PainChampions November 18, 2016 WHAT TYPES OF PAIN AFFECT THOSE WITH EHLERS-DANLOS? (PART ONE) Ehlers-Danlos syndromes disrupt our bodies at the most fundamental levels, leading to the possibility of widespread effects at varying levels of severity. These essential problems can lead to the full range of possible pain types, any or all of which can result from our having Ehlers-Danlos. Knowing which types of pain each of us has may make treating our pain easier. Generally, pain is either nociceptive (rising from stimulation of nerve cells) or neuropathic (rising from problems with the nerves themselves). But pain is more complicated than those two categories suggest, and most writing about pain in Ehlers-Danlos include, in some form, the following1: • Musculoskeletal pain, related to soft tissue and joint injuries; • Bone-related problems such as osteoarthritis and osteoporosis; • Myofascial, rising from the connective tissue wrapped around our internal structures to hold everything in place; • Headaches and head pain; and • Visceral pain from internal organs, including gastrointestinal, abdominal, and urological sources. When acute pain is untreated or managed incompletely, it can set us up for ongoing chronic pain issues quite apart from the chronic-acute pain of daily injuries in EhlersDanlos. For instance, chronic pain can be established by prolonged soft tissue/joint pain, which can activate and increase the number of NMDA receptors, thereby passing more pain signals to the brain.2 There are also complicating problems in many of us with Ehlers-Danlos, that often work in a sort of feedback loop, both worsening pain and worsened by pain — fatigue, sleep disorder, depression, anxiety. Not enough is known yet to explain why these factors arise, but let me be clear: none of these cause Ehlers-Danlos syndromes.
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However, improving any or all of these co-morbid conditions can make living with Ehlers-Danlos pain easier. MUSCULOSKELETAL PAIN This is most clearly associated with Ehlers-Danlos, starting with the joint pain many us have, from the direct problems of full dislocations and partial dislocations or slipping (subluxations). It wasn’t until the late 1990s and the subsequent decade-long NIA “Studies of Heritable Disorders of Connective Tissues” that we really began to understand that pain is an intrinsic feature of EDS. This was at least partly due to the unusual nature of EhlersDanlos dislocations — not all of us dislocate with pain, or with the evidently terrible agony most people endure when they dislocate — which may be why some doctors still hold to the outdated and mistaken notion that Ehlers-Danlos don’t cause pain. Of course our joints don’t move in isolation, they’re surrounded and supported by soft tissue. Remember that the defect in our connective tissue interferes with the structure that keeps our tissue from stretching too far. When a joint dislocates, the tissue around that joint — as well as whatever muscles, tendons, or fascia are connected to that joint directly or indirectly — all is stretched beyond the ability of that tissue to hold itself together. So it gets injured from a myriad of microscopic tears, over and over and over, each time that joint slips, multiple times a day or even an hour. Much of that damage happens in the fascia, the sheets of connective tissue that hold our bodies together by keeping in place our muscles, blood vessels, nerves, organs— pain in our fascia means we’re literally encased in pain. This is the chronic-acute pain that is inherently part of Ehlers-Danlos, and forms the background for other musculoskeletal issues. A significant number of us develop a fear of falling3 and of movement and re-injury4, both of which can worsen our problems through loss of strength and support. There are also bone-related issues in osteoarthritis and osteoporosis. While there is some conflicting evidence as to whether Ehlers-Danlos lead to osteoarthritis, to me common sense says there has to be a relationship. One of the causes of osteoarthritis is commonly held to be wear-and-tear; the Arthritis
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Foundation says, “Repetitive movements or injuries to joints (such as a fracture, surgery or ligament tears) can lead to osteoarthritis. Some athletes, for example, repeatedly damage joints, tendons and ligaments, which can speed cartilage breakdown.…An imbalance or weakness of the muscles supporting a joint can also lead to altered movement and eventual cartilage breakdown in joints.”5 It seems logical to assume that the chronic-acute effects of ongoing dislocations would contribute as well and a large percentage of those diagnosed with hypermobile Ehlers-Danlos report early-onset osteoarthritis. There is divergent discussion about how strongly and even if osteoporosis relates to Ehlers-Danlos syndromes. Certainly osteoporosis is a definitive feature of kyphoscoliotic EDS, arthrochalasia EDS, and the EDS/osteogenesis imperfecta overlap.6 Howard Levy in his GeneReview article, Ehlers-Danlos Syndrome, Hypermobility Type, says, “There is very limited and contradictory evidence regarding bone mineral density in EDS, hypermobility type. Dolan et al7 found bone density to be reduced by up to 0.9 SD in patients with EDS compared to healthy controls, but that study did not look specifically at patients with the hypermobility type of EDS. Compared to age- and sex-matched controls, Gulbahar et al8 reported bone density reduction of up to 0.5 SD among premenopausal women with joint hypermobility syndrome (now considered identical to EDS, hypermobility type). However, Carbone et al9 found no difference in bone density between women with EDS, hypermobility type and normal controls after adjusting for height, weight, and physical activity.”10 A survey by Marco Castori found that literature showed a strong association between Ehlers-Danlos and generalized joint hypermobility with reduced bone mass density in older children and adults, which matched with his personal experience.11 There is, however, literature which is more definite about effects. In 2015, a study detailed that vertebral fractures were significantly more prevalent in Ehlers-Danlos than in control participants (38.5% and 14.4% respectively, and not significantly different between hypermobile and classical types). Severe back pain was a result of vertebral fractures (no surprise, in my personal experience). The authors’ conclusion: “The occurrence of vertebral fractures in patients with normal or low-normal BMD is consistent with the hypothesis that bone quality more than bone quantity may be impaired in EDS.”12
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Clearly more needs to be learned, but in the meantime, it’s safe to say that bone health directly affects pain, and is in some way associated with EDS even if how is in question. NEUROPATHIC PAIN Neuropathy is a problem with the nerves themselves, rather than the stimulation triggering the nerves. Neuropathies most often arise in the peripheral nerves rather than the spine and brain (central nervous system). There are sensory nerves that control sensation, motor nerves that allow power and movement, and autonomic nerves (the nerves that control the systems of the body. Mononeuropathy describes a single nerve being affected, and polyneuropathy describes the involvement of multiple nerves.13 “Neuropathic pain is a complex, chronic pain state that usually is accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional, or injured. These damaged nerve fibers send incorrect signals to other pain centers. The impact of nerve fiber injury includes a change in nerve function both at the site of injury and areas around the injury.”14 Neuropathic pain seems to accompany Ehlers-Danlos. The pain shows up as burning sensations; aching or stabbing pain; even electric shock sensations going up or down the legs and feet. These sensations come in a range, from unpleasant annoyances to painful intrusions:15,16 • Paresthesias, or abnormal sensations without an obvious physical cause such as tingling, tickling, pricking, numbness or burning; • Numbness, or impaired sensation; and • Dysesthesias, or abnormal unpleasant sensations in reaction to being touched, such as burning, wetness, itching, electric shock, and pins and needles. One attempt to explain why this happens in Ehlers-Danlos is that nerves are being compressed, perhaps by being trapped in joints as they move. But many of us have neuropathic pain at rest, and in body-symmetrical patterns, which seems unlikely to be the result of random compression in joints. Another explanation is that axons themselves are damaged; this might be true for some of us, but has been said to be rare in Ehlers-Danlos.17 However, there is an explanation for this which might imply
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axon damage is more common in Ehlers-Danlos than previously noted. Nerves are surrounded by three layers of connective tissue, which may be as fragile as other connective tissue in Ehlers-Danlos, and therefore unable to protect axons from trauma when soft tissue is overstretched.18 Recent discoveries about small fiber neuropathy in Ehlers-Danlos19 may prove to be very useful in understanding Ehlers-Danlos pain. There are other causes of neuropathic pain that may apply to Ehlers-Danlos; one is complex regional pain syndrome18, an amplified musculoskeletal pain syndrome that often worsens over time. The cause of CRPS is unknown, but there are associations with dysregulation of the central nervous and autonomic nervous systems, which can be an effect of Ehlers-Danlos. VISCERAL PAIN Recurrent pain originating from internal organs is widely reported in Ehlers-Danlos. Abdominal pain is most widely reported in adults and hypermobile type EDS.20,21 Why isn’t yet explained. It may be the increased ability of an organ to distort from applied pressure in Ehlers-Danlos also increases sensitivity to pain in that organ.15 this might be particularly true if abdominal ligaments are lax and in connection with organ prolapse.22,23 Menstrual pain is common in Ehlers-Danlos, sometimes the result of other disorders, but for most women, it remains unexplained.24 Pelvic prolapse is also common in Ehlers-Danlos (particularly in hypermobile type), which clearly would contribute to discomfort and pain.25–27 Unusual chest pain is reported by many of us, too. There may be musculoskeletal sources related to the rib cage and spine, as well as from the many connective tissue functions allied with them. There may be cartilage inflammation, called costochondritis. Chest pain may also be caused by postural orthostatic tachycardia syndrome, which is a common complication in EDS. CONCLUSIONS Musculoskeletal pain is probably the most immediately recognizable form of pain in Ehlers-Danlos syndromes, as a result of mechanical issues and resulting ongoing
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trauma. But research seems clear that neuropathic pain is just as likely, although not yet explained; small fiber neuropathy may prove to be the main source. And there are a variety of visceral pains including GI, gynecologic, and chest pains. Next month will be an examination of headache and head pain as well as the complications that affect our pain; then pain management suggestions will take the focus. Mark Martino, The Ehlers-Danlos Society SOURCES Castori (2016). Pain in Ehlers-Danlos syndromes: manifestations, therapeutic strategies and future perspectives. Expert Opinion on Orphan Drugs, 4:11, 1145-1158, DOI:10.1080/21678707.2016.1238302 1
Niesters M, Martini C and Dahan A (2014). Ketamine for chronic pain: risks and benefits. Br J Clin Pharmacol. 2014;77(2):357–367. 2
Rombaut L, Malfait F, De Wandele I et al. (2011). Balance, gait, falls, and fear of falling in women with the hypermobility type of Ehlers-Danlos syndrome. Arthritis Care Res (Hoboken). 2011;63:1432–1439. 3
Celletti C, Castori M, La Torre G et al. (2013). Evaluation of kinesiophobia and its correlations with pain and fatigue in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type. Biomed Res Int. 2013;2013:580460. 4
http://www.arthritis.org/about-arthritis/types/osteoarthritis/causes.php (accessed November 15, 2016). 5
Cabral WA, Makareeva E, Colige A et al. (2005). Mutations near amino end of α1(I) collagen cause combined osteogenesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing. Journal of Biological Chemistry, vol. 280, no. 19, pp. 19259–19269, 2005. 6
Dolan AL, Arden NK, Grahame R and Spector TD (1998). Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry. Ann Rheum Dis. 1998;57:630–3. 7
Gulbahar S, Sahin E, Baydar M, Bircan C, Kizil R, Manisali M, Akalin E and Peker O (2006). Hypermobility syndrome increases the risk for low bone mass. Clin Rheumatol. 2006;25:511–4. 8
Carbone L, Tylavsky FA, Bush AJ, Koo W, Orwoll E and Cheng S (2000). Bone density in EhlersDanlos syndrome. Osteoporos Int. 2000;11:388–92. 9
Levy HP (2016). Ehlers-Danlos Syndrome, Hypermobility Type. National Center for Biotechnology Information GeneReviews, Pagon RA, Adam MP, Ardinger HH et al., editors. Seattle (WA): University of Washington, Seattle; 1993-2016. https://www.ncbi.nlm.nih.gov/books/NBK1279/ (accessed November 15, 2016). 10
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Castori M (2015).Ehlers-Danlos syndrome(s) mimicking child abuse: Is there an impact on clinical
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practice? Am J Med Genet C Semin Med Genet. 2015 Dec;169(4):289-92. doi: 10.1002/ajmg.c.31460. Epub 2015 Oct 9. Mazziotti G, Dordoni C, Maffezzoni F, Galderist F et al. (2015). High Prevalence of Vertebral Fractures in Patients with Ehlers-Danlos Syndrome. Endocrine Society’s 97th Annual Meeting and Expo, March 5–8, 2015. http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2015.BCHVD.10. SAT-225 (accessed November 15, 2016). 12
Webberley, H (2016). http://www.medicalnewstoday.com/articles/147963.php (accessed November 15, 2016). 13
Reviewed by Robinson, J (2015). Neuropathic Pain Management. http://www.webmd.com/painmanagement/guide/neuropathic-pain (accessed November 15, 2016). 14
Castori M, Morlino S, Celletti C et al. (2013). Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet A. 2013;161A:2989–3004. 15
Castori M, Morlino S, Celletti C et al. (2012). Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers-Danlos syndrome, hypermobility type): principles and proposal for a multidisciplinary approach. Am J Med Genet A. 2012;158A:2055–2070. 16
Voermans NC, Knoop H and van Engelen BG (2011). High frequency of neuropathic pain in EhlersDanlos syndrome: an association with axonal polyneuropathy and compression neuropathy? J Pain Symptom Manage. 2011;41:e4–6. 17
Stoler JM and Oaklander AL (2006). Patients with Ehlers Danlos syndrome and CRPS: a possible association? Pain. 2006;123:204–209. 18
Cazzato D, Castori M, Lombardi R et al. (2016). Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes. Neurology. 2016;87:155–159. 19
Zarate N, Farmer AD, Grahame R et al. (2010). Unexplained gastrointestinal symptoms and joint hypermobility: is connective tissue the missing link? Neurogastroenterol Motil. 2010;22:252–e78. 20
Castori M, Sperduti I, Celletti C et al. (2011). Symptom and joint mobility progression in the joint hypermobility syndrome (Ehlers-Danlos syndrome, hypermobility type). Clin Exp Rheumatol. 2011;29:998–1005. 21
Reinstein E, Pimentel M, Pariani M et al. (2012). Visceroptosis of the bowel in the hypermobility type of Ehlers-Danlos syndrome: presentation of a rare manifestation and review of the literature. Eur J Med Genet. 2012;55:548–551. 22
Dordoni C, Ritelli M, Venturini M et al. (2013). Recurring and generalized visceroptosis in EhlersDanlos syndrome hypermobility type. Am J Med Genet A. 2013;161A:1143–1147. 23
Castori M, Morlino S, Dordoni C et al. (2012). Gynecologic and obstetric implications of the joint hypermobility syndrome (a.k.a. Ehlers-Danlos syndrome hypermobility type) in 82 Italian patients. Am J Med Genet A. 2012;158A:2176–2182. 24
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McIntosh LJ, Mallett VT, Frahm JD et al. (1995). Gynecologic disorders in women with Ehlers-Danlos syndrome. J Soc Gynecol Investig. 1995;2:559–564. 25
Carley ME and Schaffer J (2000). Urinary incontinence and pelvic organ prolapse in women with Marfan or Ehlers Danlos syndrome. Am J Obstet Gynecol. 2000;182:1021–1023. 26
Mastoroudes H, Giarenis I, Cardozo L et al. (2013). Prolapse and sexual function in women with benign joint hypermobility syndrome. BJOG. 2013;120:187–192. 27