What Types of Pain Affect Those with Ehlers-Danlos (Part Two)

PainChampions January 31, 2017 WHAT TYPES OF PAIN AFFECT THOSE WITH EHLERS-DANLOS? (PART TWO) Although headaches could fit into any, if not all, of the previously named source of pain (musculoskeletal, neuropathic, and visceral), headaches in Ehlers-Danlos syndromes warrant their own topic, as their sources are hard to determine for most of us. This month also takes a look at pain sensitization and a further examination of problems that complicate pain.

HEADACHES Headaches are widely reported by those of us with Ehlers-Danlos. But headaches in EDS seem to be largely under-represented in the medical literature, even though the 1997 Sacheti study uncovered headaches in 30–40%.1 Later studies have confirmed a high rate of headaches.2,3 In general, there are four major areas of the body which are most likely to cause head pain as a result of connective tissue problems: muscular and temperomandibular joint; cervical spine; cardiovascular system; and meninges, the membranes lining the skull and vertebral channel and enclosing the brain and spinal cord. Any of these areas can cause pain, alone or in combination with others.4 Migraines with and without aura are most often reported5,6 but many other types as well: • Daily persistent headache.7 “Chronic recurrent headaches may constitute the neurologic presentation of EDS in the absence of structural, congenital, or acquired CNS lesions that correlate with their symptoms.”8 • Tension, combinations of tension and migraine, and post-traumatic headaches.8 • Dislocations and subluxations in the neck.9 • Chiari malformation.10,11 • Spontaneous cerebrospinal fluid leakage.12,13,14 • Temporormandibular joint dysfunction can also trigger headaches; TMJ prob-

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lems were found in all members of a study, along with pain on one side in 28% and both sides in 51%.15

• Mast cell activation disorder, recently noticed to be more prevalent with EDS than in general,16 is known to cause headaches.17,18 Diagram showing possible relationships between the different functional and anatomical factors contributing to some headache manifestations in EDSs. CSF, cerebrospinal fluid; FM, foramen magnum; OAAJ, occipito-atlanto-axial joint; TMJ, temporomandibular joint. From: Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F, and Grammatico P (2015). Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain. Am J Med Genet Part C 9999:1–14.

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Dr. Raeburn Forbes has compiled a list of headache pains, not limited to EDS, that I’ve found really helpful in determining what might be happening. The list includes what symptoms feel like, and in some cases, suggested treatments. His list includes pains such as ice-pick, stabbing/knife-like, sudden severe, and shooting. The headache types identified include cervicogenic, trigeminal neuralgia and trigeminal autonomic, cluster, paroxysmal hemicrania, and a number of others. If you have trouble figuring out how to talk to your doctor about your headaches, this might be a good place to start: https://www.severe-headache-expert.com/sharp-head-pain/.

SENSITIZATION TO PAIN Although the process is unclear, acute pain (and chronic-acute pain) can lead to lowered pain thresholds, or what is called pain sensitization. Those with EDS are not immune to this progression. One study of 23 women with joint hyper mobility syndrome/hypermobility EDS (JHS/hEDS) found lower pressure pain thresholds compared to controls, even in asymptomatic parts of the body,19 confirmed by a study on 27 adults.20 Other related effects have been noted: decreased cold and heat pain thresholds and an increase in the action of the neurons that carry signals from the central nervous system to the thalamus, leading to the increased perception of pain intensity.20 JHS/hEDS also seem to be very highly associated with fibromyalgia (FM), a condition not fully understood; currently, FM pain is considered to mostly result from pain pathways malfunctioning. A study investigating the association of joint hyper mobility and FM found 46.6% of the FM-affected group were hypermobile with a Beighton score of at least four, while the control group result was 28.8%.21 A later study looking at hEDS found FM in 42%.22 Complex regional pain syndrome (CRPS), is a long term condition, an amplified musculoskeletal pain syndrome, that often worsens with time. It is characterized by severe pain and sensitivity, swelling, and may initially affect one limb but then spread throughout the body. While the cause of CRPS is undetermined, CRPS is associated with dysregulation of the central nervous system23 and autonomic nervous system, already often altered in EDS. CRPS is not caused by psychological factors, but can cause psychological problems such as depression and anxiety.

A 2006 study of EDS and CRPS proposed two ways CRPS becomes a complaint in

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EDS.24 First is “stretch injury to nerves by joint dislocation or hyperextension” (I had a primary care internist who described it as EDS connective tissue stretching too far, but nerves aren’t elastic and don’t stretch with the tissue, instead separating and then reconnecting). The second is increased exposure to medical procedures, including surgery, which is documented as triggering CRPS.25,26 COMPLICATIONS THAT AFFECT PAIN PERCEPTION Fatigue; lack of sleep; distress due to depression, anxiety, interpersonal and larger societal factors; all these can make pain worse and help turn acute pain into a chronic condition (which is complicated in definition by the recurring nature of EDS chronic-acute pain, in which the same parts the body undergo repeated acute pain repeatedly). I discussed social and psychological effects in October, but I include some scientific data here that I’ve found as I continue my search to discover more about our perception of pain.

A 2012 survey of 888 people with hEDS and cEDS had these results:27 • On the Pittsburgh Sleep Quality Assessment (PSQI) a score greater than five out of 21 indicates poor sleep; the average EDS score was 12.9. Bad sleep wasn’t found to be related to pain severity or intensity, but reduced sleep quality did correlate to worsened fatigue.

• The Brief Pain Inventory resulted in 98% reporting pain that led to significant interference with everyday life; but pain didn’t correlate with sleep quality or overall fatigue.

• The Brief Fatigue Index found 92.3% reported being unusually tired, and that fatigue significantly interfered with daily life; the increased fatigue correlated to decreased sleep quality.

Clearly, fatigue and sleep disorders affect each other, and the two lower quality of life, which helps worsen psychological influences which also deepen poor quality of life. The three are combined in a reinforcing cycle which is bound to affect how we perceive pain. Pain would probably be easier for us to bear if it were a single problem,

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instead of reinforced by the myriad other difficulties faced in EDS. FATIGUE Severe fatigue is a commonly occurring feature of EDS (particularly JHS/hEDS), reported in up to 84%.28 The fatigue can be complicated and disabling, and bears a resemblance to chronic fatigue syndrome.29 Another study found 82.6% of the JHS/hEDS participants met the diagnostic criteria for chronic fatigue syndrome.30 Those with EDS fatigue rate the effect on everyday life as equal to or even larger than their pain.28 SLEEP DISORDERS People with EDS don’t sleep well, a problem well-reflected in the literature.28,31,32 The 2001 study by Verbraecken et al.31 was based on questionnaires found no instances of apnea were reported by EDS participants, but did find very high results for periodic limb movement — odd results in my view that are probably an artifact of having only nine EDS participants. The much larger 2012 survey from Cordes found 21% self-reported diagnosis of restless legs syndrome (7% were formally diagnosed) with an average of moderate symptoms.27 A 2013 paper reported the results of sleep studies in people with EDS, revealing sleepdisordered breathing in all 34 subjects as apnea (temporary complete stoppage of breathing for ten seconds or more), hypopnea (overly shallow breathing or an abnormally low respiratory rate), and flow limitations (partial obstruction of the airway). The subgroup who were also evaluated through rhinomanometry showed increased nasal resistance compared to normal.33 A group of 100 people with EDS (46 with hEDS, 35 cEDS, 19 other types) were matched with controls, and all examined with home sleep study. There was a high incidence of symptomatic obstructive apnea in the EDS group, 23% compared to 3% of the control group, with no significant differences between the EDS types. The high incidence of apnea in EDS of course contributes to other problems such as daytime sleepiness and lower quality of life.34 PSYCHOLOGICAL FACTORS

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Psychological issues like anxiety and depressions are not the cause of pain directly.

They may be a result of chronic pain, and it could be argued a result of living with a misunderstood genetic disorder. But however one views the cause and effect, their involvement changes our perception of pain for the worse.

A survey of 466 adults with JHS/hEDS found 73% endured anxiety and 69% depression.35 A recent look at data from Swedish national registries (1780 EDS and 11,082 JHS individuals, 1722 EDS siblings, and a control group) also found the association to depression — as well as statistically significant links to suicide and bipolar, autism spectrum, attention deficit hyperactivity disorders.36 The excess of depression, suicide, and attention deficit hyperactivity disorder was also found in siblings not affected by EDS, which may imply environmental or other genetic factors share a role for psychiatric issues in EDS. CONCLUSIONS Pain in EDS is a tangle of cause and effect, with clear physical traumas and less obvious complicating factors that combine and reinforce each other. Pain may have different origins, different intensities, and run different courses. Our pain probably originates relatively simply with joint instability and soft tissue injuries (especially the fascia), which can further involve our cardiovascular, respiratory, and immune systems. Headaches and head pain are particularly disruptive. Our injuries compound and recur, and weave into other problem areas — neural and brain changes including increased sensitization to pain, as well as social and psychological influences and sleep issues — and can progress from localized pain to whole-body involvement, becoming disabling in the absence of management.

Mark Martino, The Ehlers-Danlos Society SOURCES Sacheti A, Szemere J, Bernstein B, et al. (1997). Chronic pain is a manifestation of the Ehlers-Danlos syndrome. J Pain Symptom Manage. 1997;14:88–93.

1

Rombaut L, Malfait F, Cools A, et al. (2010). Musculoskeletal complaints, physical activity and health-related quality of life among patients with the Ehlers-Danlos syndrome hypermobility type.

Disabil Rehabil 2010;32:1339-45.

2

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Castori M, Camerota F, Celletti C, et al. (2010). Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010;152A:556– 564.

3

Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F, and Grammatico P (2015). Connective tissue, Ehlers–Danlos syndrome(s), and head and cervical pain. Am J Med Genet. Part C 9999:1–14.

4

Bendik EM, Tinkle BT, Al-shuik E, et al. (2011). Joint hypermobility syndrome: a common clinical disorder associated with migraine in women. Cephalalgia. 2011;31:603–613.

5

Puledda F, Viganò A, Celletti C, et al. (2015). A study of migraine characteristics in joint hypermobility syndrome a.k.a. Ehlers-Danlos syndrome, hypermobility type. Neurol Sci. 2015;36:1417–1424 6

Rozen TD, Roth JM, and Denenberg N (2006). Cervical spine joint hypermobility: a possible predisposing factor for new daily persistent headache. Cephalalgia. 2006;26:1182–1185.

7

8

Jacome DE (1999). Headache in Ehlers-Danlos syndrome. Cephalalgia. 1999;19:791–796

Di Palma F and Cronin AH (2005). Ehlers-Danlos syndrome: correlation with headache disorders in a young woman. J Headache Pain. 2005;6:474–475 / Halko GJ, Cobb R, Abeles M. Patients with type IV Ehlers-Danlos syndrome may be predisposed to atlantoaxial subluxation. J Rheumatol.

1995;22:2152–2155.

9

Milhorat TH, Bolognese PA, Nishikawa M, et al. (2007). Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and Chiari malformation type I in patients with hereditary disorders of connective tissue. J Neurosurg Spine. 2007;7:601–609.

10

Castori M, Camerota F, Celletti C, et al. (2010). Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010;152A:556– 564.

11

Schievink WI, Meyer FB, Atkinson JL, et al. (1996). Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension. J Neurosurg. 1996;84:598–605.

12

Schievink WI, Gordon OK, and Tourje J (2004). Connective tissue disorders with spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension: a prospective study. Neurosurgery.

2004;54:65–70.

13

Reinstein E, Pariani M, Bannykh S, et al. (2013). Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study. Eur J Hum Genet. 2013;21:386– 390.

14

De Coster PJ, Van den Berghe LI, and Martens LC (2005). Generalized joint hypermobility and temporomandibular disorders: inherited connective tissue disease as a model with maximum expression.

J Orofac Pain. 2005;19:47–57.

15

16

Cheung I and Vedas P (2015). A New Disease Cluster: Mast Cell Activation Syndrome, Pos-

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tural Orthostatic Tachycardia Syndrome, and Ehlers-Danlos Syndrome. J Allergy Clin Immunol.

2015;135(2):AB65 http://dx.doi.org/10.1016/j.jaci.2014.12.1146.

Frieri M, Patel R, and Celestin J (2013). Curr Allergy Asthma Rep 13: 27. doi:10.1007/s11882-0120322-z.

17

Hamilton MJ, Hornick JL, Akin C, et al (2011). A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol. 2011;128(1):147–52.

18

Rombaut L, Scheper M, De Wandele I, et al. (2015). Chronic pain in patients with the hypermobility type of Ehlers-Danlos syndrome: evidence for generalized hyperalgesia. Clin Rheumatol.

2015;34:1121–1129.

19

Di Stefano G, Celletti C, Baron R, et al. (2016). Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Eur J Pain.

Forthcoming 2016. doi:10.1002/ejp.856.

20

Sendur OF, Gurer G and Bozbas GT (2007). The frequency of hypermobility and its relationship with clinical findings of fibromyalgia patients. Clin Rheumatol. 2007;26:485–487.

21

Murray B, Yashar BM, Uhlmann WR, et al. (2013). Ehlers-Danlos syndrome, hypermobility type: a characterization of the patients’ lived experience. Am J Med Genet A. 2013;161A:2981–2988. doi:10.1002/ajmg.a.36293.

22

Jänig W and Baron R (2002). “Complex regional pain syndrome is a disease of the central nervous system”. Clinical Autonomic Research. 12 (3): 150–64. doi:10.1007/s10286-002-0022-1.

23

Stoler JM and Oaklander AL (2006). Patients with Ehlers Danlos syndrome and CRPS: a possible association? Pain. 2006;123:204–209.

24

Veldman PH, Reynen HM, Arntz IE and Goris RJ (1993). Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet 1993;8878:1012–6.

25

Oaklander AL and Brown JM (2004). Unilateral nerve injury produces bilateral loss of distal innervation. Ann Neurol 2004;55:639–44.

26

Cordes S (2012). Sleep, Pain and Fatigue in EDS. http://ehlers-danlos.com/2012-annual-conference/.

27

Voermans NC, Knoop H, van de Kamp N, et al. (2010). Fatigue is a frequent and clinically relevant problem in Ehlers-Danlos Syndrome. Semin Arthritis Rheum. 2010;40:267–274.

28

Fukuda K, Straus SE, Hickie I, et al. (1994). The chronic fatigue syndrome: a comprehensive approach to its definition and study. International chronic fatigue syndrome study group. Ann Intern Med. 1994;121:953–959.

29

Castori M, Celletti C, Camerota F, et al. (2011). Chronic fatigue syndrome is commonly diagnosed in patients with Ehlers-Danlos syndrome hypermobility type/joint hypermobility syndrome. Clin Exp 30

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Rheumatol. 2011;29:597–598.

Verbraecken J, Declerck A, Van de Heyning P, De Backer W and Wouters EFM (2001). Evaluation for sleep apnea in patients with Ehlers-Danlos syndrome and Marfan: a questionnaire study. Clin Genet 2001: 60: 360 – 365.

31

Pocinki AG (2013). Non-Restorative Sleep in EDS: A Manifestation of Autonomic Dysfunction; and, Pseudo-Psychiatric Symptoms in Ehlers-Danlos Syndrome. http://ehlers-danlos.com/2013-annualconference/.

32

Guilleminault C, Primeau M, Chiu HY, et al. (2013). Sleep-disordered breathing in Ehlers-Danlos syndrome: a genetic model of OSA. Chest. 2013;144:1503–1511. DOI: 10.1378/chest.13-0174.

33

Gaisl T, Giunta C, Sutherland K, Bratton D, et al. (2016). Obstructive sleep apnea in EhlersDanlos syndrome. A prospective case-control study. Euro Respiratory J. 2016 48: PA339; DOI: 10.1183/13993003.congress-2016.PA339.

34

Murray B, Yashar BM, Uhlmann WR, et al. (2013). Ehlers-Danlos syndrome, hypermobility type: a characterization of the patients’ lived experience. Am J Med Genet A. 2013;161A:2981–2988.

35

Cederlöf M, Larsson H, Lichtenstein P, et al. (2016). Nationwide population-based cohort study of psychiatric disorders in individuals with Ehlers-Danlos syndrome or hypermobility syndrome and their siblings. BMC Psychiatry. 2016;16:207.

36