The Pain Relief Foundation
March 11, 2015
Functional Somatic Syndromes, conditions characterized by functional disability and self reported symptoms rather than clearly demonstrable organic problems, are a common contemporary health issue . Each medical subspecialty seems to have at least one somatic syndrome for patients whose symptoms cannot otherwise be medically explained. These include: irritable bowel syndrome (gastroenterology); fibromyalgia (rheumatology); tension headaches (neurology); and chronic fatigue syndrome (immunology) . In recent years, however, a significant portion of these patients have gone on to receive a diagnoses of a little known connective tissue disorder: Ehlers-Danlos syndrome hypermobility type (EDS-HT), formerly type III . In this literature review, I will discuss the features of EDS-HT, explore EDS-HT as a possible unifying concept for various functional somatic syndromes, illuminate further implications of the described findings, outline a set of diagnostic criteria that should be implemented by healthcare professionals in functional diagnostic medicine, and propose a novel way of thinking about functional somatic syndromes.
Ehlers-Danlos Hypermobility Type (EDS-HT) Overview
EDS-HT, considered to be one and the same with joint hypermobility syndrome (JHS), is a relatively common, frequently underdiagnosed heritable condition which predisposes those afflicted to chronic, widespread musculoskeletal pain and a wide variety of articular and extra-articular features purportedly linked to constitutionally abnormal collagen. The diagnosis is primarily clinical in essence and is largely based on the Beighton score (a simple system used to quantify joint laxity and hypermobility) and medical history. It is predominantly of autosomal dominant inheritance, though the molecular basis of EDS-HT is still largely unknown except for a minority of patients mutated in TNXB and COL3A1 . Skin biopsies may show alterations in collagen fibril morphology . Early literature fixed the frequency of EDS as a whole to 1 in 5000, with EDS-HT accounting for approximately half of all registered cases. However, due to it’s vast underdiagnosis, a presumed frequency of 0.75-2% has been proposed for EDS-HT .
Hypermobility and the Autonomic Nervous System:
The Missing Link for Various Functional Somatic Syndromes
When first described, EDS-HT was considered to be a relatively benign condition, with acute and chronic joint instabilities as it’s unique clinical consequence. Recently, however, accumulated experience on the management of EDS-HT patients elucidated a more complex clinical picture. In particular, subjects with joint hypermobility appear to be more prone to developing a range of functional somatic syndromes , including fibromyalgia , chronic fatigue syndrome , headaches , complex regional pain syndrome , gastrointestinal functional disorder , pelvic organ prolapse , and orthostatic intolerance .
An underlying dysautonomic process may explain many of the aforementioned functional somatic syndromes seen in EDS-HT individuals, which are present in practically all major body systems. Leading research suggests that the pathogenic relationship between dysautonomia and congenital laxity of the connective tissue is primarily attributable to the pathological deformation of the brainstem and upper spinal cord from occipitoatlantoaxial hypermobility and cranial settling . In other words, craniocervical hypermobility and instability, and the resulting deformative stress of repetitive stretching and ventral brainstem compression, appear to underlie the observed autonomic dysfunction in hypermobile patients . As demonstrated in pathological reports of fatal cases of traumatic brain injury and numerous animal studies, repetitive stretching of nerves can lead to clumping and loss of neurofilaments and microtubules within the axon and promotes neural apoptosis . Strain also alters the electro-chemistry of the nerve by decreasing the amplitude of action potentials  and increasing calcium influx into the cell . When you apply this research to the context of hypermobile individuals, the underlying process of autonomic nervous system dysfunction becomes palpable. Unsurprisingly, the histopathological changes in neural axons that are undergone in these situations would not show up on any routine diagnostic test. In extreme cases, however, cranial settling and a reduction of the clivo-axial angle may be demonstrable on MRIs, but typically only when imaged in the upright position . This would explain why many of these patients’ diagnostic imaging reports state negative results.
In accord with craniocervical hypermobility findings, recent studies have suggested that up to 70% of patients with hypermobility have orthostatic intolerance and other forms of dysautonomia. The orthostatic effect in EDS-HT individuals may also be compounded by abnormal connective tissue in the vasculature, which results in an increase in blood vessel distensibility in response to the augmented hydrostatic pressure that occurs during orthostatic stress. This leads to exaggerated blood pooling in the lower extremities with a resultant tachycardia . While these findings were predictable, a reversed frequency study, wherein hypermobility was measured in patients diagnosed with Postural Orthostatic Tachycardia Syndrome, a prevalent form of dysautonomia in young people, found that an extraordinary 53% of participants met the diagnostic criteria for EDS-HT . Furthermore, when hypermobility was measured in individuals diagnosed with Chronic Fatigue Syndrome, a condition with a longstanding, established association with orthostatic intolerance , researchers found that 25% of Chronic Fatigue syndrome sufferers had generalized hypermobility . This phenomena, though, is likely of multifactorial consequence, as dysautonomia, chronic pain, and sleep apnea secondary to ventral brainstem compression can result in poor sleep architecture and chronic fatigue .
Ehlers-Danlos Syndrome Hypermobility Type as a Systemic Condition
The autonomic nervous system problems associated with hypermobility, alike various functional somatic disorders, are present in practically all major body systems. In the realm of gastroenterology, for instance, dysautonomia in the form of vagus nerve damage (which may result from craniocervical instability) can result in delayed gastric emptying  and affect bowel contractibility, causing nausea and the so called “irritable bowl syndrome” . Moreover, the underlying collagen abnormality of EDS-HT itself is systemic. Insufficient collagen may reduce sphincter tone and increase distensibility of the gut wall (which is likely to influence the function of surrounding cellular mechano-receptors), resulting in decreased gastrointestinal motility, gastroesophageal reflux (GERD) and/or irritable bowel syndrome (IBS). In fact, over 50% of EDS-HT individuals have GERD and/or IBS . When hypermobility was tested in patients diagnosed with functional gastrointestinal disorders (which include IBS, functional dyspepsia, and functional constipation), an astonishing 49% were found to have joint hypermobility and many of those patients went on to receive an official diagnosis of EDS-HT .
When it comes to neurological manifestations, headaches are among the most common complaint in the EDS-HT population . As a consequence of occipitoatlantoaxial hypermobility, drooping of the cerebellar tonsils and obstruction of the cerebrospinal flow at the craniocervical junction can result in intracranial pressure . In addition, rapid fluctuations in blood pressure and inadequate cerebral perfusion on upright posture caused by dysautonomia may lead to migraines . People with lax joints are also predisposed to cerviocogenic, tension, and new daily persistent headaches arising from musculoskeletal dysfunction in the temporal mandibular joints and the upper three cervical segments of the spine .
As a consequence of ligamentous laxity, rheumatological complications among the EDS-HT population are commonplace. Chronic pain in patients with joint hypermobility stems from a predisposition to injury from daily minor trauma to the joints and ligaments . Unstable joints may also lead to frequent dislocations, subluxations, sprains, and stretch injury to the nerves traversing hypermobile joints, further increasing the risk of developing chronic pain states such as arthralgia, repetitive strain injuries, and complex regional pain syndrome . There is also a high incidence of muscular pain attributable to myofacial spasms. Tender points consistent with fibromyalgia are often palpable, especially in the paravertebral musculature . In frequency studies, the prevalence of fibromyalgia in EDS-HT participants was established to be 30%  and the prevalence of EDS-HT among fibromyalgia subjects was found to be 27.3% . One theory for the origin of pain in fibromyalgia ascribes it to excessive muscle stress, which may increase the excitability of nociceptive ends of the muscle . Joint instability in hyperlax individuals may result in sustained muscle stress (an overcompensation mechanism for loose and injured joints) and over stimulation of nociceptive nerve endings (which are poorly supported by defective collagen fibrils) . An alternative, although equivocal, theory has suggested that biomechanical disturbances in the cervical spine may play a role in the pathogenesis of fibromyalgia. In a controlled study of 161 cases of traumatic injury to the cervical spine (primarily “whiplash”), fibromyalgia was diagnosed in 21.6% of those with neck injury verses 1.7% control subjects with lower extremity fractures , bringing us back to the notion that craniocervical instability, and the subsequent neurological damage, may be the underlying process in the development of functional somatic syndromes.
Further Implications of Discussed Findings in the Diagnosis and Management of Functional Somatic Syndromes
These observations suggest that a careful examination for hypermobility and connective tissue abnormalities should be an integral part of functional diagnostic medicine. Pathological deformation of the brainstem and stretch injury to neural axons due to an underlying congenital ligamentous laxity, as discussed here in the case of EDS-HT, or acquired ligamentous instability, such as whiplash, may indeed be the missing link in the pathogenesis of various functional somatic syndromes.
In a literature review of functional somatic syndromes, Wessely and colleges concluded, “a substantial overlap exists between the individual syndromes and that the similarities between them outweigh the differences” and “patients with one syndrome frequently meet diagnostic criteria for another” . For this subset of patients, generalized joint hypermobility may represent the common milieu for functional somatic syndromes with ubiquitous manifestations. The predispositions EDS-HT imposes would further explain why many of these patients are affected profoundly by emotional arousal (as it’s mediated by the autonomic nervous system) and muscle tension, and why patients with different syndromes share non-symptom characteristics such as sex (as joint laxity is more pronounced in females) and develops at a relatively young age (as EDS-HT is heritable, and hence, lifelong) .
Accordingly, articular hypermobility can be assessed by using the 9-point Beighton score, which assigns one point for each side of the body on which the patient can (1) passively dorsiflex the 5th finger >90 degrees with the forearm flat on the table, (2) passively appose the thumb to the flexor aspect of the forearm, (3) hyperextend the elbow beyond 10 degrees, and (4) hyperextend the knee beyond 10 degrees and one point for forward flexion of the trunk with the legs straight so that the palms rest flat on the floor. If a patient receives a Beighton score of 4 or more, a referral to a geneticist or rheumatologist for further evaluation is recommended . If cranial settling and a reduction in the clivo-axial angle is suspected, and upright MRI may additionally aid in diagnosis .
With this hitherto unobserved connection comes a new line of treatment for a subdivision of patients with functional somatic disorders. Physical therapy, in the form of exercises that strengthen joint-supporting muscles, and bracing may provide joint stability and help minimize articular injury . Elimination of brainstem deformation by straightening and stabilizing the craniocervical junction (via fusion surgery) may also improve pain, neural functioning, and quality of life .
Conclusion: A Paradigm Shift in the Etiology of Functional Somatic Syndromes
Disorders that lack “objective markers” are usually considered to be functional, not “organic.” This implies to some that the symptoms in functional somatic syndromes are physiological manifestations of psychosocial factors, a view that enforces an insular attitude to the etiology of disease rather than an interactive holistic approach. Consequently, when investigative results are negative, management is commonly limited to reassurance about the (apparent) absence of disease and occasionally psychiatric therapy. These treatments, however, are unpopular with patients, have low coherence rates, and seldom provide long-term therapeutic relief .
An alternative explanation is that the organic abnormalities are undetectable through cursory diagnostic testing as the underlying mechanism may be histopathological in origin, or, as seen in the case of upright MRIs on EDS-HT patients, the body may not be in the problematic position when testing takes place. The overly common cognitive error overshadowing high-tech medicine –that emotional issues are the underpinnings of illnesses lacking objectivity– must be overcome. While it is sufficient to say that, like virtually all known illnesses, psychosocial factors do play some role in functional somatic syndromes , an over emphasis on medically unexplained symptoms as being psychological bases causal reasoning on a negative. An absence of evidence does not denote an absence of organic disease –it simply means that the conditions that were tested for are not present in the individual and there is an infinite realm of alternative possibilities, such as EDS-HT.
Functional somatic disorders can only be successfully managed in the healthcare setting once a comprehensive understanding of their nature and treatment is acquired. The recognition of Ehlers-Danlos Syndrome Hypermobility type, and other disorders involving ligamentous laxity, as a possible physiological mechanism underlying various medically unexplained symptoms will help bridge the gap in physicians’ minds between described physical complaints and apparent negative test results in a subset of patients. Henceforth, in the wake of this disclosed correlation, further investigation into the role hypermobility and connective tissue abnormalities play in the etiology of these conditions, alongside a redefinition and modification of the diagnostic criteria of functional somatic syndromes, is essential to study of medically unexplained phenomena.
- Barsky, A. J., & Borus, J. F. (1999) Functional somatic syndromes. Annals of Internal Medicine, 130(11), 910.
- Wessely, S. & White, D. (2004) There is only on functional somatic syndrome. The British Journal of Psychiatry, 185(2), 95-96.
- Castori, M., Celletti, C., & Camerota, F. (2013) Ehlers-Danlos Hypermobility type: a possible unifying concept for various functional somatic syndromes. Rheumatology International. 33(3), 819-821.
- Castori, M. (2012) Ehlers-Danlos Syndrome, Hypermobility Type: An Underdiagnosed Hereditary Connective Tissue Disorder with Mucocutaneous, Articular, and Systemic Manifestations. ISRN Dermatology. 2012, 751768.
- Hausser, I., & Anton-Lamprecht, I. (1994) Differential ultrastructural aberrations of collagen fibrils in Ehlers-Danlos syndrome types I-IV as a means of diagnostics and classification. Human Genetics. 93(4), 394.
- Acasuso-Díaz, M., & Collantes-Estévez, E. (1998) Joint hypermobility in patients with Fibromyalgia syndrome.Arthritis Care and Research. 11(1), 39–42
- Castori, M., Celletti, C., Camerota, F., & Grammatico, P. (2011) Chronic fatigue syndrome is commonly diagnosed in patients with Ehlers- Danlos syndrome hypermobility type/joint hypermobility syndrome.Clinical and Experimental Rheumatology. 29(3), 597.
- Milhorat, T. H., Bolognese, P. A., Nishikawa, M., McDonnell, N. B., & Francomano, C. A. Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue. Journal of Neurosurgery. 7, 601-609.
- Henderson, F. C., Wilson, W. A., Mott, S., Mark, A., Schmidt, K., Berry, J. K., Vaccaro, A., Benzel, E. (2010) Deformative stress associated with an abnormal clivo-axial angle: A finite element analysis. Surgical Neurology International. 1(1) 30.
- Stoler, J. M., & Oaklander, A. L. (2006) Patients with Ehlers Danlos syndrome and CRPS: a possible association? 123(1), 204–209.
- Zarate, N., Farmer A.D., Grahame, R., Mohammed S. D., Knowles, C. H., Scott, S. M., & Aziz, Q. (2010) Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link?Neurogastroenterology and Motility. 22(3), 252.
- Aydeniz, A., Dikensoy, E., Cebesoy, B., Altindaf, O., Gursoy, S., Balat, O. (2010) The relation between genitourinary prolapse and joint hypermobility in Turkish women. Archives of Gynecology and Obstetrics.281(2), 301–304.
- Rowe, P.C., Barron, D.F., Calkins, H., Maumenee, I.H., Tong, P.Y., Geraghty, M. T. (1999) Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers-Danlos syndrome. The Journal of Pediatrics.135(4), 494–499.
- Smith, D. H., Hicks, R., & Povlishock, J. (2013) Therapy development for diffuse axonal injury. Journal of Neurotrauma. 30(5), 307-323.
- Saatman, K. E., Abai, B., Grosvenor, C., Vorwerk, C. K., Smith, D.H., and & Meaney, D. F. (2003) Traumatic Axonal Injury Results in Biphasic Calpain Activation and Retrograde Transport Impairment in Mice. Journal of Cerebral Blood Flow & Metabolism. 23(1) 34-42.
- Guruprakash, D. K. (2011) Effects of strain and strain rate on axonal injury in a spinal nerve root model.Wayne State University Theses. Paper 74.
- Wolf, J. A., Stys, P. K., Lusardi, T., Meaney, D. & Smith, D. H. (2001) Traumatic Axonal Injury Induces Calcium Influx Modulated by Tetrodotoxin-Sensitive Sodium Channels. The Journal of Neuroscience. 21(6), 1923–1930.
- Grubb, B. P., Kanjwal, Y., & Kosinski, D. J. (2006) The Postural Tachycardia Syndrome: A Concise Guide to Diagnosis and Management. Journal of Cardiovascular Electrophysiology. 17(1), 108-112.
- Jiménez-Cohl, P., Earle, N. M., González, B. R., & Thieck, E. J. (2012) Postural orthostatic tachycardia syndrome (POTS): report of 15 cases. Revista Medica de Chile. 140(2), 145.
- Stewart, J. M, Gewitz, M. H., Weldon, A., Arlievsky, N., Li, K., & Munoz, J. (1999) Orthostatic intolerance in adolescent chronic fatigue syndrome. Journal of Pediatrics. 103(1), 116-121.
- Nijs, J., De Meirleir, K., & Truyen, S. (2004) Hypermobility in Patients with Chronic Fatigue Syndrome: Preliminary Observations. Journal of Musculoskeletal Pain. 12(1) 9-17.
- Bagai, K., Song, Y., Ling, J. F., Malow, B., Black, B. K., Biaggioni, I., Robertson, D., & Raj, S. R. (2011) Sleep disturbances and diminished quality of life in postural tachycardia syndrome. Journal of Clinical Sleep Medicine. 7(2), 204–210.
- Smith, M. T., & Haythornthwaite, J. A. (2004) How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Medicine Reviews. 8(2), 119-132.
- Howard, R. S., Henderson, F., Hirsch, N. P., Stevens, J. M., Kendall, B. E., Crockard, H. A. (1994) Respiratory abnormalities due to craniovertebral junction compression in rheumatoid disease. Annals of the Rheumatic Diseases. 53(2), 134-136.
- Feldman, M., Corbett, D.B., Ramsey, E.J., Walsh, J. H., Richardson, C. T. (1979) Abnormal gastric function in longstanding, insulin-dependent diabetic patients. 77(1), 12-17.
- Spaziani, R., Bayati, A., Redmond, K., Bajaj, H., Bienenstock, J., Collins, S. M. & Kamath, M. V. (2008), Vagal dysfunction in irritable bowel syndrome assessed by rectal distension and baroreceptor sensitivity.Neurogastroenterology & Motility. 20(4), 336–342.
- Gastroesophageal reflux and irritable bowel syndrome in classical and hypermobile EDS. Program Nr: 362 from the 1999 ASHG Annual Meeting H.P. Levy, W. Mayoral, K. Collier, T.L. Tio, C.A. Francomano.
- Sansur, C. A., Heiss, J. D., DeVroom, H. L., Eskioglu, E., Ennis, R., & Oldfield, E. H. (2003) Pathophysiology of headache associated with cough in patients with Chiari I malformation. Journal of Neurosurgery. 98(3), 453–458.
- Low, P. A., Sandroni, P., et al. (2009) Postural Orthostatic Tachycardia Syndrome (POTS). Journal of Cardiovascular Electrophysiology. 20(3), 352-358.
- May, A., & Goadsby, P. J. (1999) The trigeminovascular system in humans: pathophysiologic implications for primary headache syndromes of the neural influences on the cerebral circulation. Journal of Cerebral Blood Flow Metabolism. 19(2), 115-27
- Hall, T., Briffa, K., & Hopper, D. (2008) Clinical Evaluation of Cervicogenic Headache: A Clinical Perspective.Journal of Manual and Manipulative Therapy. 16(2), 73–80.
- Grahame, R., Hakim, A.J. (2008) Hypermobility. Current Opinion in Rheumatology. 20(1), 106-110.
- Pascarelli, E. F., & Hsu, Y. P. (2001) Understanding work-related upper extremity disorders: clinical findings in 485 computer users, musicians, and others. Journal of Occupational Rehabilitation. 11(1), 1–21.
- Levy, H.P. (2004) Ehlers-Danlos Syndrome, Hypermobility Type.
- Hudson, N., Starr, M. R., Esdaile, J. M., & Fitzcharles, M. A. (1995) Diagnostic associations with hypermobility in Rheumatology patients. British Journal of Rheumatology. 34(12), 1157-1161.
- Bennet, R. M. (1996) Fibromyalgia and the disability dilemma: a new era in understanding a complex, multidimensional pain syndrome. Arthritis and Rheumatism. 39(10), 1627-1634.
- Zimmermann, M. (1991) Pathophysiological mechanisms of fibromyalgia. The Clinical Journal of Pain. 7(1), 8-15.
- Child, A. H. (1986) Joint hypermobility syndrome: inherited disorder of collagen synthesis. Journal of Rheumatology. 13(2) 239-243.
- Buskila, D., Neumann, L., Vaisberg, G., Alkalay, D., Wolfe, F. (1997) Increased rates of fibromyalgia following cervical spine injury: a controlled study of 161 cases of traumatic injury. Arthritis and Rheumatism. 40(3), 446- 452.
- Wessely, S., Nimnuan, C., & Sharpe, M. (1999) Functional somatic syndromes: one or many? The Lancet.354(9182), 936–939.
- Allan, L., Escobar, J. et al. (2002) Psychosocial treatments for multiple unexplained symptoms: a review of the literature. Psychosomatic Medicine. 64(6), 939-950.
- Beighton P. (1993) McKusick’s heritable disorders of connective tissue: The Ehlers-Danlos syndromes. (5th ed.). St Louis: Mosby. 206.
- Donta, S. T., Clauw, D. J., Engel, C. C., et al (2003) Cognitive behaviour therapy and aerobic exercise for Gulf War veterans’ illnesses: a randomized controlled trial. Journal of the American Medical Association. 289(11), 1396 -1404