connective tissue, ehlers-danlos syndrome(s), and...

American Journal of Medical Genetics Part C (Seminars in Medical Genetics) 169C:84–96 (2015)

A R T I C L E

Connective Tissue, Ehlers–Danlos Syndrome(s),and Head and Cervical PainMARCO CASTORI, SILVIA MORLINO, GIULIA GHIBELLINI, CLAUDIA CELLETTI,FILIPPO CAMEROTA, AND PAOLA GRAMMATICO

Marco Castodegree with agenodermatosseveral book c

Silvia Morlinactivity of theconnective tiss

Giulia Ghibelarge and smaland is pursuing

Claudia CellCamerota, shemore than 30

Filippo Caminterests includthan 40 paper

Paola GramSanCamillo-Fotesting and rapathology. She

*CorresponI-00152 Rome

DOI 10.100Article first

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Ehlers–Danlos syndrome (EDS) is an umbrella term for a growing group of hereditary disorders of the connectivetissue mainly manifesting with generalized joint hypermobility, skin hyperextensibility, and vascular and internalorgan fragility. In contrast with other well known heritable connective tissue disorders with severe cardiovascularinvolvement (e.g., Marfan syndrome), most EDS patients share a nearly normal life span, but are severely limitedby disabling features, such as pain, fatigue and headache. In this work, pertinent literature is reviewedwith focuson prevalence, features and possible pathogenic mechanisms of headache in EDSs. Gathered data arefragmented and generally have a low level of evidence. Headache is reported in no less than 1/3 of the patients.Migraine results the most common type in the hypermobility type of EDS. Other possibly related headachedisorders include tension-type headache, new daily persistent headache, headache attributed to spontaneouscerebrospinal fluid leakage, headache secondary to Chiari malformation, cervicogenic headache and neck–tongue syndrome, whose association still lacks of reliable prevalence studies. The underlying pathogenesisseems complex and variably associated with cardiovascular dysautonomia, cervical spine and temporoman-dibular joint instability/dysfunction, meningeal fragility, poor sleep quality, pain-killer drugs overuse and centralsensitization. Particular attention is posed on a presumed subclinical cervical spine dysfunction. Standardtreatment is always symptomatic and usually unsuccessful. Assessment and management procedures arediscussed in order to put some basis for ameliorating the actual patients' needs and nurturing future research.© 2015 Wiley Periodicals, Inc.

KEYWORDS: cervical spine; connective tissue; ligamentous laxity; meninges; occipitoatlantoaxial; POTS; temporomandibular

ABBREVIATIONS: cEDS, classic Ehlers–Danlos syndrome; CSF, cerebrospinal fluid; EDS, Ehlers–Danlos syndrome; EDS-HT, Ehlers–Danlossyndrome hypermobility type; HCTD, heritable connective tissue disorder; gJHM, generalized joint hypermobility; JHS,joint hypermobility syndrome; NDPH, new daily persistent headache; OAAJ, occipitoatlantoaxial joint; TMJ,temporomandibular joint; vEDS, vascular Ehlers–Danlos syndrome.

How to cite this article: Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F, Grammatico P. 2015.Connective tissue, Ehlers–Danlos syndrome(s), and head and cervical pain.

Am J Med Genet Part C 169C:84–96.

ri is a medical geneticist enrolled as senior hospital-based clinician at the San Camillo-Forlanini Hospital in Rome. He obtained his Ph.D.clinical and management study on Ehlers–Danlos syndrome(s). Major research topics include hereditary connective tissue disorders,es, clinical dysmorphology and fetal pathology. He is author and co-author of more than 100 publications in international journals andhapters.o is a M.D. resident in Medical Genetics at the Sapienza University of Rome. She has a full-time involvement in the clinical and researchDivision of Medical Genetics at the San Camillo-Hospital in Rome. Her interests mostly include clinical dysmorphology and hereditaryue disorders.llini has a PhD from UNC, Chapel Hill, School of Pharmacy where she is adjunct faculty and has worked as a clinical research scientist inl pharmaceutical companies since 2006. Recently, Giulia has developed a special interest in Ehlers Danlos syndrome, hypermobility typeadditional training in neurodevelopmental approaches and advocacy for special needs children.

etti is a physiatrist at the Division of Physical Medicine and Rehabilitation of the Umberto I University Hospital. Together with Dr. Filippois fully involved in the rehabilitation and clinical research of rare diseases, with particular interest on joint hypermobility. She is author ofpapers in international journals, most of them on Ehlers–Danlos syndrome.erota is a senior physiatrist at the Division of Physical Medicine and Rehabilitation of the Umberto I University Hospital. His speciale rehabilitative implications of rare diseases, joint hypermobility, neurodegerative disorders and cerebral palsy. He is authors of mores in international journals, many of them on Ehlers–Danlos syndrome.matico is an Associate Professor of Medical Genetics at the Sapienza University and Director of the Division of Medical Genetics at therlanini Hospital in Rome. She has various responsibilities in the regional and national Healthcare systemwith focus on genetic laboratoryre diseases. Her major diagnostic and research interests include cutaneous melanoma, disorders of sex differentiation and fetalis author of more than 150 papers in international journals and various book chapters on medical genetics.

dence to: Marco Castori, M.D., Ph.D., Division of Medical Genetics, San Camillo-Forlanini Hospital, Circonvallazione Gianicolense, 87,, Italy. E-mail: [email protected]/ajmg.c.31426published online 5 February 2015 in Wiley Online Library (wileyonlinelibrary.com).

ey Periodicals, Inc.

ARTICLE AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) 85

INTRODUCTION

Ehlers–Danlos syndrome (EDS) is anumbrella term for an increasing group ofheritable connective tissue disorders(HCTDs) sharing the variable triad of(i) generalized joint hypermobility(gJHM) and related osteoarticular com-plications, (ii) dermal dysplasia extend-ing from minor changes of skin textureto clinically relevant skin fragility anddefective scarring and (iii) vascular andinternal organ fragility with pronenessto traumatic injuries and spontaneousruptures, dissections and prolapses. Thelast classification identifies six majorvariants, including classic (cEDS),hypermobility (EDS-HT), vascular(vEDS), kyphoscoliotic, arthrochalasisand dermatosparaxis subtypes, which aredistinguished on the basis of specificdiagnostic criteria, i.e., Villefranchecriteria [Beighton et al., 1998]. In theclinical practice, adhesion to suchcriteria help in selecting patients forconfirmatory laboratory tests, which arenow available for all major EDS subtypesexcept EDS-HT [Mayer et al., 2013]. Asa whole, EDSs have a presumed cumu-lative frequency of �1/5,000 [Stein-mann et al., 2002], with cEDS and EDS-HT being the most common variants[De Paepe and Malfait, 2012]. Theextreme clinical variability of cEDS andEDS-HT [Castori, 2012a; Ritelli et al.,2013], and the lack of a reliablediagnostic test for the EDS-HT [Mayeret al., 2013] underestimate the preva-lence of EDSs. Further complexity isadded by the clinical overlap betweenEDS-HT and the joint hypermobilitysyndrome (JHS), a relatively neglectedrheumatologic condition with specificdiagnostic criteria [Grahame et al.,2000] and which results unexpectedlycommon with a presumed frequency of�1% [Hakim and Sahota, 2006]. Aninternational group of experts nowconsider these two disorders undistin-guishable at the clinical level [Tinkleet al., 2009]. Although this hypothesisstill waits molecular confirmation [DePaepe and Malfait, 2012], recent ob-servations support with evidence theconcept that EDS-HT and JHS may beindeed one and the same condition (i.e.,

JHS/EDS-HT) also at the genetic level[Hermanns-Lê et al., 2012].

For decades, practitioners’ and re-searchers’ attention was posed at thecutaneous, articular and vascular aspectsof EDSs. This generated a perspectivedistortion that separated cEDS and JHS/EDS-HT, considered relatively benigntraits, from vEDS and other variants,which, conversely, reduce lifespan ofaffected individuals and request closemultidisciplinary support. In the last twodecades, a growing number of studiespointed out the impact of EDS on qualityof life in term of symptom chronificationin those patients who skip catastrophicevents, and then reach adulthood and theold age. Accordingly, musculoskeletalpain [Voermans et al., 2010a] and chronicfatigue [Voermans et al., 2010b] arehighly reported in various forms ofEDS and are both important possibledeterminants of disability in EDS-HT[Voermans andKnoop, 2011]. The long-term management of patients affected byEDS forms with unaffected mortalityrate, as well as of long-survivors ofpotentially life-threatening subtypes, ishampered by the general ineffectivenessof available treatment strategies, as re-cently reviewed for JHS/EDS-HT [Cas-tori et al., 2012].

Among the various contributors ofquality of life in EDSs, headache is afurther largely unrecognized feature,whose association with these disordershas been only recently outlined [Sachetiet al., 1997]. Although some preliminarystudies investigated prevalent patterns ofheadaches in specific EDSs subtypes[Jacome, 1999; Bendik et al., 2011],practice still suffers for the absence of astructured theoretical backbone for fu-ture more evidence-based research. Weoffered a first and incomplete overviewofthe clinical contributors to head andcervical pain in JHS/EDS-HT in a recentreview further characterizing the naturalhistory of this condition with focus onpain and fatigue [Castori et al., 2013].Subsequently, another research grouppresented a good overview of the mostcommon HCTDs presenting headacheand speculated on the most likelypathogenicmechanisms in a neurologicalspecialized journal [Martin and Neilson,

2014; Neilson and Martin, 2014]. In thepresent paper, wewill face the same topicfrom an inverted point of view. The issueof “headache and other head and cervicalpains” inHCTDs is discussed as a possiblepresentation or late complication of aspecific multisystem disorder (i.e., EDS)with a protean natural history, in whichheadache is intermingled with multipleneurologic and non-neurologic dysfunc-tions in a wider pathogenic processsimultaneous spreading most tissues andorgans.

METHODS

This review was intended as a PubMedsearch aimed at investigating the rela-tionships between gJHM/EDSs andheadache disorders. As headache iscommonly reported by EDS patients,themain effort of this workwas to offer aknowledge toll for better classifying and,hopefully, managing patients. The liter-ature review was carried out with thefollowing keywords: [(hypermobility)OR (Ehlers-Danlos syndrome) OR(connective tissue) OR (collagen)]AND [(headache) OR (migraine)].Results were selected for papers pre-senting case reports, case series, case-control studies and reviews on headacheand/or migraine in patients with variousforms of EDS or unclassified gJHM.The reference lists of selected paperswere screened for additional works.Most identified works were case reportsand case series lacking control groups.After a formal overview of these results,an extended narrative review, guided byauthors’ clinical and personal expertise(i.e., one of us is indeed affected byEDS), was also performed in order toinvestigate the possible pathogenicmechanisms underlying headache inEDSs. A section of available manage-ment options and recommendations isalso presented with proposed adapta-tions for patients with EDSs.

HEADACHE IN EHLERS–DANLOS SYNDROMES: ANOVERVIEW

Literature review demonstrated that,although practice points out headache as

86 AMERICAN JOURNAL OF MEDICAL GENETICS PART C (SEMINARS IN MEDICAL GENETICS) ARTICLE

a relatively common finding in EDSs[Grahame, 2009], only a handful of papersinvestigated this ancillary complaint,which, in turn, has a significant impactin terms of co-morbidity and disability.

In 1997, the work by Sacheti et al.described pain features in 51 individualswith different forms of EDS (including 13patients with cEDS – ninewith type I andfour with type II, 28 with EDS-HT, onewith JHS, seven with vEDS and twowithunclassified type) and showed that neckpain and headache accounted for 30–40%of cases. A subsequent case series reportednine EDSpatients presentingwith variousforms of headache, including (i) migrainewith aura, (ii) migraine without aura, (iii)tension-typeheadache, (iv) a combinationof tension-type headache and migraineand (v) post-traumatic headache [Jacome,1999].Additionalworks, focusedon JHS/EDS-HT, confirmed the high prevalenceof headache in this condition withoutfurther characterizations [Castori et al.,2010; Rombaut et al., 2010]. Morerecently, Bendik et al. [2011] showedthat migraine (with or without aura) isapproximately three times more commonamong JHS/EDS-HTwomen comparedto controlswith a cumulative frequencyof75% (3/4).

Single case-control studies, caseseries or case reports pointed outpreliminary associations betweengJHM/EDS and specific subsets ofprimary and secondary types of head-ache, including new daily persistentheadache (NDPH) [Rozen et al.,2006], headache attributed to sponta-neous (idiopathic) cerebrospinal fluid(CSF) leakage [Schievink et al., 1996,2004] and headache secondary to Chiarimalformation [Castori et al., 2010].Cervical spine hypermobility/dysfunc-tion is also anecdotally considered apredisposing factor for cervicogenicheadache [Hall et al., 2008] and neck–tongue syndrome [Orrell and Marsen,1994; Sjaastad and Bakketeig, 2006;González de la Aleja Tejera and Porta-Etessam, 2008]. In line with this, DiPalma and Cronin [2005] report a 27-year-old woman with cEDS (type II)with a long-lasting pulsating headacheassociated with C2 dislocation, whileMathers et al. [2011] point out the

utility of looking for occult hyper-mobility at the craniocervical junctionby describing a patient with occipitalheadache and cervical spine instability.Furthermore, an early report describestwo out of three vascular EDS patientswith radiologically evident atlantoaxialsubluxation [Halko et al., 1995].

Head pain is not limited to head-ache in EDSs. In a cohort of 31 EDSpatients (including 16 with JHS/EDS-HT, nine with cEDS and six withvEDS), De Coster et al. [2005] dem-onstrated temporomandibular joint(TMJ) dysfunction in 100% of the cases,unilateral myofascial pain (i.e., templeheadache) in 83% and unilateral andbilateral TMJ arthralgia in 28% and 51%of the patients, respectively. Althoughdetails on the occurrence of myogenousheadache (i.e., headache secondary toTMJ dysfunction) in this cohort werenot presented, an increased frequency ofthis type of headache can be extrapo-lated on the basis of the higher rate ofTMJ dysfunction in tension-type head-ache [Ballegaard et al., 2008].

In vEDS, ipsilateral headache mayoccur together with additional neuro-logic features, such as ophthalmoplegiaand tinnitus, due to vascular accidents,including spontaneous direct caver-nous-carotid fistula [Chuman et al.,2002; Tanaka et al., 2014]. Similarpresentations may equally be observedin other EDS subtypes with vascularfragility. In fact, intermittent headachedue to rupture of an intracranial arterialaneurysm is observed in osteogenesisimperfecta, a well known HCTD withclinical and genetic similarities withEDSs [Havlik and Nashelsky, 2006].Mutations in COL1A1 and COL1A2,the genes most commonly associatedwith osteogenesis imperfecta, are alsoreported in specific EDS subtypes,including the EDS/osteogenesis imper-fecta overlap syndrome, EDS withvascular fragility, cardiac-valvular EDSand EDS arthrochalasis type [Marfaitand De Paepe, 2012].

Finally, a 36-year-old woman pre-senting with generalized headache for8 months and the diagnostic criteria ofJHS/EDS-HT has been described [Kur-ian and Solomon, 2013]. In this patient,

headache was subsequently attributed tospontaneous intracranial hypertension(32 cm H2O). The patient describedsimilarities of the presenting symptomwith a previous headache developedfollowing a lumbar pucture after a caraccident. The authors also speculated onthe pathogenic role of elevated plasmaIGF-1 levels they found in this patient.

POSSIBLE MECHANISMS OFHEAD AND CERVICAL PAININ EHLERS–DANLOSSYNDROMES

Available data indicate that headache isclinically and pathogenically heteroge-neous in EDSs. A discrete number ofclinical forms according to the thirdedition of the International Classifica-tion of Headache Disorders (HeadacheClassification Committee of the Inter-national Headache Society, 2013) can beidentified in EDS patients with apredominance of migraine in JHS/EDS-HT. Nevertheless, observationsuggests marked variability at presenta-tion and possible evolution in mixedchronic headache with multiple patternsaffecting the same individual withdifferent timing and chance of super-imposition. The level of evidence ofavailable data on headache in associationto EDSs and gJHM is generally low.

A wider consultation of the liter-ature offers a fragmented network ofdistinct pathophysiologic mechanismsof head pain, directly related to adysfunctional connective tissue com-posing various non-ossifying structuresof the cephalic pole. Four majoranatomic fields are identified, namelycardiovascular system, muscles and TMJ,cervical spine and meninges, whosesummative or multiplicative anomaliesmay contribute to the observed pheno-typic variability (Fig. 1). Additionalcontributors to headache manifestationsand evolutions include: sleep disturban-ces, painkiller drugs overuse and centralsensitization.

Cardiovascular System

Indirect evidence suggests that vasculardysfunction is a major contributor to

Figure 1. Diagram showing possible relationships between the different functional and anatomical factors contributing to someheadache manifestations in EDSs. CSF, cerebrospinal fluid; FM, foramen magnum; OAAJ, occipito-atlanto-axial joint; TMJ,temporomandibular joint.


headache in EDSs. Migraine is, at themoment, considered the most commonform of headache in JHS/EDS-HT[Bendik et al., 2011]. In order to explainsuch an association, it has been specu-lated that vascular dysfunction may be atrigger of head pain due to either anunderlying arteriopathy or cardiovascu-lar dysautonomia. The former is indi-rectly supported by the evidence ofreduced aortic stiffness in patients withmitral valve prolapse and JHS/EDS-HT

[Yazici et al., 2004]. Accordingly,increased intracranial vascular compli-ance may affect central nervous systemhomeostasis and, thus, causes headache.The latter refers to the high rate oforthostatic hypotension in EDS com-pared to healthy controls [Gazit et al.,2003]. A better definition of the under-lying dysautonomia in EDSs identifiesthe most common neuromediated car-diovascular dysfunction in postural or-thostatic tachycardia syndrome [Mathias

et al., 2011]. Then, a direct linkbetween headache and cardiovasculardysautonomia can be postulated, asheadache is a main symptom of chronicorthostatic intolerance in both pediatricand adults patients [Mack et al., 2010;Mathias et al., 2011]. Inappropriateneuromediated cardiovascular adapta-tion to rapid postural changes may betriggered by increased venous poolingdue to reduced peripheral vessels resil-ience [Bohora, 2010]. In particular, by


studying 37 patients with EDS-HT, DeWandele et al. [2014] collected Head-up Tilt-test data suggestive for acommon neurogenic dysfunction ofthe cardiovascular system. Whetherthis finding is a primary (pleiotropy) orsecondary/remote feature of the under-lying connective tissue defect needsfurther investigations.

Repeated evidence underlies anincreased rate of vertebral artery hypo-plasia among migraineurs compared tohealthy subjects. Although a causalrelationship between such an anatomicalvariant and migraine remains unclear[Chuang et al., 2008], this broadens thespectrum of possible cardiovascularconnections between headache andEDSs. In fact, vertebral arteries arebranches of the subclavian arteries,which get through to a stiff, anelasticpassage constituted by the transverseforamen of the cervical vertebrae, beforefusing intracranially in the basilar artery.Neck rotation may stress vertebralarteries between the transverse foraminaof C1 and C2, where rotational injury ofthe vertebral artery usually occurs. Onecould speculate that, in EDSs, thecombination of increased cervical spinemobility and reduced resilience of thevertebral artery wall due to a constitu-tionally deficient connective tissue mayfunctionally mimic vertebral arteryhypoplasia and, then, contribute tomigraine development.

Finally, EDS forms with markedvascular fragility may present withsudden/thunderclap headache due tointracranial or epiaortic vascular rup-tures. Recognition of vascular accidentand prompt treatment may be delayed inpatients affected by these EDS subtypesand suffering of chronic/recurrentbackground headache due to one ormore of the other mechanisms heredescribed.

Muscles and TemporomandibularJoint

It is well known that TMJ and cervicalspine instability associate with anincreased rate of temporal [Pasinatoet al., 2011] and neck/occipital [Sahinet al., 2008] myofascial pain. This may

result from increased pericranial mus-culotensive stress due to excessiverange of motion of the affected jointsduring daily activities, thus causingrepetitive masticatory and paravertebralmuscle damage. Some environmentalfactors, such as whiplash injuries ornon-ergonomic postures at work andschool, may facilitate myogenous painin a hypermobile individual. In thegeneral population, myogenous head-ache is usually unilateral/monofocaland may present with the additionalfeatures of focal point of tenderness ofthe involved muscle(s), induration ofthe adjacent muscle, restricted range ofmotion, presence of myofascial triggerpoint(s), as well as dizziness, tinnitusand poor balance in case of para-vertebral muscles involvement [Ben-nett, 2007]. In the presence of gJHM,simultaneous and possibly symmetricinvolvement of multiple muscles is alsopossible.

Headache attributed to TMJ dys-function may manifest as (bi-)temporalmyogenous pain with variable featuresof tension-type headache and/or mi-graine [Glaros et al., 2007]. WhetherTMJ dysfunction correlates or not withgJHM/EDS is still a matter of debate. Anearly literature review of 14 previousworks concluded that a clear associationbetween gJHM and TMJ disordercannot be delineated and further studiesare needed [Dijkstra et al., 2002].Conversely, their correlation appearsconsistent in specific populations, in-cluding children [Adair and Hecht,1993] and young/young-adult women[Pasinato et al., 2011]. Additionally,features of TMJ dysfunction can beobserved in more than 2/3 of EDSpatients [De Coster et al., 2005]. A likelyexplanation of such a discrepancy is theinverse correlation between joint-re-lated symptoms and residual gJHM, thattypically characterizes the natural his-tory of HCTDs, especially JHS/EDS-HT [Castori et al., 2011]. In otherwords, it is possible that symptomaticTMJ dysfunction is commoner amongpatients that have lost their gJHM and,then, resulted negative at standardBeighton score screening. Clear positiveassociations emerge only in studies

focused on symptomatic subpopulationsthat are inherently more “double-jointed”, such as women and children.Therefore, the correlation betweengJHM and TMJ dysfunction is expectedto be stronger than generally thought,and a link with myogenous head pain isits direct consequence.

Cervical Spine

Cervicogenic headache is a commonform of head pain, distinguishable frommigraine and tension-type headache byrestricted neck movements, pain exac-erbation by neck mobilization or ex-ternal pressure over the upper cervicaland occipital region, ipsilateral shoulderand/or arm pain and confirmatoryevidence by diagnostic anesthetic block[Sjaastad et al., 1998]. Although itspathophysiology remains largely un-known, upper (C1-C3) cervical spinedysfunction is considered a possibleunderlying mechanism [Hall et al.,2008]. The direct connection betweenthe rectus capitis posterior minor andthe dura mater, termed “myoduralbridge”, is evoked as a possible patho-genic factor in cervicogenic headache[Kahkeshani and Ward, 2012]. Themyodural bridge is essentially consti-tuted of connective tissue and itsstructural abnormality may facilitatecervicogenic headache in EDSs.

Upper cervical spine (C0-C2) hy-permobility may generate head pain alsovia direct, intermittent compression ofnerve roots, usually in association withspecific neck movements, such as lateralflexion and rotation. This is the case of“neck-tongue syndrome”, a peculiarand apparently rare form of headachedominated by sudden occipital stabassociated with (homolateral) tonguenumbness [Sjaastad and Bakketeig,2006]. In many patients, pathology ofC0-C1 and/or C1-C2, also comprisingfractures, may be demonstrated [Orrelland Marsden, 1994], with instability ofthe odontoid process pressing on the C2nerve roots at lateral flexion/rotation as apossible explanation [Bogduk, 1981].Temporary abnormal subluxation of thelateral atlantoaxial joint, which strainsthe joint capsule, was proposed as the


likely mechanism for pain in neck-tongue syndrome. This phenomenon isexpected to occur more frequently insubjects with congenitally lax joints.Non-casual concurrence of cervico-genic headache and neck-tongue syn-drome has been reported in two cases,also showing features of cervical insta-bility [Sjaastad and Bakketeig, 2006]. Itis, therefore, expected that future studieswill investigate the prevalence of cervi-cogenic headache and neck-tonguesyndrome in patients with gJHM andEDSs.

NDPH is characterized by bilateral(occipital) head pain with commonmigranous features, absence of pain-free time, moderate-to-severe intensityand female preponderance [Rozen,2011]. A preliminary study by Rozenet al. [2006] on 12 patients withNDPH finds positive Beighton scorein 10 subjects and clinical findingsindicative of cervical instability ineleven. The relationship between cer-vical spine hypermobility and headpain has been explained by the authorsas the consequence of an influence onthe trigeminal and cervical afferents tothe trigeminal nucleus caudalis by ahypermobile spine [Rozen et al.,2006]. In other words, an instablecervical spine may cause functionalbrainstem compression possibly influ-enced by neck movements and damag-ing the sensory fibers entering thenucleus caudalis. In line with this, arecent study demonstrated positionalcervical spinal cord compression infibromyalgia [Holman, 2008], a fre-quent co-morbility in gJHM [Gedaliaet al., 1993; Ofluoglu et al., 2006;Sendur et al., 2007] with possiblepathophysiologic links with EDSs.

Most features related to NDPH areprobably linked to occipitoatlantoaxialjoint (OAAJ) instability. However, alsosubaxial instability may have a role in thedevelopment of neck and head pain inJHS/EDS-HT. Generally speaking, it isstill debated whether gJHM predisposesto or rather protects from precociousosteoarthritis [Dolan et al., 2003]. Incontrast to limb joints for which causalcorrelation between gJHM and preco-cious degenerative changes is unclear,

spondylosis of the cervical spine isusually observed at C5–6, which arethemost mobile segments of the cervicalspine. Therefore, it is likely that con-stitutional gJHM may accelerate thisprocess and determine degenerative discdisease with consequent (persistent— incontrast to intermittent compressionsinherently related to a hypermobilespine) spinal cord/nerve roots compres-sion at an early age. In addition to bonycompressions of cranial nerves andbrachial plexus nerves due to an instablecervical spine, by studying peripheralnerves, Granata et al. [2013] suggest anincreased rate of spontaneous nervesubluxations, which may contribute toneuropathic pain in EDS, also possiblycomprising head and neck pain.

The mechanism by which OAAJinstability contributes to headache maybe more complex than expected. Mil-horat et al. [2007] report clinical andneuroradiological features of a largegroup of patients with failure of surgeryfor Chiari malformation type 1. Ap-proximately 13% of them have unspe-cific features of HCTD and presentmore severe and common satellitesymptoms, such as nausea, dysphagia,sleep apnea, double vision and cardio-vascular dysautonomia. Neuroradiolog-ically, these patients display OAAJhypermobility and cranial settling (i.e.,reduced distance between basion andodontoid), in addition to cerebellartonsillar descent. The authors suggestthat cranial settling and consequentherniation of the cerebellar tonsils aresecondary to the increasedmotion of theOAAJ, in turn attributed to congenitallaxity of C0-C2 ligaments. In thesepatients, brainstem symptoms, as well asheadache, may be secondary to brain-stem compression as a result of OAAJinstability combined with the conse-quences of cerebellar tonsillar descent.On a pathogenic perspective, OAAJinstability and “functional” Chiari mal-formation may have further long-termconsequences, including an incompleteand/or intermittent arachnoid block atthe foramen magnum level with con-sequent dissociation of the CSF pressurefacilitated by Valsalva’s maneuvers andheart cycle [Williams, 1981]. This

phenomenon may determine structuralfeatures, including syringomyelia [Lev-ine, 2004] which likely go underdiag-nosed in EDSs, and may contribute tothe understanding of the associatedsymptoms.

Hypothesis: Remote Implicationsof Cervical Spine Pathology inEhlers–Danlos Syndrome(s)

Previous considerations magnify therole of cervical spine instability inheadache manifestations of EDS. Con-sequences of an instable cervical spinedue to constitutionally lax ligamentsmay extend much beyond head andneck pain. Lessons come from rheu-matoid arthritis (RA), a rheumatologiccondition, which is commonly com-plicated by an acquired form of cervicalinstability. This phenomenon arisesfrom the typical destructive synovitis,which causes bone erosions and liga-mentous laxity, the latter eventuallyleading to instability of the cervicalspine variably presenting with atlan-toaxial subluxation, cranial settling andsubaxial subluxation [Wasserman et al.,2011]. Involvement of the cervicalspine is common in RA, with cranio-cervical complications observed in 30–50% of the patients who have had RAmore than 7 years, and atlantoaxialsubluxation with cervical myelopathyin 2.5% of those with RA for morethan 14 years [Moskovich et al., 1996].Neck pain with occipital headache isthe most common associated complaint[Rawlins et al., 1998]. Further forms ofhead pain include occipital neuralgia,facial pain and ear pain secondary tocompression of C1 and C2 nerve roots.Patients who develop cervical myelop-athy may also manifest a plethora ofadditional features, such as increasedfatigue and/or musculoskeletal pain,balance, gait control, coordination andproprioception deficiency, contrac-tures, paresthesias, tinnitus, vertigo,diplopia, visual deficits, dysphagia,bladder and bowel dysfunction[Wasserman et al., 2011].

Table I summarizes a spectrum ofancillary neurological findings, which arenot included in the available diagnostic

TABLE I. EDSs and JHS Ancillary Features Which May Be Influenced by anUnderlying Cervical Spine Pathology

Feature

Dizziness/vertigoNumbness (i.e., peripheral hypo/anesthesias)Dysesthesias (e.g., allodynia, hyperalgesia, burning sensations, etc.)ParesthesiasTremulousnessLimb muscle weaknessLack of balance and coordinationAbnormal movements (e.g., fasciculations, periodic limb movements, dystonias)Bladder dysfunctionUnexplained ocular/visual and auditory disturbances (e.g., tinnitus, diplopia)Minor memory and concentration disturbancesHand interosseous muscles hypotrophy


criteria of EDSs and JHS, but may be notrarely encountered in the daily activity ofspecialized clinics, especially in patientswith JHS/EDS-HT. Similarly to RA, inEDS, these features, which often representmajor burdens for affected individuals butstill remain pathogenically unexplained,may be easily traced back to repeatedcompressive damage on brainstem andspinal cord by an instable cervical spine. InEDS, a stable compressive process, such asfixed vertebral subluxation or posteriorannulus bulging, can be demonstratedrarely. In presence of cervical spine hyper-mobility, brainstem/spinal cord compres-sion is strictly influenced by neckmovements and postural changes. Con-sequently, in EDS patients with disablingsymptoms purportedly linked to an occultcervical spine pathology, standard cervicalspine X-rays in static position andMRI inclinostatism, performed as baseline inves-tigations in patients with chronic neck/head pain, usually fail to demonstratesignificant changes. This implies a generalunderestimation of cervical spine pathol-ogy inEDS andmayexplain the actual lackof knowledge on the cause of manyreported symptoms. Eventually, this causesfurtherworseningof thedisease statedue topatients’ perception of being not fullyupheld in healthcare environment. Inves-tigating the “positional cervical spinal cordcompression” may be a possible field offuture research in EDS, as demonstrated infibromyalgia patientswith aMRIprotocol,

including acquisitions in flexion andextension of the cervical spine[Holman, 2008].

Cerebrospinal Fluid and Meninges

Meninges are further structures sur-rounding the central nervous system,which display a high content in con-nective tissue and its various fibrillarcomponents.Meningeal involvement is awell consolidated concept in variousHCTDs, includingMarfan, Loeys–Dietzand EDSs [Loeys et al., 2010], as well asthe rarer and prototypic lateral menin-gocele syndrome [Gripp et al., 1997]. Inline with this, gJHM and Marfanoidhabitus is observed in a significantproportion of patients suffering fromheadache attributed to idiopathic intra-spinal hypotension [Schrijver et al., 2002;Schievink et al., 2004]. Complementar-ily, spontaneous intraspinal hypotensionis repeatedly described in Marfan syn-drome, osteogenesis imperfecta andEDSs [Eddeine et al., 2009; Voermanset al., 2009; Grosveld et al., 2011;Reinstein et al., 2013].

CSF leakage is thought to occur viathe excessive distension and/or ruptureof spontaneous dilatations (e.g., cysts andectasias), as well as microscopic, multiplefenestrations of the meninges [Schie-vink, 2006]. Neuroradiological studiesidentify a series of imaging features,which also comprise downward dis-

placement of the brain with flatteningof the pons against the clivus and Chiarimalformation-like changes [Fishmanand Dillon, 1993]. Therefore, it is likelythat at least some symptoms linked toidiopathic intraspinal hypotension aredue to an incomplete arachnoid block atthe level of the foramen magnum, thusmagnifying, by a downward spiral, thedissociation of CSF pressure. Accord-ingly, EDSs may be considered anexceptional condition in which twoapparently distinct mechanisms of headpain (i.e., OAAJ instability and sponta-neous CSF leakage) converge on thesame pathogenic mechanism (i.e., dis-sociation of the CSF pressure at theforamen magnum characterized by in-traspinal hypotension and raising of theintracranial CSF pressure) with multi-plicative deleterious effects on symptomdevelopment and treatment outcome.This hypothesis is partly supported by therepeated observation of intraspinal hy-potension due to idiopathic CSF leakageassociated withChiari malformation andsyringomyelia, the latter being consid-ered a long-term anatomic consequenceof incomplete arachnoid block at thebrainstem/spinal cord [Mamelak et al.,1996; Johnston et al., 1998; Pratiparna-watr et al., 2000; Sharma et al., 2001;Owler et al., 2004]. Intriguingly and inpartial support of the plausibility ofMonroe–Kellie hypothesis in EDS, thereis a 36-year-old woman with JHS/EDS-HT and generalized headache due toidiopathic intracranial hypertension[Kurian and Solomon, 2013]. Therefore,in EDSs, the searching for OAAJinstability and abnormal CSF drainageshould not bemutually exclusive, as bothmay concur in symptom developmentand need specific care.

Additional Contributors

It is well known that, in the generalpopulation, “headache, particularlymorning headache and chronic head-ache may be consequent to, or aggra-vated by, a sleep disorder, andmanagement of the sleep disorder mayimprove or resolve the headache”[Rains and Poceta, 2006]. Quality ofsleep is generally poor in EDSs


[Verbraecken et al., 2001; Tinkle, 2010;Voermans et al., 2010b] and possiblecauses include periodic limbmovementsand nocturnal musculoskeletal pain[Verbraecken et al., 2001; Voermanset al., 2010a]. True sleep apnea seemsrelatively rare in EDSs [Verbraeckenet al., 2001]. However, a higher rate ofnocturnal incomplete airway obstruc-tion, including primary snoring andupper airway resistance syndrome[Rains and Poceta, 2006], due tooropharyngeal hypotonia and soft tissuelaxity, may be present. Accordingly, arecent paper reporting results of poly-somnography in 34 EDS patients dem-onstrates flow limitation, apneas andhypopneas with a decrease in flowlimitation and an increase of apnea andhypopnea events with age. Rhinoman-ometry also shows increased nasalresistance [Guilleminault et al., 2013].

The third edition of the Interna-tional Classification of Headache Disor-ders recognizes medication-overuseheadache with specific entries for simpleanalgesic, opioid and combined analgesicoveruse headaches, as well as for opioid-withdrawal headache. Given the highrate of recurrent/chronic musculoskele-tal pain in various forms of EDS [Voer-mans et al., 2010a] and its usualrefractoriness to standard treatments[Castori et al., 2012], pain-killer drugsoveruse may be frequently reported inthese patients. This possibility in EDSand, particularly, JHS/EDS-HThas beenrecently emphasized [Martin and Neil-son, 2014], and accurate gathering of thedrug medical use for headache and otherpainful manifestations is crucial for

TABLE II. Checklist fo

Item

Full neurological assessment (history and exaAssessing temporomandibular jointAssessing cervical spine mobility/instability (Checking for pericranial muscle hyperalgesiaChecking for postural intolerance and influeChecking for sleep quality by appropriate scChecking for pain-killer drugs chronic use/o

avoiding amplification of side effectsrelated to drugs.

The natural history of headache inJHS/EDS-HT tells us an evolvingphenotype with progressive chronifica-tion and mixture of different clinicalforms of headache in the same individual[Castori et al., 2013]. A contributor tosuch a transformation may be theneuronal plasticity leading to painsensitization. Its existence in JHS/EDS-HT has been first postulated in2009 by Grahame by describing kinesi-ophobia as a major prognostic determi-nant in JHS/EDS-HT. This hypothesiswas subsequently supported by moreobjective data [Rombaut et al., 2011].Kinesiophobia is a maladaptive cogni-tion considered one cognitive counter-part of central sensitization. Rombautet al. [2014] demonstrated primary andsecondary hyperalgesia in JHS/EDS-HT, a preliminary but encouragingproof for central sensitization in EDS.On a practical point of view, chron-ification, loss of pain localization, so-matic hyperalgesia and allodynia areanamnestic features suggestive for theinstauration of central sensitization in anEDS headache patient.

ASSESSMENTCONSIDERATIONS

Assessing and managing headache dis-orders in EDSs is a frustrating task.Such a complexity is two-fold. First,practitioners not previously experi-enced in HCTDs have difficulties insuspecting and, then, promptly diag-nosing EDS. Second, even when a

r Assessing the Headache Patient with Ehler

mination)

also including postural intraoral/perioral/retroau/tendernessnces on headache triggering/modulationales/questionnaires (e.g., Epworth sleepiness scalveruse

patient is recognized as affected by aspecific EDS variant, the clinical ap-proach to the referring symptom (e.g.,headache) lacks of any systemized bodyof evidence supporting the practi-tioner’s work. Among the variousforms of EDS, special attention shouldbe posed at variants with increasedvascular fragility, namely vEDS, kypho-scoliotic and cEDS with arterial rup-ture [De Paepe and Malfait, 2012]. Inthese subtypes, rapid diagnosis may becrucial for more accurately tailoringdangerous interventions, such as cath-eterization [Malfait and De Paepe,2009] for angio-TC and MRI withgadolinium enhancement, and pru-dently evaluating symptoms, particu-larly in case of thunderclap or unusuallypainful headaches. Especially in thesecircumstances, formal confirmation ofthe EDS subtype by reliable laboratorytests according to Mayer et al. [2013]should be encouraged.

Outside the emergence of excru-ciating headache in a patient withsuspected/confirmed EDS subtypewith increased vascular risk, the patientshould be carefully assessed by inves-tigating all the potential contributors tohead pain as previously illustrated(Table II). Recorded symptoms mayguide specific instrumental investiga-tions with the aim of identifying and,possibly, quantifying the contribution ofthe various possible triggers pleiotropi-cally related to the underlying connec-tive tissue dysplasia (Table III). Theassessment phase should be carriedour carefully following specific “redflags”, whose adherence may be useful

s–Danlos Syndrome

ricular paresthesias)

e)

TABLEIII.

Possibly

UsefulInvestigationsforHeadachein

Ehlers–Dan

losSyn

dromes

Investigation

Incase

ofFeatures

tosearch

Brain

angio-MRI

Thu

nderclap

orun

usually

painfulheadache

Intracranialvascular

accident

Tilt-test

Ortho

static

intolerance

Posturalorthostatic

tachycardiaor

otherdysauton

omic

profiles.

Polysomno

graphy

Morning

headache

Sleepfragmentatio

n,arou

salsandno

cturnalapneas.

Static

anddynamic

cervicalspine

radiog

raph

atstandard

projectio

n

Occipitalheadache

with

features

ofcervicalspineinstability

Fixedvertebraesublux

ations,spon

dylosis,lossof

theph

ysiologicalcurvature,

measurementof

theanterior

andpo

sterioratlantod

entalintervals,radiog

raph

icsig

nsof

cranial

settlin

g(M

cGregor’slin

e,Ranaw

atindex,

etc.),antero-andpo

stero-listhesis

atflexion

andhyperextensio

n,changesin

length

oftheanterior

andpo

sterioratlantod

ental

intervals,po

steriortiltin

gof

thedens

ofC2at

flexion

.Static

anddynamic

cervicalspineradiog

raph

atop

enmou

th/odo

ntoidprojectio

n

Neck–

tongue

synd

rome

Lateraldeviationof

theod

ontoid

process;laterallisthesisof

C1-C2.

Brain

MRIwith

outgado

linium

Migraine,

occipitalheadache,

orthostatic

headache

White

matterlesio

ns,cerebellartonsillar

herniatio

n,engorgem

entof

veno

usstructures,pituitary

hyperemia,saggingof

thebrain,

subduralflu

idcollections.

CervicalspineMRIwith

outgado

linium

Occipitalheadache,

symptom

sof

myelopathy

Cervicalspon

dylosis,cervicalcompressio

nof

thebrainstem/spinalcord.

TotalspineMRIwith

outgado

linium

Ortho

static

headache,

symptom

sof

myelopathy

Dilatatio

ns/ectasias/diverticulaof

themeninges,dilateddu

ralveins,extrathecalcerebrospinalflu

idcollections,syringom

yelia.

Brain/spine

MRIwith

gado

linium

Ortho

static

headache

with

negative/

inconsistentresults

atMRIwith

out

gado

linium

Enh

ancementof

thepachym

eninges.


for subsequent treatment planning(Table IV).

MANAGEMENTCONSIDERATIONS

Data on treatment outcomes of head-ache in EDSs are still missing in theliterature. Unpublished experience sug-gests that in the most common forms ofEDSs, headache disorders rarely havespontaneous resolution and are usuallylinked to degenerative processes ofcollagen-rich non-ossified tissues. Dis-ease progression is unpredictable.Nevertheless, an onset in the form ofepisodic/recurrent single-type head-ache and slow progression in a chronic,mixed and highly disabling headache isfrequently observed, at least, in the JHS/EDS-HT [Castori et al., 2013]. Singletreatment unsuccessfulness is commonand the planning of more integratedapproaches suffers of the likely simulta-neousness of multiple pathophysiolog-ical processes. Therefore, at themoment, prevention strategies appearthe most effective approach for symp-tom control in the a-/oligo-sympto-matic patient. General lifestylerecommendations for the congenitallyhypermobile patient and the headachepatient with orthostatic intolerance maybe found in Castori et al. [2012] andMack et al. [2010] and are summarizedin Table V.

Standardized pharmacologic treat-ments for most primary headache dis-orders, mainly including migraine, areavailable [Bendtsen et al., 2012]. Anyadjustment specifically addressed forEDS has not yet been published. Inlight of some empiric considerations ofdisease characteristics and anecdotalobservations, specific drugs, includingacetylsalicylic acid, myorelaxants, corti-costeroids (chronic treatments), opioidsand anti-epileptics, should be handledwith care due an increased risk of sideeffects, at least, in JHS/EDS-HT [Cas-tori et al., 2012]. Expert opinion ondrug therapy in EDS is reported in thereview by Martin and Nelson [2014]with annotations by type of headache.Among the various psychologicalapproaches, behavioral treatments,

TABLE IV. Red Flags in Treating Headache in the Ehlers-Danlos Syndromes

Red flag

Classify accurately (co-) existent headache disorder(s)Support symptomatic classification by searching organic triggers, as proposed in Table IIPromote an integrated approach by using simultaneously multiple therapeutic resourcesPostpone the use of drugs with presumed higher rate of side effects in Ehlers–Danlos syndromea

Consider first physical therapy and conservative approachesPromote adhesion to general lifestyle recommendations, as proposed in Table V

aIncluding acetilsalycilic acid, myorelaxants, corticosteroids (chronic treatments), opioids and anti-epileptics.


including relaxation, biofeedback andcognitive-behavioral therapy, are themost promising for various forms ofheadache [Nicholson et al., 2011]. Inlight of the prominent role of malad-aptive cognitions in pain chronicizationin JHS/EDS-HT, a potentially highimpact has been recently envisaged forcognitive behavioral therapy [Grahame,2009].

Physical therapy for head/neck painis usually focused on treating TMJ,upper spine and limbs. No specificguidelines are available for the hyper-mobile patient; however, some practicalconsiderations emerge from availableliterature. In particular, TMJ dysfunc-tion/instability may be conservatively

TABLE V. Lifestyle RecommendationEhlers-Danlos Syndrome Patie

Recommendations

Promote regular, aerobic fitnessPromote postural and ergonomic hygiene ofPromote daily relaxation activitiesPromote early treatment of malocclusionAvoid hard foods intake and excessive jaw mAvoid high-impact sports/activitiesAvoid excessive weight lifting/carryingIn case of orthostatic intolerance (or documPromote assumption of generous isotonicPromote assumption of high salt intake (aPromote use of elastic stocks (and/or abdoPromote sleeping on a sloping surface (10Avoid large meals (especially of refined caAvoid prolonged sitting positions and prolAvoid sudden head-up postural changesIllustrate counter-maneuvers to apply in c

managed by orofacial myofunctionaltherapy [de Felício et al., 2010]. Neckpain is successfully treated with ther-apeutic exercises [Pangarkar and Lee,2011], spinal manipulation with betterresults than mobilization [Vernon andHumphreys, 2008] and traction.Although, any trial is not availableinvestigating the effects of traction byan evidenced-based approach, isolatedobservations suggest effective applica-tions of this technique for treatingsyringomyelia and basilar invagination[Joseph and Rajshekhar, 2003]. Whilebasilar invagination seems rare in EDSexcept in forms with markedly reducedbone mass (e.g., EDS kyphoscoliotic,EDS/osteogenesis imperfecta overlap),

s and Prevention Strategies for thent with Focus on Headache

the spine and upper limbs

ovements (ice, gums, etc.)

ented cardiovascular dysautonomia):liquid intake (2–2.5 L/day)voided in case of arterial hypertension)minal binders)–15 degree grade)rbohydrate)onged recumbency

ase of exacerbation of symptoms

neck traction may be considered anadjuvant pre-treatment and/or post-treatment in case of undeferred surgicalintervention [Simsek et al., 2006; Bo-telho et al., 2007; Peng et al., 2011], aspreviously demonstrated in other ge-netic disorders with OAAJ instability,such as Down syndrome [Taggard et al.,1999]. Chiropractic management hasbeen reported successfully in two adultEDS patients with headache [Collocaand Polkinghorn, 2003]. Hence, chiro-practic may be considered an alternativetherapeutic resource in EDS, althoughits use should be performed with agentle touch considering softness oftissues. Acupuncture is a furthernon-traditional treatment reportedlysuccessful in selected cases of EDSpatients with headache [Martin andNelson, 2014].

Consolidated evidence indicatesimprovement of symptoms by orthosisapplications in various forms of head-ache possibly related to gJHM. Inparticular, neuromuscular orthosis maybe considered in NDPH [Didier et al.,2011] and headache attributed to TMJdysfunction/instability [Cooper andKleinberg, 2009], while palatal non-occluding splint may be successfullyused for improving quality of life ofmigraineurs [Shevel, 2005]. Moreover,application of cervical collar resultseffective in >50% pediatric patientswith atlantoaxial rotatory subluxation[Beier et al., 2012], a possible compli-cation of gJHM.

Formally, surgery has a very limitedapplication for the treatment of head-ache in EDS. Occasionally, headachemay be associated with Chiari


malformation, which is reasonablytreated with surgery. Nevertheless, re-cent evidence indicates a very lowefficacy for standard surgery of Chiarimalformation in patients with heredi-tary connective tissue disorders due tothe high risk of recurrence [Milhoratet al., 2007]. The advent of innovativetechniques and accurate patients’ strat-ification could identify, in the future,discrete applications for invasive ap-proaches in highly selected subjects.Injections of autologous blood are awell consolidated treatment option forpersistent spinal CSF leakage [Schie-vink, 2006]. Prolotherapy with 10%dextrose or autologous blood is a furtherpromising approach for symptomaticTMJ instability [Refai et al., 2011;Triantafillidou et al., 2012]. Comparablywith other conditions (e.g., RA andDown syndrome) with cervical spineinstability due to ligamentous laxity,canonical surgery could be consideredin presence of marked instability andunresponsiveness to conservative treat-ments. The surgical repertoire includesvarious approaches, comprising occipi-tovertebral fusion [Garrido and Sasso,2012], C1-C2 posterior fixation (Jacob-son et al., 2012) and subaxial cervicalfixation [Pelton et al., 2012]. Possibleapplications of these or, perhaps, noveltechniques could be considered in thefuture, after accurate neuroimagingstudy and repeated evidence of failureof other approaches.

Finally, in all EDS patients, spinalanesthesia should be performed withcare in order to avoid the risk of post-dural puncture headache [Turnbull andShepherd, 2003], in consideration of apresumed meningeal fragility. More ingeneral, any surgical procedure shouldbe performed after accurate planningand considering the peculiarities of andthe risks related to the underlyingdisorder, in order to avoid preventablecomplications also including headache[Burcharth and Rosenberg, 2012; Cas-tori, 2012b].

CONCLUSIONS

The present review outlined a veryfragmented picture of headache in

EDSs. While practice and literatureindicate a high prevalence of this featurein EDS, available data do notmirrorwithevidence such a clinical need. At themoment, we have a too small knowledgeof the spectrum of headache disorderslinked to gJHM/EDS and, consequently,of the underlying pathophysiologicmechanisms, as well as potentially effica-cious treatments. Except of a limitednumber of preventive interventionsrelating to patients’ lifestyle and practi-tioners’ choices, management of head-ache in EDS still relies on personalexperience rather than shared informa-tion. We hope that the dissection of theclinical and pathological basis of head-ache in EDSwill become a field of futureresearch, whose outcomes could extendbeyond the group of patients withgeneralized HCTDs but also to individ-uals manifesting limited/regional fea-tures of a hereditary or acquiredconnective tissue dysplasia.

ACKNOWLEDGMENTS

No funding was active on this project.All authors declare that there is noconflict of interest concerning thiswork.

REFERENCES

Adair SM, Hecht C. 1993. Association ofgeneralized joint hypermobility with his-tory, signs, and symptoms of temporoman-dibular joint dysfunction in children. PediatrDent 15:323–326.

Ballegaard V, Thede-Schmidt-Hansen P, SvenssonP, Jensen R. 2008. Are headache andtemporomandibular disorders related. Ablinded study. Cephalalgia 28:832–841.

Beier AD, Vachhrajani S, Bayerl SH, Aguilar CY,Lamberti-Pasculli M, Drake JM. 2012.Rotatory subluxation: Experience fromthe hospital for sick children. J NeurosurgPediatr 9:144–148.

Beighton P, De Paepe A, Steinmann B, TsipourasP, Wenstrup RJ. 1998. Ehlers-Danlos syn-dromes: revised nosology, Villefranche,1997. Ehlers-Danlos National Foundation(USA) and Ehlers-Danlos Support Group(UK). Am J Med Genet 77:31–37.

Bendik EM, Tinkle BT, Al-shuik E, Levin L,Martin A, Thaler R, Atzinger CL, Rueger J,Martin VT. 2011. Joint hypermobilitysyndrome: A common clinical disorderassociated with migraine in women. Ceph-alalgia 31:603–613.

Bendtsen L, Birk S, Kasch H, Aegidius K,Sørensen PS, Thomsen LL, Poulsen L,

Rasmussen MJ, Kruuse C, Jensen R. 2012.Reference programme: Diagnosis and treat-ment of headache disorders and facial pain.Danish Headache Society, 2nd Edition. JHeadache Pain 13:S1–S29.

Bennett R. 2007. Myofascial pain syndromes andtheir evaluation. Best Pract Res ClinRheumatol 21:427–445.

Bogduk N. 1981. An anatomical basis for theneck-tongue syndrome. J Neurol NeurosurgPsychiatry 44:202–208.

Bohora S. 2010. Joint hypermobility syndromeand dysautonomia: Expanding spectrum ofdisease presentation and manifestation. In-dian Pacing Electrophysiol J 10:158–161.

Botelho RV, Neto EB, Patriota GC, Daniel JW,Dumont PA, Rotta JM. 2007. Basilarinvagination: Craniocervical instabilitytreated with cervical traction and occipito-cervical fixation. Case report. J NeurosurgSpine 7:444–449.

Burcharth J, Rosenberg J. 2012. Gastrointestinalsurgery and related complications in patientswith Ehlers-Danlos syndrome: A systematicreview. Dig Surg 29:349–357.

Castori M, Camerota F, Celletti C, Danese C,Santilli V, Saraceni VM, Grammatico P.2010. Natural history and manifestations ofthe hypermobility type Ehlers-Danlos syn-drome: A pilot study on 21 patients. Am JMed Genet A 152A:556–564.

Castori M, Morlino S, Celletti C, Celli M,Morrone A, Colombi M, Camerota F,Grammatico P. 2012. Management of painand fatigue in the joint hypermobilitysyndrome (a.k.a. Ehlers-Danlos syndrome,hypermobility type): Principles and proposalfor a multidisciplinary approach. Am J MedGenet A 158A: 1:2055–2070.

Castori M, Morlino S, Celletti C, Ghibellini G,Bruschini M, Grammatico P, Blundo C,Camerota F. 2013. Re-writing the naturalhistory of pain and related symptoms in thejoint hypermobility syndrome/Ehlers-Dan-los syndrome, hypermobility type. Am JMed Genet A 161A: 1:2989–3004.

Castori M, Sperduti I, Celletti C, Camerota F,Grammatico P. 2011. Symptom and jointmobility progression in the joint hyper-mobility syndrome (Ehlers-Danlos syn-drome, hypermobility type). Clin ExpRheumatol 29:998–1005.

Castori M. 2012a. Ehlers-Danlos syndrome,hypermobility type: An underdiagnosedhereditary connective tissue disorder withmucocutaneous, articular, and systemicmanifestations. ISRN Dermatol 2012:751768.

Castori M. 2012b. Surgical recommendations inEhlers-Danlos syndrome(s) need patientclassification: The example of Ehlers-Danlossyndrome hypermobility type (a.k.a. jointhypermobility syndrome). Dig Surg 29:453–455.

Chuang YM, Hwang YC, Lin CP, Liu CY. 2008.Toward a further elucidation: Role ofvertebral artery hypoplasia in migrainewith aura. Eur Neurol 59:148–151.

Chuman H, Trobe JD, Petty EM, Schwarze U,Pepin M, Byers PH, Deveikis JP. 2002.Spontaneous direct carotid-cavernous fistulain Ehlers-Danlos syndrome type IV: Twocase reports and a review of the literature. JNeuroophthalmol 22:75–81.


Colloca CJ, Polkinghorn BS. 2003. Chiropracticmanagement of Ehlers-Danlos syndrome: Areport of two cases. J Manipulative PhysiolTher 26:448–459.

Cooper BC, Kleinberg I. 2009. Relationship oftemporomandibular disorders to muscletension-type headaches and a neuromuscularorthosis approach to treatment. Cranio27:101–108.

De Coster PJ, Van den Berghe LI, Martens LC.2005. Generalized joint hypermobility andtemporomandibulardisorders: Inherited con-nective tissue disease as a model with maxi-mum expression. J Orofac Pain 19:47–57.

de Felício CM, de Oliveira MM, da Silva MA.2010. Effects of orofacial myofunctionaltherapy on temporomandibular disorders.Cranio 28:249–259.

De Paepe A, Malfait F. 2012. The Ehlers-Danlossyndrome, a disorder with many faces. ClinGenet 82:1–11.

De Wandele I, Rombaut L, Leybaert L, Van deBorne P, De Backer T,Malfait F, De Paepe A,Calders P. 2014. Dysautonomia and itsunderlying mechanisms in the hypermobil-ity type of Ehlers-Danlos syndrome. SeminArthritis Rheum 44:93–100.

Di Palma F, Cronin AH. 2005. Ehlers-Danlossyndrome: Correlation with headache dis-orders in a young woman. J Headache Pain6:474–475.

Didier H, Marchetti C, Borromeo G, Tullo V,D’amico D, Bussone G, Santoro F. 2011.Chronic daily headache: Suggestion for theneuromuscular oral therapy. Neurol Sci 32:():S161–S164.

Dijkstra PU, Kropmans TJ, Stegenga B. 2002. Theassociation between generalized joint hyper-mobility and temporomandibular joint dis-orders: A systematic review. J Dent Res81:158–163.

Dolan AL, Hart DJ, Doyle DV, Grahame R,Spector TD. 2003. The relationship of jointhypermobility, bone mineral density, andosteoarthritis in the general population: TheChingford Study. J Rheumatol 30:799–803.

Eddeine HS, Dafer RM, Schneck MJ, Biller J.2009. Bilateral subdural hematomas in anadult with osteogenesis imperfecta. J StrokeCerebrovasc Dis 18:313–315.

Fishman RA, Dillon WP. 1993. Dural enhance-ment and cerebral displacement secondaryto intracranial hypotension. Neurology43:609–611.

Garrido BJ, Sasso RC. 2012. Occipitocervicalfusion. Orthop Clin North Am 43:1–9.

Gazit Y, Nahir AM, Grahame R, Jacob G. 2003.Dysautonomia in the joint hypermobilitysyndrome. Am J Med 115:33–40.

Gedalia A, Press J, Klein M, Buskila D. 1993. Jointhypermobility and fibromyalgia in school-children. Ann Rheum Dis 52:494–496.

Glaros AG,UrbanD, Locke J. 2007. Headache andtemporomandibular disorders: Evidence fordiagnostic and behavioural overlap. Cepha-lalgia 27:542–549.

González de la Aleja Tejera J, Porta-Etessam J.2008. [Neck-tongue syndrome. Possiblejoint hypermobility as an aetiopathogenicprocess]. An Pediatr (Barc) 69:484–485.

Grahame R, Bird HA, Child A. 2000. The revised(Brighton 1998) criteria for the diagnosis ofbenign joint hypermobility syndrome(BJHS). J Rheumatol 27:1777–1779.

Grahame R. 2009. Joint hypermobility syndromepain. Curr Pain Headache Rep 13:427–433.

Granata G, Padua L, Celletti C, Castori M,Saraceni VM, Camerota F. 2013. Entrap-ment neuropathies and polyneuropathies injoint hypermobility syndrome/Ehlers-Dan-los syndrome. Clin Neurophysiol 124:1689–1694.

Gripp KW, Scott CI, Jr, Hughes HE, WallersteinR, Nicholson L, States L, Bason LD, KaplanP, Zderic SA, Duhaime AC, Miller F,Magnusson MR, Zackai EH. 1997. Lateralmeningocele syndrome: three new patientsand review of the literature. Am J MedGenet 70:229–239.

Grosveld WJ, Gilhuis HJ, Voermans NC. 2011.Spontaneous intracranial hypotension in apatient with classical type Ehlers-Danlossyndrome. Neurol India 59:633–634.

Guilleminault C, Primeau M, Chiu HY, YuenKM, Leger D, Metlaine A. 2013. Sleep-disordered breathing in Ehlers-Danlos syn-drome: A genetic model of OSA. Chest144:1503–1511.

Hakim AJ, Sahota A. 2006. Joint hypermobilityand skin elasticity: The hereditary disordersof connective tissue. Clin Dermatol 24:521–533.

Halko GJ, Cobb R, Abeles M. 1995. Patients withtype IV Ehlers-Danlos syndrome may bepredisposed to atlantoaxial subluxation. JRheumatol 22:2152–2155.

Hall T, Briffa K, Hopper D. 2008. Clinicalevaluation of cervicogenic headache: Aclinical perspective. J Man Manip Ther16:73–80.

Havlik DM, Nashelsky MB. 2006. Rupturedcerebral artery aneurysm and bacterialmeningitis in a man with osteogenesisimperfecta. Am J Forensic Med Pathol27:117–120.

Headache Classification Committee of the Inter-national Headache Society. 2013. TheInternational Classification of HeadacheDisorders (beta version). ClassificationCommittee of the International HeadacheSociety (IHS) 33:629–808.

Hermanns-Lê T, Reginster MA, Piérard-Fran-chimont C, Delvenne P, Piérard GE,Manicourt D. 2012. Dermal ultrastructurein low Beighton score members of 17families with hypermobile-type Ehlers-Danlos syndrome. J Biomed Biotechnol2012:878107.

Holman AJ. 2008. Positional cervical spinal cordcompression and fibromyalgia: A novelcomorbidity with important diagnosticand treatment implications. J Pain 9:613–622.

Holman AJ. 2008. Positional cervical spinal cordcompression and fibromyalgia: A novelcomorbidity with important diagnostic andtreatment implications. J Pain 9:613–622.

Jacobson ME, Khan SN, An HS. 2012. C1-C2 posterior fixation: indications, technique,and results. Orthop Clin North Am 43:11–18.

Jacome DE. 1999. Headache in Ehlers-Danlossyndrome. Cephalalgia 19:791–796.

Johnston I, Jacobson E, Besser M. 1998. Theacquired Chiari malformation and syringo-myelia following spinal CSF drainage: Astudy of incidence and management. ActaNeurochir (Wien) 140:417–427.

Joseph V, Rajshekhar V. 2003. Resolution ofsyringomyelia and basilar invagination aftertraction. Case illustration. 298.

Kahkeshani K, Ward PJ. 2012. Connectionbetween the spinal dura mater and sub-occipital musculature: evidence for themyodural bridge and a route for itsdissection–A review. Clin Anat 25:415–422.

KurianM, SolomonGD. 2013. Can elevated IGF-1 levels among patients with Ehlers-Danlossyndrome cause idiopathic intracranial hy-pertension. Headache 53:1666–1669.

Levine DN. 2004. The pathogenesis of syringo-myelia associated with lesions at the foramenmagnum: A critical review of existingtheories and proposal of a new hypothesis.J Neurol Sci 220:3–21.

Loeys BL, Dietz HC, Braverman AC, CallewaertBL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, MilewiczDM, Pyeritz RE, Sponseller PD, Words-worth P, De Paepe AM. 2010. The revisedGhent nosology for the Marfan syndrome. JMed Genet 47:476–485.

Mack KJ, Johnson JN, Rowe PC. 2010. Ortho-static intolerance and the headache patient.Semin Pediatr Neurol 17:109–116.

Malfait F, De Paepe A. 2009. Bleeding in theheritable connective tissue disorders: Mech-anisms, diagnosis and treatment. Blood Rev23:191–197.

Mamelak AN, Fishman RA, Dillon WP, WilsonCB. 1996. Spontaneous intracranial hypo-tension. J Neurosurg 85:192–193.

Martin VT, Neilson D. 2014. Joint hypermobilityand headache: The glue that binds thetwo together – Part 2. Headache 54:1403–1411.

Mathers KS, Schneider M, Timko M. 2011.Occult hypermobility of the craniocervicaljunction: A case report and review. J OrthopSports Phys Ther 41:444–457.

Mathias CJ, Low DA, Iodice V, Owens AP, KirbisM, Grahame R. 2011. Postural tachycardiasyndrome–current experience and concepts.Nat Rev Neurol 8:22–34.

Mayer K, Kennerknecht I, Steinmann B. 2013.Clinical utility gene card for: Ehlers-Danlossyndrome types I-VII and variants – update.Eur J Hum 21:doi:10.1038/ejhg.2012.162

Milhorat TH, Bolognese PA, Nishikawa M,McDonnell NB, Francomano CA. 2007.Syndrome of occipitoatlantoaxial hypermo-bility, cranial settling, and chiari malforma-tion type I in patients with hereditarydisorders of connective tissue. J NeurosurgSpine 7:601–609.

MoskovichR, Shott S, Zhang ZH. 1996. Does thecervical canal to body ratio predict spinalstenosis. Bull Hosp Jt Dis 55:61–71.

Neilson D, Martin VT. 2014. Joint Hypermobilityand Headache: Understanding the GlueThat Binds the Two Together - Part 1.Headache 54:1393–1402.

Nicholson RA, Buse DC, Andrasik F, Lipton RB.2011. Nonpharmacologic treatments formigraine and tension-type headache: Howto choose and when to use. Curr TreatOptions Neurol 13:28–40.

Ofluoglu D, Gunduz OH, Kul-Panza E, Guven Z.2006. Hypermobility in women with fi-bromyalgia syndrome. Clin Rheumatol25:291–293.


Orrell RW, Marsden CD. 1994. The neck-tonguesyndrome. J Neurol Neurosurg Psychiatry57:348–352.

Owler BK, Halmagyi GM, Brennan J, Besser M.2004. Syringomyelia with Chiari malforma-tion; 3 unusual cases with implications forpathogenesis. Acta Neurochir (Wien)146:1137–1143.

Pangarkar S, Lee PC. 2011. Conservative treat-ment for neck pain: Medications, physicaltherapy, and exercise. Phys Med RehabilClin N Am 22:503–520.

Pasinato F, Souza JA, Corrêa EC, Silva AM. 2011.Temporomandibular disorder and general-ized joint hypermobility: Application ofdiagnostic criteria. Braz J Otorhinolaryngol77:418–425.

Pelton MA, Schwartz J, Singh K. 2012. Subaxialcervical and cervicothoracic fixation tech-niques–indications, techniques, and out-comes. Orthop Clin North Am 43:19–28.

Peng X, Chen L, Wan Y, Zou X. 2011. Treatmentof primary basilar invagination by cervicaltraction and posterior instrumented reduc-tion together with occipitocervical fusion.Spine (Phila Pa 1976) 36:1528–1531.

Pratiparnawatr P, Tiamkao S, Tanapaisal C,Kanpittaya J, Jitpimolmard S. 2000. Down-beating nystagmus and postural hypotensiondue to basilar invagination. J Med AssocThai 83:1530–1534.

Rains JC, Poceta JS. 2006. Headache and sleepdisorders: Review and clinical implicationsfor headache management. Headache46:1344–1363.

Rawlins BA, Girardi FP, Boachie-Adjei O. 1998.Rheumatoid arthritis of the cervical spine.Rheum Dis Clin North Am 24:55–65.

Refai H, Altahhan O, Elsharkawy R. 2011.The efficacy of dextrose prolotherapy fortemporomandibular joint hypermobility:A preliminary prospective, randomized,double-blind, placebo-controlled clini-cal trial. J Oral Maxillofac Surg 69:2962–2970.

Reinstein E, Pariani M, Bannykh S, Rimoin DL,Schievink WI. 2013. Connective tissuespectrum abnormalities associated withspontaneous cerebrospinal fluid leaks: Aprospective study. Eur J Hum Genet21:386–390.

Ritelli M, Dordoni C, Venturini M, Chiarelli N,Quinzani S, TraversaM, Zoppi N, VascellaroA, Wischmeijer A, Manfredini E, GaravelliL, Calzavara-Pinton P, Colombi M. 2013.Clinical and molecular characterization of40 patients with classic Ehlers-Danlos syn-drome: identification of 18 COL5A1 and 2COL5A2 novel mutations. Orphanet J RareDis 8:58.

Rombaut L, Malfait F, Cools A, De Paepe A,Calders P. 2010. Musculoskeletal com-plaints, physical activity and health-relatedquality of life among patients with theEhlers-Danlos syndrome hypermobilitytype. Disabil Rehabil 32:1339–1345.

Rombaut L, Malfait F, De Wandele I, Thijs Y,Palmans T, De Paepe A, Calders P. 2011.Balance, gait, falls, and fear of falling inwomen with the hypermobility type ofEhlers-Danlos syndrome. Arthritis Care Res(Hoboken) 63:1432–1439.

Rombaut L, ScheperM,DeWandele I, DeVries J,Meeus M, Malfait F, Engelbert R, Calders P.2014. Chronic pain in patients with thehypermobility type of Ehlers-Danlos syn-drome: Evidence for generalized hyper-algesia. Clin Rheumatol (in press) .

Rozen TD, Roth JM, Denenberg N. 2006.Cervical spine joint hypermobility:Apossiblepredisposing factor for new daily persistentheadache. Cephalalgia 26:1182–1185.

Rozen TD. 2011. New daily persistent headache:Clinical perspective. Headache. 51:641–649.

Sacheti A, Szemere J, Bernstein B, Tafas T,Schechter N, Tsipouras P. 1997. Chronicpain is a manifestation of the Ehlers-Danlossyndrome. J Pain Symptom Manage 14:88–93.

Sahin N, Karataş O, Ozkaya M, Cakmak A,Berker E. 2008. Demographics features,clinical findings and functional status in agroup of subjects with cervical myofascialpain syndrome. Agri 20:14–19.

Schievink WI, Gordon OK, Tourje J. 2004.Connective tissue disorders with spontane-ous spinal cerebrospinal fluid leaks andintracranial hypotension: A prospectivestudy. Neurosurgery 54:65–70.

Schievink WI, Meyer FB, Atkinson JL, Mokri B.1996. Spontaneous spinal cerebrospinal fluidleaks and intracranial hypotension. J Neuro-surg 84:598–605.

Schrijver I, SchievinkWI, Godfrey M, Meyer FB,Francke U. 2002. Spontaneous spinal cere-brospinal fluid leaks and minor skeletalfeatures of Marfan syndrome: A micro-fibrillopathy. J Neurosurg 96:483–489.

Sendur OF, Gurer G, Bozbas GT. 2007. Thefrequency of hypermobility and its relation-ship with clinical findings of fibromyalgiapatients. Clin Rheumatol 26:485–487.

Sharma P, Sharma A, Chacko AG. 2001.Syringomyelia in spontaneous intracranialhypotension. Case report. J Neurosurg95:905–908.

Shevel E. 2005. Craniomandibular muscles,intraoral orthoses and migraine. ExpertRev Neurother 5:371–377.

Simsek S, Yigitkanli K, Belen D, Bavbek M.2006. Halo traction in basilar invagination:Technical case report. Surg Neurol66:311–314.

Sjaastad O, Bakketeig LS. 2006. Neck-tonguesyndrome and related (?) conditions. Ceph-alalgia 26:233–240.

Sjaastad O, Fredriksen TA, Pfaffenrath V. 1998.Cervicogenic headache: Diagnostic criteria.The Cervicogenic Headache InternationalStudy Group. Headache 38:442–445.

Steinmann B, Royce PM, Superti-Furga A.2002. The Ehlers-Danlos syndrome. In:Royce PM, Steinmann B, editors. Con-nective tissue and its heritable disorders,2nd edition. New York: Wiley-Liss pp.431–524.

Taggard DA, Menezes AH, Ryken TC. 1999.Instability of the craniovertebral junctionand treatment outcomes in patients withDown’s syndrome. Neurosurg Focus6:e3.

Tanaka T, Hayakawa M, Sadato A, Adachi K,Watabe T, Maeda S, Ohmura M, Hirose Y.

2014. Transvenous embolization for carotid-cavernous fistula in a patient with vasculartype of Ehlers-Danlos syndrome–directsuperior ophthalmic vein approach: Casereport. Neurol Med Chir (Tokyo) 54:155–60.

Tinkle BT, Bird HA, Grahame R, Lavallee M,Levy HP, Sillence D. 2009. The lack ofclinical distinction between the hypermo-bility type of Ehlers-Danlos syndrome andthe joint hypermobility syndrome (a.k.a.hypermobility syndrome). Am J Med GenetA 149A:2368–2370.

Tinkle BT., 2010. Joint hypermobility handbook – aguide for the issues & management of Ehlers-Danlos syndrome hypermobility type and thehypermobility syndrome. Greens Fork: LeftPaw Press.

Triantafillidou K, Venetis G, Markos A. 2012.Short-term results of autologous bloodinjection for treatment of habitual TMJluxation. J Craniofac Surg 23:689–692.

Turnbull DK, Shepherd DB. 2003. Post-duralpuncture headache: Pathogenesis, preven-tion and treatment. Br J Anaesth 91:718–29.

Verbraecken J, Declerck A, Van de Heyning P, DeBacker W, Wouters EF. 2001. Evaluation forsleep apnea in patients with Ehlers-Danlossyndrome and Marfan: A questionnairestudy. Clin Genet 60:360–365.

Vernon H, Humphreys BK. 2008. Chronicmechanical neck pain in adults treated bymanual therapy: a systematic review ofchange scores in randomized controlledtrials of a single session. J Man ManipTher 16:E42–E52.

Voermans NC, Dijk KG, Bos MM, Geus-Oei LF,Verrips A, Lindert EJ. 2009. Postural head-ache in Marfan syndrome associated withspinal cysts and liquor hypotension. Neuro-pediatrics 40:201–204.

Voermans NC, Knoop H, Bleijenberg G, vanEngelen BG. 2010a. Pain in ehlers-danlossyndrome is common, severe, and associatedwith functional impairment. J Pain Symp-tom Manage 40:370–378.

Voermans NC, Knoop H, van de KampN, HamelBC, Bleijenberg G, van Engelen BG. 2010b.Fatigue is a frequent and clinically relevantproblem in Ehlers-Danlos Syndrome. SeminArthritis Rheum 40:267–274.

Voermans NC, Knoop H. 2011. Both pain andfatigue are important possible determinantsof disability in patients with the Ehlers-Danlos syndrome hypermobility type. Dis-abil Rehabil 33:706–707.

Wasserman BR, Moskovich R, Razi AE. 2011.Rheumatoid arthritis of the cervical spine–clinical considerations. Bull NYU Hosp JtDis 69:136–148.

Williams B. 1981. Chronic herniation of thehindbrain. Ann R Coll Surg Engl 63:9–17.

Yazici M, Ataoglu S, Makarc S, Sari I, Erbilen E,Albayrak S, Yazici S, Uyan C. 2004. Therelationship between echocardiographicfeatures of mitral valve and elastic propertiesof aortic wall and Beighton hypermobilityscore in patients with mitral valve prolapse.Jpn Heart J 45:447–460.

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