS population. bility syndromes (JHS) have been the filum. Finally, a microsurgical observed, causality has not been demon- resection of the filum terminale DYSTONIAS AND OTHER strated. In one large series, one third of (usually a 10 mm segment for pathol- MOVEMENT DISORDERS patients with “fixed dystonia” were ogy) is performed (Fig. 5). The filum found to have JHS [Kassavetis et al., tends to be taut, and to briskly retract Epidemiology 2012]. The authors suggested that move- upon sectioning. However, findings ment avoidance may have been adopted are variable, and there is no evidence Movement disorders can be broadly to avoid pain, and in time resulted in fixed to suggest that the intraoperative divided into hyperkinetic disorders dystonia. The etiology of the fixed findings predict or correlate with (too much movement) or hypokinetic dystonia has also been variously attrib- the surgical outcome and severity of movement occurring in the conscious uted to peripheral injury [van Rooijen the TCS [Pang and Wilberger, 1982; state. The hyperkinetic movement dis- et al., 2011], and psychogenic movement Milhorat et al., 2009]. In some cases, orders—including dystonia, tremor, disorder [Hallett, 2016]. it may be necessary to perform a chorea, myoclonus, and tic disorders— lumbar stabilization across the are observed in the EDS population motion segment in which the filum according to anecdotal reports from Clinical and Diagnostic Findings was sectioned. The resected filum large series of patients, but have not should be sent for histopathological been documented in the peer-reviewed Neurological evaluation and EEG to evaluation. literature. 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). 206 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

The diagnosis of psychogenic move- limited walking distance; physical find- However, TNX deficiency accounts for ment disorder has been met with some ings include , reduction only a very small percentage of patients skepticism [Palmer et al., 2016], but is of vibration sense, and mild impairment with hEDS. Reduced quantitative mus- distinguished from malingering, and of mobility and daily activities [Voer- cle function appears to be secondary to thought to result from psychological mans et al., 2009b]. muscle dysfunction rather than reduced causes [Hallett, 2016]; it is characterized muscle mass [Rombaut et al., 2012]. by involuntary, disabling movements, Abnormal myo-tendinous junctions in abrupt in onset, a waxing/waning the muscle belly [Penisson-Besnier et al., course, changes in the nature of the Musculoskeletal pain starts 2013], mild to moderate myopathy and/ movement over time, worsening with early, is chronic and or neuropathy, and defects of the stress, anxiety or depression, and im- extracellular matrix of the connective provement with distraction; they are debilitating. Neuromuscular tissue investing muscle and peripheral difficult to diagnose and treat. Prognosis disease manifests nerve may increase muscle dysfunction for improvement is better in patients symptomatically with muscle [Voermans et al., 2009b, 2012; Syx et al., with a shorter duration of illness [Lang, 2015]. 2006]. weakness, myalgia, easy The pathophysiological mechanism fatigability, and limited of peripheral neuropathy in hEDS appears, in part, to result from abnormal Treatment walking distance; physical stretching and pressure upon peripheral There is no established treatment algo- findings include muscle nerves that results from joint subluxa- rithm for movement disorders in pa- tion. The connective tissue of peripheral tients with EDS. weakness, reduction of nerves might fail to resist excessive vibration sense, and mild mechanical stress: increased vulnerabil- ity is linked to underlying genetic Areas Needing Research impairment of mobility and defects in TNXB, collagens I, III, daily activities. or V deficient epi-, peri-, and endo- (1) Establish studies to determine the neurium [Voermans et al., 2009b; epidemiology and etiology of move- Granata et al., 2013]. This defect might ment disorders in EDS, and to Brachial and/or lumbosacral plexus also relate to the occurrence of axonal demonstrate whether there is a co- neuropathies and other compression polyneuropathy in various types of EDS morbid relationship. mono-neuropathies are not uncommon [Muellbacher et al., 1998]. (2) Develop evidence-based treatment in EDS [Voermans et al., 2006; van Abnormal extracellular matrix in strategies for movement disorders in Rooijen et al., 2011]. The presence of generalized connective tissue structure the EDS population. or small-fiber neuropathy suggests molecular overlap between probably explains a higher prevalence of inherited connective tissue disorders neuropathic symptoms (paresthesias/ and certain congenital myopathies, NEUROMUSCULAR numbness in hands or feet) than regis- awareness of which may be helpful in FEATURES OF EHLERS- tered on neurophysiological or ultra- recognition of these rare disorders DANLOS SYNDROME sound testing. There is a high prevalence [Voermans et al., 2008; Donkervoort of ulnar nerve luxation at the elbow et al., 2015]. Epidemiology detected on dynamic ultrasound [Gran- EDS, especially hEDS, is associated with ata et al., 2013]. Clinical and Diagnostic Features high prevalence of myalgia, nocturnal muscle cramps involving the calves, The approach to neuromuscular symp- Etiology hypotonia, progressive muscle weak- toms and signs, and helpful ancillary ness, poorly developed musculature, Some pathophysiologic studies are avail- investigations has been thoroughly and scapular winging, which to some able on the relationship between tenas- reviewed [Merrison and Hanna, extent may be the result of avoidance of cin-x(TNX) deficient EDS and 2009], and supplemented by the exercise due to hypermobility and neuromuscular complications. Human WUSTL database on neuromuscular instability of joints [Banerjee et al., and murine studies suggest a correlation disorders. 1988; Palmeri et al., 2003]. between TNX levels and degree of Musculoskeletal pain starts early, is neuromuscular involvement, and a cor- Treatment chronic and debilitating [Voermans responding role of the extracellular et al., 2010]. Neuromuscular disease matrix defect in muscle and peripheral A recent study on medical consumption manifests symptomatically with muscle nerve dysfunction in EDS [Huijing and outcome reported the impact of weakness, myalgia, easy fatigability, and et al., 2010; Voermans et al., 2011]. pain upon daily functioning in hEDS. RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 207

Most patients (92%) used pain medi- meningocele principally affects males, from a mediastinal cystic extension behind cations; 52% underwent physical fills the sacrum, and typically involves the trachea. therapy—including neuromuscular ex- all of the sacral roots. Dural ectasia may The most common syndrome, ercises, massage, and electrotherapy—of present with large intra-abdominal occurring in approximately 70% of whom two thirds reported a positive cysts associated with connective dis- symptomatic patients, is comprised of outcome. The study concluded that the orders [Nabors et al., 1988; Stern, sacral pain, worse when sitting and impaired functional status of hEDS 1988]. standing, and improved when lying patients strongly determined the high There is a general presumption that down; pain in the S2–S5 dermatomes rate of treatment consumption, which these cystic abnormalities, including in the pelvis and perineum, in underscores the importance of develop- Tarlov cysts, are incidental findings. the Sl and S2 dermatomes, and less ment of evidence-based guidelines for However, the belief that all Tarlov cysts commonly L5 root dermatome. Bowel treatment [Rombaut et al., 2011]. There are asymptomatic has no support in the and bladder dysfunction are common. is increasing evidence that treatment literature. An unpublished review at One third of patients have bowel and should consist of a multidisciplinary Johns Hopkins on 756 patients with bladder dysfunction, and sensory com- program. One study demonstrated suc- symptomatic spinal cysts, found 18 with plaints related to nerve roots S2, S3, S4 cess combining physical therapy, cogni- large sacral internal meningoceles with without sciatica. A small group of tive behavioral therapy, and group dramatic associated sacral erosion, of patients have bowel and bladder dys- therapy, followed by individual home whom 16 were women with Marfan function and sacral root sensory loss exercises and weekly guidance by phys- disease or EDS. The remainder had without pain. iotherapist for three months, then typical Tarlov cysts, with a female to readmission for reevaluation and further male ratio of seven to one, usually on training advice. Patients reported im- sacral nerve roots. A small number Treatment proved performance of daily activities, existed on the lumbar, thoracic or Of patients undergoing surgical obliter- muscle strength and endurance, reduced cervical roots. Delay in treatment re- ation of the Tarlov cysts, successful kinesiophobia, and increased participa- sulted because most patients had been outcomes are reported in 80–88% of tion in daily life [Bathen et al., 2013]. told that the cysts were asymptomatic patients, with few complications [Voy- and did not need to be treated, or that no adzis et al., 2001; Feigenbaum and satisfactory treatment existed, or that Areas Needing Research Henderson, 2006]. Alternatively, pa- treatment was too dangerous to con- tients may undergo aspiration of the template. Rarely, there may be massive cyst and injection of the cysts with fibrin (1) The contributions of the various dilatation of the lumbar and sacral thecal glue, although the results are less causative factors to muscle dysfunction sac, with extensions of the subarachnoid satisfactory [Patel et al., 1997]. in EDS, including increased compli- space along nerve roots and into abdo- ance of the series-elastic component of men and pelvis. muscle tissue, failure of maximal Areas Needing Research voluntary muscle activation, and im- Etiology paired proprioception. (2) Clinical trials of physical training and The finding of inflammatory cells in (1) Determine the prevalence of Tarlov cognitive behavioral therapy on mus- the walls of symptomatic Tarlov cysts cysts in the general population and the cle strength and endurance in EDS [Voyadzis et al., 2001] begs comparison hEDS and classic type EDS patients. with the recent findings inflammatory populations. (3) The development of evidence-based cells in the fila terminale of EDS patients (2) Define the ratio of symptomatic versus guidelines to improve muscle strength. with TCS [Klinge, 2015]. asymptomatic patients, and the factors that appear to trigger pain. (3) Compare the pathophysiology of Tar- TARLOV CYST SYNDROME Clinical and Diagnostic Findings lov cysts in the general population Tarlov cysts are a radiological diagnosis. versus the EDS population. Epidemiology The Tarlov cysts appear primarily in the (4) A prospective randomized trial to Tarlov cysts are perineurial cysts that sacrum, at the level of the root ganglia, compare treatments: surgical resection may impose pressure upon adjacent causing erosion of the surrounding bone versus aspiration and injection of fibrin neural structures. Numerous small sur- (Fig. 6). Cervical and thoracic Tarlov cysts glue. gical series describe the spectrum of may produce pain and neurological (5) Longitudinal studies of natural and pathology, but there is significant con- symptoms or deficits in the distribution clinical history of Tarlov cysts in EDS. fusion in the reported literature with of the involved nerve root, or myelopathic (6) Utility of urodynamic studies as op- other cystic structures: the sacral me- from an extradural or subarachnoid cyst in posed to patient report for symptoms ningocele and dural ectasia. The sacral the high thoracic region, or symptomatic of neurogenic bladder. 208 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

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’clock position (T2 weighted MRI, 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 childhood. A not so benign multisystem on 12 women. Am J Med Genet disorder? Rheumatology 44:744–750. 161:3005–3011. Incompetent connective tissue results in Arnasson O, Carlsson C, Pellettieri L. 1987. Batzdorf U, Henderson F, Rigamonti D. 2015. Surgical and conservative treatment of Consensus statement. In Co-morbidities lax ligaments within the axial skeleton, cervical spondylotic radiculopathy and my- that complicate the treatment and outcomes peripheral nerve sheaths, and possibly elopathy. Acta Neurochir 84:48–53. of Chiari malformation. Lulu: Ulrich Batz- the architecture of the myoneural and Arundine M, Aarts M, Lau A, TymianskiM. 2004. dorf (Hardcover). Vulnerability of central neurons to secondary Bendik EM, Tinkle BT, Al-shuik E, Levin L, muscular endplates. Ligamentous laxity insults after in vitro mechanical stretch. Martin A, Thaler R, Atzinger CL, Rueger J, of the axial skeleton in particular, J Neurosci 24:8106–8123. Martin VT. 2011. Joint hypermobility subjects the central and radicular ner- Aufschnaiter K, Fellner F,Wurm G. 2008. Surgery syndrome: A common clinical disorder in adult onset tethered cord syndrome associated with migraine in women. Ceph- vous system to entrapment, deforma- (ATCS): Review of literature on occasion alalgia 31:603–613. tion, and biophysical deformative of an exceptional case. Neurosurg Rev Bui CJ, Tubbs S, Oakes WJ. 2007. Tethered cord stresses. Biophysical stress is increasingly 31:371–384. syndrome in children: A review. Neurosurg Bademci G, Saygun M, Batay F, Cakmak A, Basar Focus 23:E2. recognized in the alteration of gene H, Anbarci H, Unal B. 2006. Prevalence of Burstein R, Noseda R, Borsook D. 2015. expression, cellular function, and ulti- primary tethered cord syndrome associated Migraine: Multiple processes, complex mately phenotypic expression. Clinical with occult spinal dysraphism in primary pathophysiology. J Neurosci 35:6619–6629. school children in Turkey. Pediatr Neuro- Caetano de Barros M, Farias W, Ataide L, Lins S. practice guidelines, based upon stronger surg 42:4–13. 1968. Basilar impression and Arnold-Chiari epidemiological and pathophysiological Ball AK, Clarke CE. 2006. Idiopathic intracranial malformation. A study of 66 cases. J Neurol evidence, are needed for the diagnosis hypertension. Lancet Neurol 5:433–442. Neurosurg Psychiatry 31:596–605. Banerjee G, Agarwal RK, Shembesh NM, el Castillo M, Wilson JD. 1995. Spontaneous and treatment of the various neurologi- Mauhoub M. 1988. Ehlers–Danlos syn- resolution of a Chiari I malformation: MR cal and spinal manifestations of EDS. drome-masquerading as primary muscle demonstration. AJNR Am J Neuroradiol disease. Postgrad Med J 64:126–127. 16:1158–1160. Bathen T, Hångmann AB, Hoff M, Andersen LØ, Castori M, Voermans NC. 2014. Neurological Rand-Hendriksen S. 2013. Multidisciplinary manifestations of Ehlers–Danlos syndrome- REFERENCES treatment of disability in ehlers-danlos syn- (s): A review. Iran J Neurol 13:190–208. drome hypermobility type/hypermobility Castori M, Morlino S, Ghibellini G, Celletti C, Adib N, Davies K, Grahame R, Woo P,Murray K. syndrome: A pilot study using a combination Camerota F, Grammatico P. 2015. Connec- 2005. Joint hypermobility syndrome in of physical and cognitive-behavioral therapy tive tissue, Ehlers–Danlos syndrome(s), and RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 209

head and cervical pain. Am J Med Genet Part Grabb PA, Mapstone TB, Oakes WJ. 1999. Ventral Jelsma LD, Geuze RH, Klerks MH, Niemeijer AS, C Semin Med Genet 169C:84–96. brain stem compression in pediatric and Smits-Engelsman BC. 2013. The relation- Casucci G, Villani V, Cologno D, D’Onofrio F. young adult patients with Chiari I malfor- ship between joint mobility and motor 2012. Migraine and metabolism. Neurol Sci mations. Neurosurgery 44:520–527. performance in children with and without 33:S81–S85. Granata G, Padua L, Celletti C, Castori M, the diagnosis of developmental coordination Celletti C, Galli M, Cimolin V, Castori M, Saraceni V, Camerota F. 2013. Entrapment disorder. BMC Pediatr 13:35. Albertini G, Camerota F.2012. Relationship neuropathies and polyneuropathies in joint Kahn EN, Muraszko KM, Maher CO. 2015. between fatigue and gait abnormality in joint hypermobility syndrome/Ehlers–Danlos Prevalence of Chiari I malformation and hypermobility syndrome/Ehlers–Danlos syndrome. Clin Neruophysiol 124: Syringomyelia. Neurosurg Clin N Am syndrome hypermobility type. Res Dev 1689–1694. 26:501–507. Disabil 33:1914–1918. Halko GJ, Cobb R, Abeles M. 1995. Patients with Kassavetis P,Batla A, Parees I, Saifee TA, Schrag A, Corbett JJ, Savino PJ, Thompson HS, Kansu T, type IV Ehlers–Danlos syndrome may be Cordivari C, Bhatia KP, Edwards MJ. 2012. Schatz NJ, Orr LS, Hopson D. 1982. Visual predisposed to atlantoaxial subluxation. Joint hypermobility syndrome: A risk factor loss in pseudotumor cerebri. Follow-up of J Rheumatol 22:2152–2155. for fixed dystonia? Mov Disord 27:1070. 57 patients from five to 41 years and a profile Hallett M. 2016. Functional (psychogenic) move- Klekamp J. 2012. Neurological deterioration after of 14 patients with permanent severe visual ment disorders—Clinical presentations. Par- foramen magnum decompression for Chiari loss. Arch Neurol 39:461–474. kinsonism Relat Disord 22:S149–S152. malformation Type I: Old or new pathol- Cusick JF, Ackmann JJ, Larson SJ. 1977. Mechan- Hankinson TC, Anderson RC. 2010. Craniover- ogy? J Neurosurg Pediatr 10:538–547. ical and physiological effects of dentatotomy. tebral junction abnormalities in Down Klimo P Jr, Kan P, Rao G, Apfelbaum R, J Neurosurg 46:767–775. syndrome. Neurosurgery 66:32–38. Brockmeyer D. 2008. Os odontoideum: Donkervoort S, Bonnemann C, Loeys B, Jung- Harris JH Jr., Carson GC, Wagner LK. 1994. Presentation, diagnosis, and treatment in a bluth H, Voermans N. 2015. The neuro- Radiologic diagnosis of traumatic occipito- series of 78 patients. J Neurosurg Spine muscular differential diagnosis of joint vertebral dissociation: 1. Normal occipito- 9:332–342. hypermobility. Am J Med Genet 169:23–42. vertebral relationships on lateral radiographs Klinge PM. Histopathological evidence of clinically Dvorak J, Hayek J, Zehnder R. 1987. CT- of supine subjects. AJR Am J Roentgenol relevant filum pathology in Tethered Cord functional diagnostics of the rotatory insta- 162:881–886. Syndromes with little radiographic evidence bility of the upper cervical spine: Part 2. Headache Classification Committee of the Inter- including hypermobility syndromes. CSF An evaluation on healthy adults and national Headache Society (IHS). 2013. The Research Colloquium Conference Proceed- patients with suspected instability. Spine International Classification of Headache ings, September 26, 2015, New Orleans, 12:726–731. Disorders, 3rd edition (beta version). Ceph- Louisiana. Ellenbogen RG, Armonda RA, Shaw DW, Winn alalgia 33:629–808. Kothari P, Freeman B, Grevitt M, Kerslake R. HR. 2000. Toward a rational treatment of Henderson FC, Geddes JF, Crockard HA. 1993. 2000. Injury to the spinal cord without Chiari I malformation and syringomyelia. Neuropathology of the brainstem and spinal radiological abnormality (SCIWORA) Neurosurg Focus 8:1–10. cord in end stage rheumatoid arthritis: in adults. J Bone Joint Surg Br 82: Estemalik E, TepperS. 2013. Preventive treatment Implications for treatment. Ann Rheum 1034–1037. in migraine and the new US guidelines. Dis 52:629–637. Kress H, Aldington D, Alon E, Coaccioli S, Collett Neuropsychiatr Dis Treat 9:709–720. Henderson FC, Geddes JF, Vaccaro AR, Woodard B, Coluzzi F, Huygen F, Jaksch W, Kalso E, Fabiano AJ, Khan MF, Rozzelle CJ, Li V. 2009. E, Berry KJ, Benzel EC. 2005. Stretch- Kocot-Kepska M, Mangas AC, Ferri CM, Preoperative predictors for improvement associated injury in cervical spondylotic Mavrocordatos P, Morlion B, Muller-€ after surgical untethering in occult tight myelopathy: New concept and review. Schwefe G, Nicolaou A, Hernandez CP, filum terminale syndrome. Pediatr Neuro- Neurosurgery 56:1101–1113. Sichere P. 2015. A holistic approach to surg 45:256–261. Henderson FC, Wilson WA, Benzel EC. 2010a. chronic pain management that involves all Farb RI, Vanek I, Scott JN, Mikulis DJ, Willinsky Pathophysiology of cervical myelopathy: stakeholders: Change is needed. Curr Med RA, Tomlinson G, terBrugge KG. 2003. Biomechanics and deformative stress. In: Res Opin 31:1743–1754. Idiopathic intracranial hypertension: The Benzel EC, editor. Spine surgery: Techni- Lang AE. 2006. General overview of psychogenic prevalence and morphology of sinovenous ques, complication avoidance, and manage- movement disorders: Epidemiology, diag- stenosis. Neurology 60:1418–1424. ment, Vol 1. 3rd edition. Philadelphia, PA: nosis, and prognosis. In: Hallett M, Fahn S, Feigenbaum F, Henderson F. 2006. Surgical Elsevier Churchill Livingstone. Jankovic J, Lang A, Cloninger C, Yudofsky management of meningeal cysts, including Henderson FC, Wilson WA, Mott S, Mark A, S, editors. Psychogenic movement disorders perineural (Tarlov) cysts and meningeal Schmidt K, Berry JK, Vaccaro A, Benzel E. —Neurolgy and neuropsychiatry. PL: Lip- diverticula. 18:154–160. 2010b. Deformative stress associated with an pincott Williams & Wilkins. pp 35–41. Ferrari MD, Klever RR, Terwindt GM, Ayata C, abnormal clivo-axial angle: A finite element Lindenburg R, Freytag E. 1970. Brainstem lesions van den Maagdenberg AM. 2015. Migraine analysis. Surg Neurol Int 1:30. characteristic of traumatic hyperextension of pathophysiology: Lessons from mouse mod- Hoffman HJ, Hendrick EB, Humphreys RP. the head. Arch Pathol 90:509–515. els and human genetics. Lancet Neurol 1976. The tethered spinal cord: Its protean Liu XZ, Xu XM, Hu R, Du C, Zhang SX, 14:65–80. manifestations, diagnosis and surgical cor- McDonald JW, Dong HX, Wu YJ, Fan GS, Fielding JW, Stillwell WT, Chynn K, Spyropou- rection. Childs Brain 2:145–155. Jacquin MF, Hsu CY, Choi DW. 1997. los E. 1978. Use of computed tomography Huijing PA, Voermans NC, Baan GC, Buse TE, Neuronal and glial apoptosis after traumatic for the diagnosis of atlanto-axial rotatory van Engelen BG, de Haan A. 2010. Muscle . J Neurosci 17:5395–5406. fixation. J Bone Joint Surg Am 60: characteristics and altered myofascial force MacKenzie JM, Rankin R. 2003. Sudden death due 1102–1104. transmission in tenascin-X-deficient mice, a to atlantoaxial subluxation in Marfan syndrome. Geddes J, Whitwell H, Graham D. 2000. mouse model of Ehlers–Danlos syndrome. Am J Forensic Med Pathol 24:369–370. Traumatic axonal injury: Practical issues J Appl Physiol 109:986–995. Martin V, Neilson D. 2014. Joint hypermobility for diagnosis in medicolegal cases. Neuro- Jacome D. 1999. Headache in Ehlers–Danlos andheadache:Thegluethatbindsthetwo pathol Appl Neurobiol 26:105–116. syndrome. Cephalalgia 19:791–796. together—Part 2. Cephalalgia 54:1403–1411. Gelfand AA, Gelfand JM, Goadsby PJ. 2013. Jafari S, Maxwell W,Neilson M, Graham D. 1997. Martin MD, Bruner HJ, Maiman DJ. 2010. Migraine and multiple sclerosis: Epidemiol- Axonal cytoskeletal changes after non- Anatomic and biomechanical considerations ogy and approach to treatment. Mult Scler disruptive axonal injury. J Neurocytol of the craniovertebral junction. Neurosur- Relat Disord 2:73–79. 26:201–221. gery 66:2–6. Goel A, Sharma P.2005. Craniovertebral junction Jang HS, Cho KH, Chang H, Jin ZW, Maxwell WL, Kosanlavit R, McCreath BJ, Reid realignment for the treatment of basilar Rodriguez-Vazquez JF, Murakami G. O, Graham DI. 1999. Freeze-fracture and invagination with syringomyelia: Prelimi- 2016. The filum terminale revisited: A cytochemical evidence for structural and nary report of 12 cases. Neurol Med histological study in human fetuses. Pediatr functional alteration in the axolemma and 45:512–518. Neurosurg 51:9–19. myelin sheath of adult guinea pig 210 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) RESEARCH REVIEW

fibers after stretch injury. J Neurotrauma Chiari Type I anomaly. J Neurosurg Pediatr cardiovascular disease: Systematic review 16:273–284. 2:179–187. and meta-analysis. BMJ 339:b3914. Menendez JA, Wright NM. 2007. Techniques of Palmer S, Terry R, Rimes KA, Clark C, Selecki BR. 1969. The effects of rotation of the posterior C1-C2 stabilization. Neurosur- Simmonds J, Horwood J. 2016. Physiother- atlas on the axis: Experimental work. Med J gery 60:S103–S111. apy management of joint hypermobility Aust 1:1012–1015. Menezes AH, Traynelis VC. 2008. Anatomy and syndrome—A focus group study of patient Shedid D, Benzel EC. 2007. Cervical spondylosis biomechanics of normal craniovertebral and health professional perspectives. Phys- anatomy: Pathophysiology and biomechan- junction (a) and biomechanics of stabiliza- iotherapy 102:93–102. ics. Neurosurgery 60:S7–13. tion (b). Childs Nerv Syst 24:1091–1100. Palmeri S, Mari F, Meloni I, Malandrini A, Ariani Shi R, Whitebone J. 2006. Conduction deficits Menezes AH. 2012. Craniovertebral junction F, Villanova M, Pompilio A, Schwarze U, and membrane disruption of spinal cord abnormalities with herniation Byers P, Renieri A. 2003. Neurological axons as a function of magnitude and rate of and syringomyelia: Regression of syringo- presentation of Ehlers-Danlos syndrome strain. J Neurophysiol 95:3384–3390. myelia after removal of ventral cranioverte- type IV in a family with parental mosaicism. Steilen D, Hauser R, Woldin B, Sawyer S. 2014. bral junction compression: Clinical article. Clin Genet 63:510–515. Chronic neck pain: Making the connection J Neurosurg 116:301–309. Pang D, Wilberger JE Jr. 1982. Tethered cord between capsular ligament laxity and cervi- Merrison AF, Hanna MG. 2009. The bare syndrome in adults. J Neurosurg 57:32–47. cal instability. Open Orthop J 8:326–345. essentials: Muscle disease. Pract Neurol Patel MR, Louie W, Rachlin J. 1997. Percutane- Stern WE. 1988. Dural ectasia and the Marfan 9:54–65. ous fibrin glue therapy of meningeal cysts of syndrome. J Neurosurg 69:221–227. Milhorat TH, Chou MW,Trinidad EM, Kula RW, the sacral spine. AJR Am J Roentgenol Strahle J, Muraszko KM, Kapurch J, Bapuraj JR, Mandell M, Wolpert C, Speer MC. 1999. 168:367–370. Garton HJ, Maher CO. 2011. Natural Chiari I malformation redefined: Clinical Penisson-Besnier I, Allamand V, Beurrier P, history of Chiari malformation Type I and radiographic findings for 364 symptom- Martin L, Schalkwijk J, van Vlijmen- following decision for conservative treat- atic patients. Neurosurgery 44:1005–1017. Willems I, Gartioux C, Malfait F, Syx D, ment. J Neurosurg Pediatr 8:214–221. Milhorat TH, Bolognese PA, Nishikawa M, Macchi L, Marcorelles P, Arbeille B, Croue Syx D, Damme T, Symoens S, Maiburg MC, Laar McDonnell NB, Francomano CA. 2007. A, De Paepe A, Dubas F. 2013. Compound I, Morton J, Suri M, Del Campo M, Hausser Syndrome of occipitoatlantoaxial hypermo- heterozygous mutations of the TNXB gene I, Hermanns-L^e T. 2015. Genetic heteroge- bility, cranial settling, and Chiari malforma- cause primary myopathy. Neuromuscul neity and clinical variability in musculocon- tion Type I in patients with hereditary Disord 23:664–669. tractural Ehlers–Danlos syndrome caused by disorders of connective tissue. 7:601–609. Pierangeli G, Giannini G, Favoni V, Sambati L, impaired Dermatan Sulfate biosynthesis. Milhorat TH, Bolognese PA, Nishikawa M, Cevoli S, Cortelli P. 2012. Migraine and Hum Mutat 36:535–547. Francomano CA, McDonnell NB, Roon- cardiovascular diseases. Neurol Sci 33: Taniguchi D, Tokunaga D, Hase H, Mikami Y, prapunt C, Kula RW. 2009. Association of S47–S50. Hojo T, Ikeda T, Oda R, Takatori R, Imai Chiari malformation type I and tethered Radhakrishnan K, Thacker AK, Bohlaga NH, K, Kida Y. 2008. Evaluation of lateral cord syndrome: Preliminary results of sec- Maloo JC, Gerryo SE. 1993. Epidemiology instability of the atlanto-axial joint in tioning filum terminale. Surg Neurol of idiopathic intracranial hypertension: A rheumatoid arthritis using dynamic open- 72:20–35. prospective and case-control study. J Neurol mouth view radiographs. Clin Rheumatol Milhorat TH, Nishikawa M, Kula RW, Dlugacz Sci 116:18–28. 27:851–857. YD. 2010. Mechanisms of cerebellar tonsil Ripa P, Ornello R, Degan D, Tiseo C, Stewart J, Thompson EM, Strong MJ, Warren G, Woltjer herniation in patients with Chiari malfor- Pistoia F,Carolei A, Sacco S. 2015. Migraine RL, Selden NR. 2014. Clinical significance mations as guide to clinical management. in menopausal women: A systematic review. of imaging and histological characteristics of Acta Neurochir. 152:1117–1127. Int J Womens Health 7:773–782. filum terminale in tethered cord syndrome. Muellbacher W, Finsterer J, Mamoli B, Bittner Rombaut L, Malfait F, De Wandele I, Cools A, J Neurosurg Pediatr 13:255–259. RE, Trautinger F. 1998. Axonal polyneur- Thijs Y, De Paepe A, Calders P. 2011. Tredwell SJ, Newman DE, Lockitch G. 1990. opathy in Ehlers–Danlos syndrome. Muscle Medication, surgery, and physiotherapy Instability of the upper cervical spine in Nerve 21:972–974. among patients with the hypermobility Down syndrome. J Pediatr Orthop Muhle C, Weinert D, Falliner A, Wiskirchen J, type of Ehlers–Danlos syndrome. Arch 10:602–606. Metzner J, Baumer M, Brinkmann G, Heller Phys Med Rehabil 92:1106–1112. Tu A, Steinbok P. 2013. Occult tethered cord M. 1998. Dynamic changes of the spinal Rombaut L, Malfait F,De Wandele I, Taes Y,Thijs syndrome: A review. Childs Nerv Syst canal in patients with cervical spondylosis at Y, De Paepe A, Calders P. 2012. Muscle 29:1635–1640. flexion and extension using magnetic reso- mass, muscle strength, functional perfor- TubbsR, Beckman J, Naftel R, Chern J, WellonsJ, nance imaging. Invest Radiol 33:444–449. mance, and physical impairment in women Rozzelle C, Blount J, Oakes W. 2011a. Nabors MW,Pait TG, Byrd EB, Karim NO, Davis with the hypermobility type of Ehlers– Institutional experience with 500 cases of DO, Kobrine AI, Rizzoli HV. 1988. Danlos syndrome. Arthritis Care Res surgically treated pediatric Chiari malfor- Updated assessment and current classifica- 64:1584–1592. mation Type I. J Neurosurg Pediatr tion of spinal meningeal cysts. J Neurosurg Royo-Salvador MB. 1996. Syringomyelia, scoliosis 7:248–256. 68:366–377. and idiopathic Arnold–Chiari malformations: Tubbs RS, Hallock JD, Radcliff V, Naftel RP, Nagashima C, Tsuji R, Kubota S, Tajima K. 1981. A common etiology. Rev Neurol 24:937–959. Mortazavi M, Shoja MM, Loukas M, Atlanto-axial, Atlanto-occipital dislocations, Rubio-Agusti I, Kojovic M, Chandrashekar HS, Cohen-Gadol AA. 2011b. Ligaments of developmental cervical canal stenosis in the Edwards MJ, Bhatia KP. 2012. Cervical the craniocervical junction. J Neurosurg Ehlers–Danlos syndrome (author’s transl). dystonia and joint hypermobility syndrome: Spine 14:697–709. No Shinkei Geka 9:601–608. A dangerous combination. Mov Disord van Hemert S, Breedveld AC, Rovers JM, Nappi RE, Nappi G. 2012. Neuroendocrine 27:203–204. Vermeiden JP, Witteman BJ, Smits MG, de aspects of migraine in women. Gynecol Satti SR, Leishangthem L, Chaudry MI. 2015. Roos NM. 2014. Migraine associated with Endocrinol 28:37–41. Meta-analysis of CSF diversion procedures gastrointestinal disorders: Review of the NINDS Common Data Elements. 2016. Clinical and dural venous sinus stenting in the setting literature and clinical implications. Front Research Common Data Elements (CDEs): of medically refractory idiopathic intracra- Neurol 5:241. Radiological metrics standardization for nial hypertension. AJNR Am J Neuroradiol van Rooijen DE, Geraedts EJ, Marinus J, Jankovic craniocervical instability. 2016. Available: 36:1899–1904. J, van Hilten JJ. 2011. Peripheral trauma and https://commondataelements.ninds.nih. Savasta S, Merli P, Ruggieri M, Bianchi L, Sparta movement disorders: A systematic review of gov/CM.aspx#66 = Data_Standards [Ac- MV. 2011. Ehlers–Danlos syndrome and reported cases. J Neurol Neurosurg Psychi- cessed Jan 2016]. neurological features: A review. Childs Nerv atry 82:892–898. Novegno F, Caldarelli M, Massa A, Chieffo D, Syst 27:365–371. Voermans N, Bonnemann€ C, Huijing P, Massimi L, Pettorini B, Tamburrini G, Di Schurks M, Rist PM, Bigal ME, Buring JE, Lipton Hamel B, Van Kuppevelt T, De Rocco C. 2008. The natural history of the RB, Kurth T. 2009. Migraine and Haan A, Schalkwijk J, Van Engelen B, RESEARCH REVIEW AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 211

Jenniskens G. 2008. Clinical and molec- tenascin-X knockout mice, a model of Wolf JA, Stys PK, Lusardi T, Meaney D, Smith ular overlap between myopathies and Ehlers–Danlos syndrome. Connect Tissue DH. 2001. Traumatic axonal injury induces inherited connective tissue diseases. Res 52:422–432. calcium influx modulated by tetrodotoxin- Neuromusc Disord 18:843–856. Voermans NC, Knoop H, Bleijenberg G, van sensitive sodium channels. J Neurosci Voer mans N, Bonnemann€ C, Lammens M, van Engelen BG. 2010. Pain in Ehlers–Danlos 21:1923–1930. Engelen B, Hamel B. 2009b. Myopathy and syndrome is common, severe, and associated Yamada S, Won DJ, Pezeshkpour G, Yamada BS, polyneuropathy in an adolescent with the with functional impairment. J Pain Symp- Yamada SM, Siddiqi J, Zouros A, Colohan kyphoscoliotic type of Ehlers–Danlos syn- tom Manage 40:370–378. AR. 2007. Pathophysiology of tethered cord drome. Am J Med Genet Part A 149A: Voermans NC, van Alfen N, Pillen S, Lammens syndrome and similar complex disorders. 2311–2316. M, Schalkwijk J, Zwarts MJ, van Rooij IA, Neurosurg Focus 23:1–10. Voermans N, Drost G, Van Kampen A, Hamel BC, van Engelen BG. 2009a. Yarbrough CK, Powers AK, Park TS, Leonard JR, Gabreëls-Festen A, Lammens M, Hamel Neuromuscular involvement in various Limbrick DD, Smyth MD. 2011. Patients B, Schalkwijk J, Van Engelen B. 2006. types of Ehlers–Danlos syndrome. Ann with Chiari malformation Type I presenting Recurrent neuropathy associated with Neurol 65:687–697. with acute neurological deficits: Case series. Ehlers–Danlos syndrome. J Neurol Volman M, Mojadidi MK, Gevorgyan R, Kaing J Neurosurg Pediatr 7:244–247. 253:670–671. A, Agrawal H, Tobis J. 2013. Incidence of Yoshizumi T, Murata H, Ikenishi Y, Sato M, Voermans N, Kempers M, Lammens M, Van Alfen patent foramen ovale and migraine headache Takase H, Tateishi K, Nakanowatari S, N, Janssen M, Bonnemann€ C, Van Engelen in adults with congenital heart disease with Suenaga J, Kawahara N. 2014. Occipitocer- B, Hamel B. 2012. Myopathy in a 20-year- no known cardiac shunts. Catheter Cardi- vical fusion with relief of odontoid invagi- old female patient with D4ST-1 deficient ovasc Interv 81:643–647. nation: Atlantoaxial distraction method Ehlers–Danlos syndrome due to a homozy- Voyadzis J, Bhargava P,Henderson FC. 2001. Tarlov using cylindrical titanium cage for basilar gous CHST14 mutation. Am J Med Genet cysts: A study of 10 cases with review of the invagination—Case report. Neurosurg Rev Part A 158A:850–855. literature. J Neurosurg 95:25–32. 37:519–525. VoermansN,VerrijpK,EshuisL,BalemansM, White AA, Panjabi MM. 1990. Clinical biome- Zhang H, Bai J. 2007. Development and Egging D, Sterrenburg E, van Rooij I, van chanics of the spine. Philadelphia: Lippincott. validation of a finite element model of der Laak J, Schalkwijk J, van der Maarel Wiesel S, Rothman R. 1979. Occipitoatlantal the occipito-atlantoaxial complex under SM. 2011. Mild muscular features in hypermobility. Spine 4:187. physiologic loads. Spine 32:968–974.