Journal of the Neurological Sciences 340 (2014) 99–102
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Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Ehlers–Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study Daniel Wallman a,⁎, Janice Weinberg b, Anna Depold Hohler c,1 a b c
Boston University School of Medicine, 72 East Concord St, A-302, Boston, MA 02118, USA Department of Biostatistics, Boston University School of Public Health, Boston University Medical Campus, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118, USA Boston University School of Medicine/BMC, 725 Albany Street, 7th Floor, Boston, MA 02118, USA
a r t i c l e
i n f o
Article history: Received 16 November 2013 Received in revised form 5 February 2014 Accepted 2 March 2014 Available online 11 March 2014 Keywords: Postural Tachycardia Syndrome Ehlers–Danlos Syndrome Autonomic dysfunction
a b s t r a c t Objective: This study examines a possible relationship between Ehlers–Danlos Syndrome (EDS) and Postural Tachycardia Syndrome (POTS). Design/methods: We retrospectively reviewed 109 medical records of patients suffering from autonomic dysfunction exhibiting at least one POTS symptom from one urban clinic for EDS and POTS diagnoses between 2006 and 2013. The presence of EDS within the POTS and non-POTS populations was calculated and compared to that of the general population. Results: The review revealed 39 (36F:3M) patients with POTS (mean ± SD age, 32.5 ± 11.8 years) with 7 cases of EDS yielding a prevalence of 18% (95% exact CI: 8%, 34%), a statistically significant difference from the suggested prevalence of EDS in the general population of 0.02% (p b 0.0001). 70 patients (53F:17M) without POTS (mean ± SD age, 51.1 ± 14.7 years) contained 3 cases of EDS, yielding a prevalence of 4% (95% exact CI: 1%, 12%), a statistically significant difference from the general population (p b 0.0001). The prevalence of EDS was significantly higher in the POTS group compared to the non-POTS group (p = 0.0329). The odds ratio comparing the odds of EDS for POTS versus non-POTS patients is 4.9 (95% CI: 1.2, 20.1). Conclusion: The presence of EDS may be significantly higher in patients with POTS than that of the general population and in autonomic patients without POTS. We suspect an additional underlying mechanism of POTS caused by EDS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Postural Tachycardia Syndrome (POTS) is a common form of orthostatic intolerance with an unknown incidence across various ages. Patients suffering from POTS experience an increase in heart rate of greater than 30 beats per minute when moving from a supine to upright position. Adolescents, however, are held to a slightly more strict threshold of an increase in heart rate greater than 40 beats per minute. Patients generally experience lightheadedness, dimming of vision, confusion, anxiety and other symptoms that occur upon standing, suffering substantial disability and may be relieved upon sitting or lying down [1,2]. The etiology of POTS is presently unknown. Studies, however, do present mechanisms and subtypes of POTS, including the neuropathic subtype [1,2], the hyperadrenergic subtype [1,3] the physical deconditioning mechanism [4,5] and the volume dysregulation mechanism [6–8]. Additionally, studies have linked joint hypermobility syndrome with POTS
[9–11], providing a potential link between Ehlers–Danlos Syndrome (EDS) and POTS. EDS is a heterogeneous group of inherited abnormalities of connective tissue characterized by skin hyper-extensibility, joint hypermobility, and connective tissue fragility [12,13]. The mechanistic relationship between EDS and POTS has been considered and suggested; vascular insufficiencies have been witnessed in patients with EDS [13,14]. In this retrospective study, medical records of 109 individuals were reviewed for POTS and EDS in order to determine if EDS is a predictor of POTS by analyzing the presence of EDS amongst patients with POTS than amongst the general population. Furthermore, concurrent genetic testing of our patients was employed to ensure definitive EDS diagnosis. De Paepe et al. have performed extensive work in this area and have updated the Villefranche classification scheme with a more granular classification scheme, consisting of twelve subtypes, which we follow in this study [15]. 2. Material and methods
⁎ Corresponding author. Tel.: +1 203 981 8338; fax: +1 617 638 8465. E-mail addresses: [email protected] (D. Wallman), [email protected] (J. Weinberg), [email protected] (A.D. Hohler). 1 Tel.:+1 617 638 8456; fax: +1 617 638 8465.
http://dx.doi.org/10.1016/j.jns.2014.03.002 0022-510X/© 2014 Elsevier B.V. All rights reserved.
We retrospectively reviewed 109 medical records of patients suffering from autonomic dysfunction exhibiting at least one POTS symptom from a single, subspecialty neurological urban clinic for EDS and POTS
100
D. Wallman et al. / Journal of the Neurological Sciences 340 (2014) 99–102
diagnoses between 2006 and 2013. The clinic predominantly treats patients with movement disorders and autonomic dysfunction referred from primary care physicians, cardiologists and general neurologists. The cohort was established by screening the medical records in the neurology department for ICD — 9 codes that contained one or more of the following terms: orthostatic hypotension, paroxysmal tachycardia, autonomic neuropathy, syncope or tachycardia. Those charts were then reviewed for a complete neurologic assessment with an assessment and plan related to autonomic dysfunction; patients with this assessment and plan were considered to be autonomic dysfunction patients. We then divided this group based on a POTS diagnosis. POTS is currently defined by a heart rate increment of 30 beats/min or more within 10 min of standing or head-up tilt (HUT) in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. All patients that fulfilled these POTS criteria after undergoing a tilt-table test were diagnosed with POTS. Two subsets were established: patients diagnosed with POTS and patients who did not have POTS but who do have autonomic dysfunction issues as defined above. We revisited the medical records of the two subsets for the diagnosis of EDS in order to compare its presence within these groups. Lastly, we used the prevalence of EDS within the general population as a third marker for comparison. All EDS diagnoses were initially made by a clinician, not necessarily a geneticist. EDS diagnoses of POTS patients were then confirmed by a geneticist; a geneticist often performs a more thorough screen than that of the clinician and it provides a suggestion of the type of EDS. Additionally, genetic screening was employed when patient consent was obtained and insurance coverage was available. Only the known genes impacted by EDS can be tested. Therefore, results may be inconclusive. All patients were between the ages of 14 and 60 years old. While it is noted that POTS is more prevalent in females than males at a ratio of 4.5:1 [11], we included both genders in our study population since EDS does not affect males and females differently nor are the genes affected sex-linked [16]. The presence of EDS within the POTS and non-POTS populations was calculated and compared to the prevalence in the general population using a one sample binomial exact test. Additionally, the two patients groups were compared using Fisher's exact test. The odds ratio comparing these groups is reported. Statistical significance was assessed at the p b 0.05 level. All analyses were performed using SASv9.3. 3. Results The review revealed 39 (36F:3M) patients with POTS (mean ± SD age, 32.5 ± 11.8 years) with 7 cases of EDS yielding a prevalence of 18% (95% exact CI: 8%, 34%), a highly statistically significant difference to the suggested prevalence of EDS in the general population at 1 in 5000, or 0.02% (p b 0.0001) [17]. 70 patients (53F:17M) without POTS (mean ± SD age, 51.1 ± 14.7 years) contained 3 cases of EDS, yielding a prevalence of 4% (95% exact CI: 1%, 12%), also a statistically significant difference to the general population (p b 0.0001). The prevalence of EDS is significantly higher in the POTS group compared to the non-POTS group (p = 0.0329) with an odds ratio comparing the odds of EDS for POTS versus non-POTS patients of 4.9 (95% CI: 1.2, 20.1). Age and gender were the only demographics tracked in this cohort; all patients who were referred to the clinic, as mentioned above, were selected for this study based on the presence of autonomic dysfunction symptoms. The genetic consult results are displayed in Table 1. All EDS diagnoses were initially made by a physician, not necessarily a geneticist. The 7 POTS patients diagnosed clinically with EDS, however, were examined further by a geneticist to confirm the clinical diagnosis. Four of the 7 patients gave consent to have a genetic screen of the genes known to be impacted by EDS. Two of these 4 patients presented with variants of uncertain significance in the COL5A1 gene, determined to be linked to the classic EDS type [15]. A geneticist did not examine the nonPOTS patients diagnosed with EDS.
Table 1 List of genetic consult and testing results. G = Guanine, A = Adenine, but type details not provided. ⁎ consult performed at an external institution, confirmed with patient, but type details not provided. Patient
Genetic consult diagnosis
Genetic testing
5 8 24 26
Positive, type unknown⁎ Positive, type unknown⁎
None None Negative Variant of uncertain significance: c.2331+16GNA. on COL5A1. None
30 32 39
Positive for classic subtype Positive for classic subtype Positive for classic subtype or vascular; may have hypermobility Positive for classic subtype Positive for classic subtype
Negative Variant of uncertain significance: c.787-15GNA. on COL5A1
4. Discussion Researchers have discovered and created different classifications and mechanisms to describe POTS, yet the etiology of most POTS cases is unknown. One potential mechanism that has not been exhaustively researched is the relationship between joint hypermobility syndrome (JHS) and autonomic dysfunction, such as in POTS. Gazit et al. have studied the effects of JHS on the peripheral nervous system and demonstrated a relationship between the autonomic nervous system-related symptoms and JHS, suggesting that dysautonomia is an extra-articular manifestation in JHS [9]. Further investigation between JHS and POTS was performed by Kanjwal et al., noting that patients with POTS tended to be younger with JHS (30 ± 13 years, range 10–53) when compared to patients without JHS (40 ± 11 years, range 19–65) (p b 0.05) [18]. JHS and EDS were initially considered separately within patients; EDS frequently presents with more extreme effects beyond the hyperelastic skin and joint hypermobility [14]. EDS has since been divided into twelve different types based on their symptomology and the structural differences of collagen [15]. Patients who present with joint hypermobility are now often evaluated for the hypermobility and classic EDS subtypes; joint hypermobility is a symptom of these two subtypes and the clinical difference between them is blurred [10]. JHS also shares symptomology with other connective tissue disorders, such as Marfan's Syndrome and Osteogenesis Imperfectus [10]. Rowe et al. introduced this mechanism by identifying 12 adolescent patients who initially presented with Chronic Fatigue Syndrome (CFS) that clinically presented with either the classical EDS type or the hypermobility type symptomology, however their EDS diagnoses were not confirmed by genetic consults [13]. Furthermore, the studies performed by Gazit et al. and Kanjwal et al. on the relationship between joint hypermobility and POTS suggested a linked mechanism between EDS and POTS [9,18]. A mechanistic relationship between POTS and EDS has yet to be defined and proven [11]. Interestingly, the vascular and vascular-like subtypes of EDS with life threatening arterial and intestinal implications [19], are not linked with POTS in the literature. The prevalence of EDS within the general population has been suggested by Steinmen et al. to be 1 in 5000 people, or 0.02% [17]. Our study presents a statistically higher presence of clinically diagnosed EDS within our POTS patient cohort at 18%. Our study also performed a similar analysis on our patients without POTS but with autonomic dysfunction for comparison; 4% of this population had EDS, although their results were not genetically confirmed. It should be noted that our study did not identify all of our autonomic dysfunction patients without POTS; only those with at least one POTS symptom, therefore this rate may not be reflective of the non-POTS autonomic dysfunction group in general. However, it appears that the odds ratio of having EDS with a POTS diagnosis is significantly higher as compared to having autonomic dysfunction without POTS. Another novel facet to this study is that our population of EDS patients may represent at least three types of EDS (classical, hypermobile and potentially vascular). With this increase in presence and variation of EDS presentation, we must consider
D. Wallman et al. / Journal of the Neurological Sciences 340 (2014) 99–102
an additional underlying mechanism of POTS as caused by the connective tissue disorder in general, rather than just joint hypermobility. All types of EDS are linked to sequence variations in genes encoding for fibrillar proteins and/or collagen processing enzymes that lead to reduced structural integrity within the different systems of the body [11]. The vascular system contains vessels that are supported by elastin and collagen. For example, the aorta, the largest arterial vessel, has three concentric structural layers — the tunica intima, tunica media and tunica adventitia. Each layer has some type of collagen embedded in its matrix along with other proteins and substances. Specifically, the tunica media is comprised of elastic lamellae within a matrix of type III collagen that provide the vessel with its extreme elasticity. Vessel compliance has been shown to increase in large vessels due to the gradual extension of elastin whereas compliance decrease is attributed to the advanced age of elastin or an increase in collagen [20,21]. The mutations in the first four types of EDS may compromise this matrix and thus the compliance of the vessel may change, altering the flow of blood throughout the body and potentially leading to POTS symptoms. Another concept to consider is the effect of EDS on the autonomic system. In the great vessels, such as the aorta, the nerve bundles that innervate the vessel reside in the tunica adventitia. A disruption of this layer via compromised connective tissue may, in fact, disrupt the innervation as well. This could be the cause of autonomic dysfunction witnessed in EDS patients as well as the underlying autonomic dysfunction of POTS observed in these patients. Further investigation into both of these mechanisms is warranted. The variants of unknown origin identified in our EDS patients ought to be considered as well. Of the four types of EDS in consideration, the classic and vascular types all have identified genetic defects detectable by genotyping. The classic subtype is linked to genes COL5A1/COL5A2 and COL1A1 [22,23] and the vascular subtype is linked to COL3A1 [24]; the hypermobility subtype does not have a known genetic defect. Furthermore, many variants of unknown significance have been found in patients with each type of EDS and are still being found today. Our study also brings to surface the variants of unknown significance found in our patients, both on the COL5A1 gene: a point mutation of a Guanine to Adenine at c.787-15 and a point mutation of Guanine to Adenine at c.2331+16. Although currently inconclusive, it is possible that future genetic research of these variants in a POTS and EDS positive population may yield interesting results and may shed more light on the underlying POTS mechanism. 5. Study limitations This study is the largest analysis of POTS patients and genetically confirmed EDS patients; obtaining a large data set is difficult in this patient population because of the low prevalence of POTS. The current scope of this study focused the EDS genetic analysis on the POTS patients; further expansion of this analysis to all autonomic dysfunction patients may provide us with higher rates in those patients. A definitive diagnosis of POTS requires tilt-table testing which all of our POTS patients were evaluated with. Our study may be strengthened, however, if a tilt-table test had been performed on all of our patients, in order to confirm the absence of POTS in the appropriate patients. Additionally, there is potential for a referral bias in our study: patients with EDS and patients with autonomic dysfunction are referred to our clinic. The classification of patients afflicted with EDS based on genetics and clinical presentation has been proven to be difficult to separate from joint hypermobility syndrome by Tinkle et al. Tinkle et al. suggest that the Beighton scale for hypermobility along with the Brighton Scale should be employed in order to distinguish JHS from EDS [25]. Although we could not retrospectively apply the score in this study, future studies should follow this suggestion and may want to consider the prevalence of JHS and EDS together, suggested to be 20% of the general population by Tinkle et al. [25]. Lastly, the rigorous evaluation of EDS provided by the geneticist confirmed their diagnoses; expansion of genetic analysis
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to non-POTS patients may also contribute to changes in the EDS rates in those groups. 6. Conclusion The presence of EDS may be higher in patients with POTS than that of the general population or in non-POTS autonomic dysfunction patients. With this new data, we suspect that EDS may be a predictor of POTS and that there may be an additional underlying mechanism of POTS caused by the change in connective tissue from EDS. Future studies on the genetics of EDS are currently ongoing; detail from those studies may help in revising the proposed mechanisms. Conflict of interest and IRB approval On behalf of all authors, the corresponding author states that there is no conflict of interest. Furthermore, this study was IRB approved. All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Acknowledgments The authors thank the Boston University School of Medicine and the Medical Student Summer Research Program for providing guidance for this project. References [1] Low PA, Opfer-Gehrking T, Textor SC, Benarroch EE, Win-Kuang S, Schondorf R, et al. Postural tachycardia syndrome (POTS). Neurology [Internet]. Lippincott Williams & Wilkins; 1995 [cited 2013 Jun 25];45(4):S19–S25. Available from: http://cat.inist. fr/?aModele=afficheN&cpsidt=3538365]. [2] Jacob G, Costa F, Shannon J, Roberston R, Wathen M, Stein M, et al. The neuropathic postural tachycardia syndrome. N Engl J Med 2000;343(14):1008–14. [3] Streeten P, Health Y. Pathogenesis of hyperadrenergic orthostatic hypotension. J Clin Invest 1990;86:1582–8 [(November)]. [4] Masuki S, Eisenach JH, Schrage WG, Johnson CP, Dietz NM, Wilkins BW, et al. Reduced stroke volume during exercise in postural tachycardia syndrome. J Appl Physiol [Internet] 2007 Oct [cited 2013 Jun 25];103(4):1128–35. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/17626834. [5] Joyner MJ, Masuki S. POTS versus deconditioning: the same or different? Clin Auton Res [Internet] 2008 Dec [cited 2013 Jun 25];18(6):300–7. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/18704621. [6] Streeten D, Thomas D, Bell D. the roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med 2000;320(1):1–8. [7] Raj S, Robertson D. Blood volume perturbations in the postural tachycardia syndrome. Am J Med 2007;334(1):57–60. [8] Medow MS. Defects in cutaneous angiotensin converting enzyme 2 and angiotensin(1–7) production in postural tachycardia syndrome. 2010;53(5):767–74. [9] Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med [Internet] 2003 Jul [cited 2013 Jun 25];115(1):33–40. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0002934303002353. [10] Hakim A, Grahame R. Joint hypermobility. Best Pract Res Clin Rheumatol 2003;17(6):989–1004 [[Internet] Available from: http://www.ncbi.nlm.nih.gov/ pubmed/15123047.]. [11] Benarroch E. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin. Proc., 87(12). Elsevier Inc.; Dec 2012 [[Internet]. Dec [cited 2013 Jun 25]. Available from: http://linkinghub.elsevier.com/retrieve/pii/ S0025619612008968]. [12] Thould AK, Beighton P. The Ehlers–Danlos syndrome. Ann Rheum Dis 1970;29(3):332–3. [13] Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers–Danlos syndrome. J Pediatr 1999;35(4):494–9 [[Internet]. Available from: http://www.ncbi.nlm.nih. gov/pubmed/10518084]. [14] Tucker DH, Miller E, Jacoby WJ. Ehlers–Danlos syndrome with a sinus of valsalva aneurysm and aortic insufficiency simulating rheumatic heart disease. Am J Med 1963;35(5):715–20. [15] De Paepe a, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet [Internet] 2012 Jul [cited 2013 Sep 16];82(1):1–11. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/22353005. [16] Wenstrup R, De Paepe A. Ehlers–Danlos syndrome , classic type. GeneReviews; 2007.
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[17] Steinmann B, Royce PM, Superti-Furga A. The Ehlers–Danlos syndrome. In: Royce P, Steinmann B, editors. Connect. tissue its heritable Disord. Mol. Genet. Med. Asp. 2nd ed. New York: Wiley-Liss; 2002. p. 431–524. [18] Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Blair P. Comparative clinical profile of postural orthostatic tachycardia patients with and without joint hypermobility syndrome. Ind Pacing Electrophysiol J 2010;10(4):173–8. [19] Watanabe A, Shimada T. The vascular type of Ehlers–Danlos syndrome. J Nippon Med Sch 2008;75(5):254–61. [20] Roach M, Burton A. The reason for the shape of the distensibility curves of arteries. Can J Biochem 1957;35:681–90. [21] Samila Z, Carter S. The effect of age on the unfolding of elastin lamellae and collagen fibers with stretch in human carotid arteries. Can J Physiol Pharmacol 1981;59:1050–7.
[22] De Paepe A, Nuytinck L, Hausser I, Anton-Lamprecht I, Naeraert J-M. Mutations in the COL5A1 gene are causal in the Ehlers–Danlos syndromes I and II. Am J Hum Genet 1997;60:547–54. [23] Schalkwijk J, Zweers M, Steijlen P, Dean W, Taylor G, Van Vlijmen I, et al. A recessive form of Ehlers–Danlos syndrome caused by tenascin-X deficiency. N Engl J Med 2001;345(16):547–54. [24] Pepin M, Schwarze U, Superti-Furga A, Byers PH. Clinical and genetic features of Ehlers–Danlos syndrome type IV, the vascular type. [Ne.] 2000;342(10):673–80. [25] Tinkle BT, Ha Bird, Grahame R, Lavallee M, Levy HP, Sillence D. The lack of clinical distinction between the hypermobility type of Ehlers–Danlos syndrome and the joint hypermobility syndrome (a.k.a. hypermobility syndrome). Am J Med Genet A [Internet] 2009 Nov [cited 2013 Sep 16];149A(11):2368–70. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19842204.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Ehlers–Danlos Syndrome and Postural Tachycardia Syndrome: A relationship study Daniel Wallman a,⁎, Janice Weinberg b, Anna Depold Hohler c,1 a b c
Boston University School of Medicine, 72 East Concord St, A-302, Boston, MA 02118, USA Department of Biostatistics, Boston University School of Public Health, Boston University Medical Campus, 801 Massachusetts Avenue, 3rd Floor, Boston, MA 02118, USA Boston University School of Medicine/BMC, 725 Albany Street, 7th Floor, Boston, MA 02118, USA
a r t i c l e
i n f o
Article history: Received 16 November 2013 Received in revised form 5 February 2014 Accepted 2 March 2014 Available online 11 March 2014 Keywords: Postural Tachycardia Syndrome Ehlers–Danlos Syndrome Autonomic dysfunction
a b s t r a c t Objective: This study examines a possible relationship between Ehlers–Danlos Syndrome (EDS) and Postural Tachycardia Syndrome (POTS). Design/methods: We retrospectively reviewed 109 medical records of patients suffering from autonomic dysfunction exhibiting at least one POTS symptom from one urban clinic for EDS and POTS diagnoses between 2006 and 2013. The presence of EDS within the POTS and non-POTS populations was calculated and compared to that of the general population. Results: The review revealed 39 (36F:3M) patients with POTS (mean ± SD age, 32.5 ± 11.8 years) with 7 cases of EDS yielding a prevalence of 18% (95% exact CI: 8%, 34%), a statistically significant difference from the suggested prevalence of EDS in the general population of 0.02% (p b 0.0001). 70 patients (53F:17M) without POTS (mean ± SD age, 51.1 ± 14.7 years) contained 3 cases of EDS, yielding a prevalence of 4% (95% exact CI: 1%, 12%), a statistically significant difference from the general population (p b 0.0001). The prevalence of EDS was significantly higher in the POTS group compared to the non-POTS group (p = 0.0329). The odds ratio comparing the odds of EDS for POTS versus non-POTS patients is 4.9 (95% CI: 1.2, 20.1). Conclusion: The presence of EDS may be significantly higher in patients with POTS than that of the general population and in autonomic patients without POTS. We suspect an additional underlying mechanism of POTS caused by EDS. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Postural Tachycardia Syndrome (POTS) is a common form of orthostatic intolerance with an unknown incidence across various ages. Patients suffering from POTS experience an increase in heart rate of greater than 30 beats per minute when moving from a supine to upright position. Adolescents, however, are held to a slightly more strict threshold of an increase in heart rate greater than 40 beats per minute. Patients generally experience lightheadedness, dimming of vision, confusion, anxiety and other symptoms that occur upon standing, suffering substantial disability and may be relieved upon sitting or lying down [1,2]. The etiology of POTS is presently unknown. Studies, however, do present mechanisms and subtypes of POTS, including the neuropathic subtype [1,2], the hyperadrenergic subtype [1,3] the physical deconditioning mechanism [4,5] and the volume dysregulation mechanism [6–8]. Additionally, studies have linked joint hypermobility syndrome with POTS
[9–11], providing a potential link between Ehlers–Danlos Syndrome (EDS) and POTS. EDS is a heterogeneous group of inherited abnormalities of connective tissue characterized by skin hyper-extensibility, joint hypermobility, and connective tissue fragility [12,13]. The mechanistic relationship between EDS and POTS has been considered and suggested; vascular insufficiencies have been witnessed in patients with EDS [13,14]. In this retrospective study, medical records of 109 individuals were reviewed for POTS and EDS in order to determine if EDS is a predictor of POTS by analyzing the presence of EDS amongst patients with POTS than amongst the general population. Furthermore, concurrent genetic testing of our patients was employed to ensure definitive EDS diagnosis. De Paepe et al. have performed extensive work in this area and have updated the Villefranche classification scheme with a more granular classification scheme, consisting of twelve subtypes, which we follow in this study [15]. 2. Material and methods
⁎ Corresponding author. Tel.: +1 203 981 8338; fax: +1 617 638 8465. E-mail addresses: [email protected] (D. Wallman), [email protected] (J. Weinberg), [email protected] (A.D. Hohler). 1 Tel.:+1 617 638 8456; fax: +1 617 638 8465.
http://dx.doi.org/10.1016/j.jns.2014.03.002 0022-510X/© 2014 Elsevier B.V. All rights reserved.
We retrospectively reviewed 109 medical records of patients suffering from autonomic dysfunction exhibiting at least one POTS symptom from a single, subspecialty neurological urban clinic for EDS and POTS
100
D. Wallman et al. / Journal of the Neurological Sciences 340 (2014) 99–102
diagnoses between 2006 and 2013. The clinic predominantly treats patients with movement disorders and autonomic dysfunction referred from primary care physicians, cardiologists and general neurologists. The cohort was established by screening the medical records in the neurology department for ICD — 9 codes that contained one or more of the following terms: orthostatic hypotension, paroxysmal tachycardia, autonomic neuropathy, syncope or tachycardia. Those charts were then reviewed for a complete neurologic assessment with an assessment and plan related to autonomic dysfunction; patients with this assessment and plan were considered to be autonomic dysfunction patients. We then divided this group based on a POTS diagnosis. POTS is currently defined by a heart rate increment of 30 beats/min or more within 10 min of standing or head-up tilt (HUT) in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min or higher. All patients that fulfilled these POTS criteria after undergoing a tilt-table test were diagnosed with POTS. Two subsets were established: patients diagnosed with POTS and patients who did not have POTS but who do have autonomic dysfunction issues as defined above. We revisited the medical records of the two subsets for the diagnosis of EDS in order to compare its presence within these groups. Lastly, we used the prevalence of EDS within the general population as a third marker for comparison. All EDS diagnoses were initially made by a clinician, not necessarily a geneticist. EDS diagnoses of POTS patients were then confirmed by a geneticist; a geneticist often performs a more thorough screen than that of the clinician and it provides a suggestion of the type of EDS. Additionally, genetic screening was employed when patient consent was obtained and insurance coverage was available. Only the known genes impacted by EDS can be tested. Therefore, results may be inconclusive. All patients were between the ages of 14 and 60 years old. While it is noted that POTS is more prevalent in females than males at a ratio of 4.5:1 [11], we included both genders in our study population since EDS does not affect males and females differently nor are the genes affected sex-linked [16]. The presence of EDS within the POTS and non-POTS populations was calculated and compared to the prevalence in the general population using a one sample binomial exact test. Additionally, the two patients groups were compared using Fisher's exact test. The odds ratio comparing these groups is reported. Statistical significance was assessed at the p b 0.05 level. All analyses were performed using SASv9.3. 3. Results The review revealed 39 (36F:3M) patients with POTS (mean ± SD age, 32.5 ± 11.8 years) with 7 cases of EDS yielding a prevalence of 18% (95% exact CI: 8%, 34%), a highly statistically significant difference to the suggested prevalence of EDS in the general population at 1 in 5000, or 0.02% (p b 0.0001) [17]. 70 patients (53F:17M) without POTS (mean ± SD age, 51.1 ± 14.7 years) contained 3 cases of EDS, yielding a prevalence of 4% (95% exact CI: 1%, 12%), also a statistically significant difference to the general population (p b 0.0001). The prevalence of EDS is significantly higher in the POTS group compared to the non-POTS group (p = 0.0329) with an odds ratio comparing the odds of EDS for POTS versus non-POTS patients of 4.9 (95% CI: 1.2, 20.1). Age and gender were the only demographics tracked in this cohort; all patients who were referred to the clinic, as mentioned above, were selected for this study based on the presence of autonomic dysfunction symptoms. The genetic consult results are displayed in Table 1. All EDS diagnoses were initially made by a physician, not necessarily a geneticist. The 7 POTS patients diagnosed clinically with EDS, however, were examined further by a geneticist to confirm the clinical diagnosis. Four of the 7 patients gave consent to have a genetic screen of the genes known to be impacted by EDS. Two of these 4 patients presented with variants of uncertain significance in the COL5A1 gene, determined to be linked to the classic EDS type [15]. A geneticist did not examine the nonPOTS patients diagnosed with EDS.
Table 1 List of genetic consult and testing results. G = Guanine, A = Adenine, but type details not provided. ⁎ consult performed at an external institution, confirmed with patient, but type details not provided. Patient
Genetic consult diagnosis
Genetic testing
5 8 24 26
Positive, type unknown⁎ Positive, type unknown⁎
None None Negative Variant of uncertain significance: c.2331+16GNA. on COL5A1. None
30 32 39
Positive for classic subtype Positive for classic subtype Positive for classic subtype or vascular; may have hypermobility Positive for classic subtype Positive for classic subtype
Negative Variant of uncertain significance: c.787-15GNA. on COL5A1
4. Discussion Researchers have discovered and created different classifications and mechanisms to describe POTS, yet the etiology of most POTS cases is unknown. One potential mechanism that has not been exhaustively researched is the relationship between joint hypermobility syndrome (JHS) and autonomic dysfunction, such as in POTS. Gazit et al. have studied the effects of JHS on the peripheral nervous system and demonstrated a relationship between the autonomic nervous system-related symptoms and JHS, suggesting that dysautonomia is an extra-articular manifestation in JHS [9]. Further investigation between JHS and POTS was performed by Kanjwal et al., noting that patients with POTS tended to be younger with JHS (30 ± 13 years, range 10–53) when compared to patients without JHS (40 ± 11 years, range 19–65) (p b 0.05) [18]. JHS and EDS were initially considered separately within patients; EDS frequently presents with more extreme effects beyond the hyperelastic skin and joint hypermobility [14]. EDS has since been divided into twelve different types based on their symptomology and the structural differences of collagen [15]. Patients who present with joint hypermobility are now often evaluated for the hypermobility and classic EDS subtypes; joint hypermobility is a symptom of these two subtypes and the clinical difference between them is blurred [10]. JHS also shares symptomology with other connective tissue disorders, such as Marfan's Syndrome and Osteogenesis Imperfectus [10]. Rowe et al. introduced this mechanism by identifying 12 adolescent patients who initially presented with Chronic Fatigue Syndrome (CFS) that clinically presented with either the classical EDS type or the hypermobility type symptomology, however their EDS diagnoses were not confirmed by genetic consults [13]. Furthermore, the studies performed by Gazit et al. and Kanjwal et al. on the relationship between joint hypermobility and POTS suggested a linked mechanism between EDS and POTS [9,18]. A mechanistic relationship between POTS and EDS has yet to be defined and proven [11]. Interestingly, the vascular and vascular-like subtypes of EDS with life threatening arterial and intestinal implications [19], are not linked with POTS in the literature. The prevalence of EDS within the general population has been suggested by Steinmen et al. to be 1 in 5000 people, or 0.02% [17]. Our study presents a statistically higher presence of clinically diagnosed EDS within our POTS patient cohort at 18%. Our study also performed a similar analysis on our patients without POTS but with autonomic dysfunction for comparison; 4% of this population had EDS, although their results were not genetically confirmed. It should be noted that our study did not identify all of our autonomic dysfunction patients without POTS; only those with at least one POTS symptom, therefore this rate may not be reflective of the non-POTS autonomic dysfunction group in general. However, it appears that the odds ratio of having EDS with a POTS diagnosis is significantly higher as compared to having autonomic dysfunction without POTS. Another novel facet to this study is that our population of EDS patients may represent at least three types of EDS (classical, hypermobile and potentially vascular). With this increase in presence and variation of EDS presentation, we must consider
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an additional underlying mechanism of POTS as caused by the connective tissue disorder in general, rather than just joint hypermobility. All types of EDS are linked to sequence variations in genes encoding for fibrillar proteins and/or collagen processing enzymes that lead to reduced structural integrity within the different systems of the body [11]. The vascular system contains vessels that are supported by elastin and collagen. For example, the aorta, the largest arterial vessel, has three concentric structural layers — the tunica intima, tunica media and tunica adventitia. Each layer has some type of collagen embedded in its matrix along with other proteins and substances. Specifically, the tunica media is comprised of elastic lamellae within a matrix of type III collagen that provide the vessel with its extreme elasticity. Vessel compliance has been shown to increase in large vessels due to the gradual extension of elastin whereas compliance decrease is attributed to the advanced age of elastin or an increase in collagen [20,21]. The mutations in the first four types of EDS may compromise this matrix and thus the compliance of the vessel may change, altering the flow of blood throughout the body and potentially leading to POTS symptoms. Another concept to consider is the effect of EDS on the autonomic system. In the great vessels, such as the aorta, the nerve bundles that innervate the vessel reside in the tunica adventitia. A disruption of this layer via compromised connective tissue may, in fact, disrupt the innervation as well. This could be the cause of autonomic dysfunction witnessed in EDS patients as well as the underlying autonomic dysfunction of POTS observed in these patients. Further investigation into both of these mechanisms is warranted. The variants of unknown origin identified in our EDS patients ought to be considered as well. Of the four types of EDS in consideration, the classic and vascular types all have identified genetic defects detectable by genotyping. The classic subtype is linked to genes COL5A1/COL5A2 and COL1A1 [22,23] and the vascular subtype is linked to COL3A1 [24]; the hypermobility subtype does not have a known genetic defect. Furthermore, many variants of unknown significance have been found in patients with each type of EDS and are still being found today. Our study also brings to surface the variants of unknown significance found in our patients, both on the COL5A1 gene: a point mutation of a Guanine to Adenine at c.787-15 and a point mutation of Guanine to Adenine at c.2331+16. Although currently inconclusive, it is possible that future genetic research of these variants in a POTS and EDS positive population may yield interesting results and may shed more light on the underlying POTS mechanism. 5. Study limitations This study is the largest analysis of POTS patients and genetically confirmed EDS patients; obtaining a large data set is difficult in this patient population because of the low prevalence of POTS. The current scope of this study focused the EDS genetic analysis on the POTS patients; further expansion of this analysis to all autonomic dysfunction patients may provide us with higher rates in those patients. A definitive diagnosis of POTS requires tilt-table testing which all of our POTS patients were evaluated with. Our study may be strengthened, however, if a tilt-table test had been performed on all of our patients, in order to confirm the absence of POTS in the appropriate patients. Additionally, there is potential for a referral bias in our study: patients with EDS and patients with autonomic dysfunction are referred to our clinic. The classification of patients afflicted with EDS based on genetics and clinical presentation has been proven to be difficult to separate from joint hypermobility syndrome by Tinkle et al. Tinkle et al. suggest that the Beighton scale for hypermobility along with the Brighton Scale should be employed in order to distinguish JHS from EDS [25]. Although we could not retrospectively apply the score in this study, future studies should follow this suggestion and may want to consider the prevalence of JHS and EDS together, suggested to be 20% of the general population by Tinkle et al. [25]. Lastly, the rigorous evaluation of EDS provided by the geneticist confirmed their diagnoses; expansion of genetic analysis
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to non-POTS patients may also contribute to changes in the EDS rates in those groups. 6. Conclusion The presence of EDS may be higher in patients with POTS than that of the general population or in non-POTS autonomic dysfunction patients. With this new data, we suspect that EDS may be a predictor of POTS and that there may be an additional underlying mechanism of POTS caused by the change in connective tissue from EDS. Future studies on the genetics of EDS are currently ongoing; detail from those studies may help in revising the proposed mechanisms. Conflict of interest and IRB approval On behalf of all authors, the corresponding author states that there is no conflict of interest. Furthermore, this study was IRB approved. All human studies have been approved by the appropriate ethics committee and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Acknowledgments The authors thank the Boston University School of Medicine and the Medical Student Summer Research Program for providing guidance for this project. References [1] Low PA, Opfer-Gehrking T, Textor SC, Benarroch EE, Win-Kuang S, Schondorf R, et al. Postural tachycardia syndrome (POTS). Neurology [Internet]. Lippincott Williams & Wilkins; 1995 [cited 2013 Jun 25];45(4):S19–S25. Available from: http://cat.inist. fr/?aModele=afficheN&cpsidt=3538365]. [2] Jacob G, Costa F, Shannon J, Roberston R, Wathen M, Stein M, et al. The neuropathic postural tachycardia syndrome. N Engl J Med 2000;343(14):1008–14. [3] Streeten P, Health Y. Pathogenesis of hyperadrenergic orthostatic hypotension. J Clin Invest 1990;86:1582–8 [(November)]. [4] Masuki S, Eisenach JH, Schrage WG, Johnson CP, Dietz NM, Wilkins BW, et al. Reduced stroke volume during exercise in postural tachycardia syndrome. J Appl Physiol [Internet] 2007 Oct [cited 2013 Jun 25];103(4):1128–35. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/17626834. [5] Joyner MJ, Masuki S. POTS versus deconditioning: the same or different? Clin Auton Res [Internet] 2008 Dec [cited 2013 Jun 25];18(6):300–7. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/18704621. [6] Streeten D, Thomas D, Bell D. the roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med 2000;320(1):1–8. [7] Raj S, Robertson D. Blood volume perturbations in the postural tachycardia syndrome. Am J Med 2007;334(1):57–60. [8] Medow MS. Defects in cutaneous angiotensin converting enzyme 2 and angiotensin(1–7) production in postural tachycardia syndrome. 2010;53(5):767–74. [9] Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med [Internet] 2003 Jul [cited 2013 Jun 25];115(1):33–40. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0002934303002353. [10] Hakim A, Grahame R. Joint hypermobility. Best Pract Res Clin Rheumatol 2003;17(6):989–1004 [[Internet] Available from: http://www.ncbi.nlm.nih.gov/ pubmed/15123047.]. [11] Benarroch E. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin. Proc., 87(12). Elsevier Inc.; Dec 2012 [[Internet]. Dec [cited 2013 Jun 25]. Available from: http://linkinghub.elsevier.com/retrieve/pii/ S0025619612008968]. [12] Thould AK, Beighton P. The Ehlers–Danlos syndrome. Ann Rheum Dis 1970;29(3):332–3. [13] Rowe PC, Barron DF, Calkins H, Maumenee IH, Tong PY, Geraghty MT. Orthostatic intolerance and chronic fatigue syndrome associated with Ehlers–Danlos syndrome. J Pediatr 1999;35(4):494–9 [[Internet]. Available from: http://www.ncbi.nlm.nih. gov/pubmed/10518084]. [14] Tucker DH, Miller E, Jacoby WJ. Ehlers–Danlos syndrome with a sinus of valsalva aneurysm and aortic insufficiency simulating rheumatic heart disease. Am J Med 1963;35(5):715–20. [15] De Paepe a, Malfait F. The Ehlers–Danlos syndrome, a disorder with many faces. Clin Genet [Internet] 2012 Jul [cited 2013 Sep 16];82(1):1–11. Available from: http:// www.ncbi.nlm.nih.gov/pubmed/22353005. [16] Wenstrup R, De Paepe A. Ehlers–Danlos syndrome , classic type. GeneReviews; 2007.
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