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Anxiety and joint hypermobility: An unexpected association: Examining this link can improve diagnosis and treatment of both disorders.

Joint hypermobility syndrome (JHS)--also known as Ehlers-Danlos type 3-hypermobile type (hEDS) (1)--is a poorly recognized connective tissue disorder characterized by increased joint laxity that may affect 10% to 25% of the general population. (2) Researchers are increasingly recognizing an association between JHS/hEDS and psychiatric symptoms and disorders, specifically anxiety. In this review, we describe the clinical presentation of JHS/hEDS, propose a new "Neuroconnective phenotype" based on the link between anxiety and JHS/hEDS, and discuss factors to consider when treating anxiety in a patient who has JHS/ hEDS.

JHS/hEDS: A complex disorder

Although JHS/hEDS is a heritable condition, several factors are known to influence its prevalence and visibility, including age, sex, and ethnicity; the prevalence is higher among younger patients, females, and African Americans. (2) Its known basis is the type and distribution pattern of collagen, and one of the key features used to identify this syndrome is greater joint laxity, meaning increased distensibility of the joints in passive movements as well as a hypermobility in active movements.

Although first described by two dermatologists (Edvard Ehlers and Henri-Alexandre Danlos) at the beginning of the 20th century, JHS/hEDS is now considered a multi-systemic condition. Thus, JHS/hEDS includes a wide range of musculoskeletal features, and over the recent years, extra-articular symptoms, such as easy bruising or hypertrophic scarring, have gained recognition. (3) Moreover, individuals with JHS/hEDS frequently present with stress-sensitive illnesses, such as fibromyalgia, or chronic fatigue syndrome. (4) The Table (2,5,6) provides a description of musculoskeletal and extra-articular features of JHS/hEDS.

The link between JHS/hEDS and anxiety

Psychiatric symptoms are being increasingly recognized as a key feature of JHS/ hEDS. Our group published the first case control study on the association between JHS/hEDS and anxiety in 1988. (7) Additional studies have consistently replicated and confirmed these findings in clinical and nonclinical populations, and in adult and geriatric patients. (8-12) Specifically, JHS/hEDS has been associated with a higher frequency and greater intensity of fears, greater anxiety severity and somatic concerns, and higher frequency of the so-called endogenous anxiety disorders. (6-13) There also is limited but growing evidence that JHS/ hEDS is associated with depressive disorders, eating disorders, and neurodevelopmental disorders as well as alcohol and tobacco misuse. (6,8,11,14,15)

Moving toward a new phenotype.

Whereas there is increasing evidence of somatic comorbidity in several major psychiatric disorders, present psychiatric nosology does not include specific psychiatric illnesses associated with medical conditions other than organic dementias and secondary psychiatric conditions. However, the overwhelming data on clinical comorbidity (both somatic and psychiatric) require new nosologic approaches. Following the accumulated evidence on this topic over the past 30 years, our group described the "Neuroconnective phenotype" (Figure 1) on the basis of the collected genetic, neurophysiological, neuroimaging, and clinical data. (6) The core of the phenotype includes the "anxiety-joint laxity" association and has 5 dimensions that allow for minor overlap (somatic symptoms, somatic illnesses, psychopathology, behavioral dimensions, and somatosensory symptoms). Each of the 5 dimensions includes features that may be present at different degrees with individual variations.

Biologic hypotheses that have been proposed to explain the link between anxiety and JHS/hEDS are described in the Boa (6,16-28) (page 18).

How JHS/hEDS is diagnosed

The Beighton criteria are the most common set of criteria used to diagnose JHS/ hEDS. (29) In 2000, Grahame et al (30) developed the Brighton criteria, which include some extra-articular features. The "Hospital del Mar" criteria (31) (also known as the "Bulbena criteria") were obtained after a multivariate analysis of margins from the Beighton criteria and the original set of criteria described by Rotes. They showed consistent indicators of reliability, internal consistency, and better predictive validity. (31)
What underlying mechanisms link anxiety and joint hypermobility?

Interestingly, both anxiety and joint
hypermobility syndrome/Ehlers-Danlos
type 3-hypermobile type (JHS/hEDS) are
often underdiagnosed and undertreated,
and have similar prevalence in the general
population. While it is possible that some
psychiatric symptoms can be a consequence
of adaptation and difficulties in dealing with
chronic illnesses, biologic hypotheses have
been considered to explain the association
between JHS/hEDS and anxiety. The most
accepted biologic hypotheses include:

* genetic risks

* interoceptive sensitivity

* somatosensory amplification

* emotion processing variances

* autonomic nervous system dysfunction.

A duplication of chromosome 15
(DUP-25) was found in patients with both
JHS/hEDS and an anxiety disorder, (16) but to
date, this finding has not been replicated. (17,18)
The fact that both conditions are highly
heritable suggests high likelihood of a
genetic linkage. Other theories about the
neural connections between mind and
body have been proposed. Brain and body
are intrinsically and dynamically coupled;
perceptions, emotions, and cognitions
respond to and change the state of the
body. (19) In this sense, body perception and
dysautonomia have gained recognition.

Patients with JHS/hEDS have higher
interoception, (20) meaning greater signaling
and perception of internal bodily sensations.
This is in line with Critchley's hypothesis, in
which he describes the influence of visceral
inputs over thoughts, feelings, and behavior. (21)
Consistent with Critchley's views, Porges
described the Polyvagal Theory, (22) which is
phylogenetic approach relating the autonomic
nervous system to behavior. Atypical
body awareness is a feature of multiple
disorders, including anxiety, depression,
and JHS/hEDS. (19,23,25) Interestingly, a recent
neuroimaging study found that interception
sensitivity mediated the relationship between
anxiety and hypermobility. (20)

JHS/hEDS patients have greater
exteroception (perception of environment),
nocioception (pain perception), and
somatosensory amplification. (6,26) At the
same time, they also have decreased
proprioception, (27) which could explain the
coordination difficulties they experience.
Neuroimaging studies have confirmed that
individuals with JHS/hEDS have structural
differences in key emotion processing
regions, notably affecting the amygdala
bilaterally. (28)

Together, these findings increase our
understanding about the mechanisms
through which vulnerability to anxiety
disorders and somatic symptoms arises in
certain patients.

Recently, several self-assessment questionnaires have been developed. Specifically, based on the Hakim and Grahame questionnaire, (32) our group developed a novel self-assessment questionnaire that includes pictures to facilitate the diagnosis. (33)

However, despite multiple ways of assessing JHS/hEDS, it remains mostly undiagnosed and untreated. Because of this, a new clirucian-administered checklist has been developed, (34) although this checklist does not include the psychiatric aspects of the disorder, so clinicians who use this checklist should ensure that the patient receives additional psychiatric assessment.

Transforming the clinical value into specific interventions

Anxiety disorders are chronic, disabling, and represent the 6th leading cause of disability worldwide. (35) They have a significant impact due to the high cost of frequent medical evaluations and treatment of the physical components of the disorder. (36) As a clinical marker for a homogeneous type of anxiety, JHS/hEDS can provide valuable information about a patient's complete clinical picture, especially about the somatic aspects of the disorder.

No randomized controlled trials have been conducted to evaluate pharmacotherapy as treatment for JHS/hEDS. In a cohort study, the overall use of psychotropics was significantly higher in patients with JHS/ hEDS compared with controls. (37) Anxiety symptoms often are treated with antidepressants, and patients with JHS/hEDS are extremely sensitive to adverse effects. Particularly at the beginning of treatment, they may feel uneasy and restless, and have significant gastrointestinal symptoms, which can exacerbate their anxiety symptoms. Because the anticholinergic effects of tertiary tricyclic antidepressants can reduce abdominal pain and improve bowel movements, this class of medication should be considered. The likelihood of success is greater if medications are started at low doses and are titrated extremely slowly.

Current nosology of anxiety disorders neglects the somatic aspects and physical manifestations of anxiety, and in general, therapeutic interventions focus only cognitive/psychological aspects of anxiety. Cognitive-behavioral therapy (CBT) may be effective in treating the cognitive distortions associated with the chronicity of the illness and negative emotions. Baeza-Velasco et al (38) found that patients with JHS/hEDS have a tendency toward dysfunctional coping strategies, and CBT may be useful to address those symptoms. Moreover, these individuals often suffer from kinesiophobia and hyperalgesia. Some pilot CBT strategies have been developed, and research suggests that along with exercise, CBT can be a valuable pain management tool in patients with JHS/hEDS. (39)

Nonetheless, these patients often suffer from several somatic complaints and bodily manifestations (eg, somatosensory amplification, dysautonomia) that require treatment. Thus, interventions that address mind and body connections should be implemented. Some research found meditative therapies for anxiety disorders can be effective, (40,41) although further randomized controlled trials are needed.

Based on our proposed "Neuroconnective phenotype," we suggest a new therapeutic approach to address the 5 dimensions of this phenotype.

Somatic symptoms, such as blue sclera, dislocations, scars, easy bruising, and leptosomatic somatotype, do not require specific intervention, but they provide information about the physical phenotype of JHS/hEDS and can facilitate the diagnosis.

Somatic illnesses. Treatment must address often-found comorbid medical conditions, such as irritable bowel syndrome, other gastrointestinal conditions, temporomandibular dysfunction, fatigue, fibromyalgia, and dysautonomia. Obviously specific attention must be paid to JHS/hEDS, which responds relatively well to physical treatments, including aerobic exercise, and particularly well to expert physiotherapy. Relaxation and meditation techniques also are effective.

Psychopathology. Ensure proper assessment and treatment not only of the anxiety disorder and its dimensions (ie, anticipatory anxiety, high loss sensitivity, depersonalization, impulse phobias, or avoidance behavior), but also of the other related conditions, such as mood disorders, substance use disorders, or eating disorders.

Behavioral dimensions. Defense mechanisms often take individuals with JHS/ hEDS to the extremes of a circumflex behavioral model in which the most typical axes include the following: me/others, loss/excess of control, avoidance/invasion, fight/flight, and dependency/isolation. A rich psychotherapeutic approach that focuses on these defense mechanisms and behavioral axes is required to balance these mechanisms.

Somatosensory symptoms. Be aware of, validate, and provide understanding of the patient's increased sensitivities, including greater pain, body perception, meteorosensitivity, and higher sensitivity to medications and adverse effects.

Additional research is needed

Future directions for exploring the link between anxiety and JHS/hEDS should include the development of new nosologic approaches, the expansion of the therapeutic dimension, and unmasking the common biologic mechanisms using evolutionary models.

Clinical Point

JHS/hEDS has been associated with increased fears and greater anxiety severity

Clinical Point

The core of the 'Neuroconnective phenotype'is an association between joint laxity and anxiety

Clinical Point

Atypical body awareness is a feature of multiple disorders, including anxiety and JHS/hEDS

Clinical Point

Patients with JHS/ hEDS may be extremely sensitive to adverse effects of antidepressants used to treat anxiety

Related Resources

* Bulbena A, Baeza-Velasco C, Bulbena-Cabre A, et al. Psychiatric and psychological aspects in the EhlersDanlos syndromes. Am J Med Genet C Semin Med Genet. 2017;175(1):237-245.

* TheEhlers-DanlosSociety.hEDSDiagnosticChecklist. https://

Clinical Point

CBT may be useful to address dysfunctional coping strategies in patients with JHS/hEDS

Bottom Line

Recognizing the link between anxiety and joint hypermobility syndrome/Ehlers-Danlos type 3-hypermobile type (JHS/hEDS) has provided a way to better understand psychopathologic and somatic conditions. In patients who present with an anxiety disorder, clinicians should screen for JHS/hEDS to properly evaluate and treat all dimensions of the newly described "Neuroconnective phenotype."


The authors report no financial relationships with any manufacturer whose products are mentioned in this article or with manufacturers of competing products.

Andrea Bulbena-Cabre, MD, PhD, MSc(Res)

Advanced Psychiatry Research Fellow Mental Illness Research and Clinical Center (MIRECC) James J. Peters Veterans Affairs Medical Center Icahn School of Medicine at Mount Sinai New York, New York

Antonio Bulbena, MD, MSc(Cantab), PhD

Full Professor and Chairman Department of Psychiatry and Forensic Medicine Autonomous University of Barcelona Barcelona, Spain Research Director Institute of Neuropsychiatry and Addictions (INAD), Parc de Salut Mar Barcelona Hospital del Mar Medical Research Institute (IMIM) Centro de Investigation en red de Salud Mental (CIBERSAM) Barcelona, Spain


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Caption: Anxiety and joint hypermobility

Caption: Figure 1: The Neuroconnective phenotype: 5 Dimensions

Caption: Figure 2: Elbow hyperextension
Musculoskeletal and extra-articular features of JHS/hEDS

Category          Features

Musculoskeletal   Joint: Joint laxity, arthralgia/myalgia,
                  dislocation/subluxation, osteoarthritis,
                  chondromalacia patellae, temporomandibular
                  joint dysfunction, pain
                  Soft tissue: Ligament/muscle/meniscus tear,
                  epicondylitis, bursitis, tendinitis, capsulitis,
                  Baker cysts
                  Spine: Disc prolapse, loose back syndrome,
                  spondylolysis, spinal abnormalities, spinal
                  stenosis, scoliosis

Extra-articular   Neurologic: Dysautonomia, headache, chronic
                  regional pain syndrome, carpal tunnel syndrome,
                  developmental coordination disorder, fixed dystonia
                  Gastrointestinal: Visceroptosis, irritable bowel
                  syndrome, gastroesophageal reflux, hiatus hernia,
                  chronic constipation, rectal evacuatory
                  dysfunction, functional gastrointestinal disorder,
                  Crohn's disease, oropharyngeal dysphagia
                  Mucosa: Blue sclera, xerostomia, xerophthalmia,
                  vaginal dryness, agenesis/ absence of the lingual
                  frenulum, mucosal fragility (with subsequent
                  spontaneous bleeding)
                  Urologic: Urinary stress incontinence
                  Gynecologic: Pelvic organ prolapse,
                  irregular menses, meno/metrorrhagias, dysmenorrhea
                  Psychiatric: Anxiety, depression, eating disorders,
                  psychological distress
                  Skin: Skin hyperextensibility, hypertrophic
                  scarring, skin fragility, striae, easy
                  bruising (capillary fragility), atopy
                  Cardiovascular: Mitral valve prolapse,
                  postural tachycardia syndrome, Chiari
                  malformation, aortic valve regurgitation
                  Others: Fibromyalgia, chronic fatigue syndrome,
                  somatosensory amplification, increased
                  interoception and exteroception,
                  decreased proprioception

JHS/hEDS: joint hypermobility syndrome/Ehlers-Danlos
type 3-hypermobile type

Source: References 2,5,6
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Author:Bulbena-Cabre, Andrea; Bulbena, Antonio
Publication:Current Psychiatry
Article Type:Report
Date:Apr 1, 2018
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