Vulvodynia Causes and Diagnosis

Transcription

1 North American Chapter of The International Society for The Study of Vulvovaginal Disease Vulvodynia Causes and Diagnosis Hope K. Haefner, MD No conflicts of interest North American Chapter of The International Society for The Study of Vulvovaginal Disease Additional Information careservices/womens health library/center vulvardiseases/resources providers or search Google for Resources for Providers University of Michigan 1

2 Learning Objectives At the end of this presentation, the participant will: Understand the current classification system for vulvar pain (2015 Consensus Terminology and Classification of Persistent Vulvar Pain) Explore the various causes of vulvodynia Be familiar with the diagnosis of vulvodynia North American Chapter of The International Society for The Study of Vulvovaginal Disease Additional Information careservices/womens health library/center vulvardiseases/resources providers or search Google for Resources for Providers University of Michigan 2

3 North American Chapter of The International Society for The Study of Vulvovaginal Disease Resources for Providers - Michigan Medicine - University of Michigan Resources for Providers. Vulvar Diseasesr. Patient Education Booklet: This booklet describes various vulvar conditions as outlined below: Diseases of the Vulva; Some suggested vulvar pain and itching measures; Vulvar Self Exam; Yeast Infections; Lichen Sclerosus; Lichen Planus; Vulvodynia; Squamous Cell Hyperplasia.. North American Chapter of The International Society for The Study of Vulvovaginal Disease Tijuana, Mexico August, 2017 Vaginal and Vulvar Colposcopy (PPT PDF) Vulvar Diagnosis and Treatment (PPT PDF) Vulvodynia Approach, Diagnosis, and Treatment (PPT PDF) Chicago, Advocate Lutheran Grand Rounds February 2018 Management of Complex Vulvovaginal Conditions (PPT PDF) Your Diagnosis Is (PDF) Severe Itch Scratch Cycle Tips (PDF) 3

4 Definition of Vulvodynia International Society for the Study of Vulvovaginal Disease (ISSVD) Chronic discomfort Burning Stinging Irritation Rawness Question 1 I see patients with vulvodynia Yes No 4

5 Question 2 I like to see patients with vulvodynia Yes No 8.3% of women have vulvodynia Reed BD, Harlow SD, Sen A, Legocki LJ, Edwards RM, Arato N, Haefner HK. Prevalence and demographic characteristics of vulvodynia in a population-based sample. Am J Obstet Gynecol

6 By age 40 years, 7-8% in Boston and Minneapolis/St. Paul reported vulvar pain consistent with vulvodynia. Harlow BL, Kunitz CG, Nguyen RHN, Rydell SA, Turner RM, Maclehose RF. Prevalence of symptoms consistent with a diagnosis of vulvodynia: Population-based estimates from 2 geographic regions. Am J Obstet Gynecol. 2014;210:40.e1-40.e8. Diagnosis of Vulvodynia Define disease Cotton swab test Vulvoscopy? 6

7 Not tender; no area of vulva described as area of burning Alternative diagnosis Define disease Cotton swab test Vulvoscopy Thorough history Diagnosis of Vulvodynia 7

8 Does Degree of Vulvar Sensitivity Predict Vulvodynia Characteristics and Prognosis? Reed BD, Plegue MA, Harlow SD, Haefner HK, Sen A. Journal of Pain 2016 Volume 18, Issue 2, Pages Various Terms Utilized for Vulvar Pain Prior to 2003 Essential vulvodynia Dysesthetic vulvodynia Vulvar vestibulitis syndrome Vulvar dysesthesia (generalized or localized) Provoked vulvar dysesthesia Spontaneous vulvar dysesthesia CONTROVERSY! 8

9 Generalized Generalized Localized

10 Localized April 2015 Support from the National Vulvodynia Association 10

11 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia A. Vulvar pain caused by a specific disorder* Infectious (eg, recurrent candidiasis, herpes) Inflammatory (eg, lichen sclerosus, lichen planus, immunobullous disorders) Neoplastic (eg, Paget disease, squamous cell carcinoma) Neurologic (eg, postherpetic neuralgia, nerve compression or injury, neuroma) Trauma (eg, female genital cutting, obstetric) Iatrogenic (eg, postoperative, chemotherapy, radiation) Hormonal deficiencies (eg, genitourinary syndrome of menopause [vulvovaginal atrophy], lactational amenorrhea) B. Vulvodynia Vulvar pain of at least 3 months duration, without clear identifiable cause, which may have potential associated factors The following are the descriptors: Localized (eg, vestibulodynia, clitorodynia) or Generalized or Mixed (Localized and Generalized) Provoked (eg, insertional, contact) or Spontaneous or Mixed (Provoked and Spontaneous) Onset (primary or secondary) Temporal pattern (intermittent, persistent, constant, immediate, delayed) * Women may have both 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. 11

12 Etiologies 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. 12

13 Painful Bladder Syndrome Embryologic Derivation Urogenital sinus Urogenital sinus Similarities Between Interstitial Cystitis/Bladder Pain Syndrome and Vulvodynia: Implications for Patient Management Intertwined from the perspectives of embryology, pathology and epidemiology Similar responses to therapies Fariello and Moldwin

14 Oxalates and Vestibulodynia Oxalates and Vestibulodynia Greenstein A, Militscher I, Chen J, Matzkin H, Lessing JB, Abramov L. Hyperoxaluria in women with vulvar vestibulitis syndrome. J Reprod Med Jun;51(6):500-2 Harlow BL, Abenhaim HA, Vitonis AF, Harnack L. Influence of dietary oxalates on the risk of adultonset vulvodynia. Journal of Reproductive Medicine 2008;53(3):

15 For the life of me, I don t know how I got that yeast infection. I was in and out of that bakery in less than a minute. Recurrent Yeast Infections and Vulvodynia: Can We Believe Associations Based on Self-Reported Data? Harlow BL, Caron RE, Parker SE, Chatterjea D, Fox MP, Nguyen RHN. JOURNAL OF WOMEN S HEALTH Volume 26, Number 10, October 1, Mary Ann Liebert, Inc. 15

16 Recurrent Yeast Infections and Vulvodynia: Can We Believe Associations Based on Self-Reported Data? Positive relationship between yeast infections preceding and following the diagnosis of vulvodynia -Varies from strong to nonexistent depending on the relative accuracy of the recalled diagnosis of yeast infections among cases and controls 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. 16

17 Inflammatory response Candida Mannose binding lectin NALP3 expressed in macrophages Neurotransmitters - Guanosine triphosphate cyclohydrolase (GCH1) Genetics G protein coupledreceptors - Melanocortin-1 receptor Neuroinflammatory (cytokines) - Interleukins (IL) MicroRNA New thoughts - Dectin 1 - Familiality Inflammatory response Candida Mannose binding lectin NALP3 expressed in macrophages Neurotransmitters - Guanosine triphosphate cyclohydrolase (GCH1) Genetics G protein coupledreceptors - Melanocortin-1 receptor Neuroinflammatory (cytokines) - Interleukins (IL) MicroRNA New thoughts - Dectin 1 - Familiality 17

18 Genetics Inflammatory response Candida Mannose binding lectin NALP3 expressed in macrophages Neurotransmitters - Guanosine triphosphate cyclohydrolase (GCH1) G protein coupledreceptors - Melanocortin-1 receptor Neuroinflammatory (cytokines) - Interleukins (IL) MicroRNA New thoughts - Dectin 1 - Familiality Familiality Analysis of Provoked Vestibulodynia Treated by Vestibulectomy Supports Genetic Predisposition 183 potential vestibulectomy probands were identified using CPT codes Relative risk of vestibulectomy was elevated in first-degree (20 [6.6-47], P <.00001), second-degree (4.5 [0.5-16], P =.07), and third-degree female relatives (3.4 [ ], P =.03) Suggests that vestibulodynia treated by vestibulectomy has a genetic predisposition Morgan et al

19 Catechol-O-methyltransferase gene polymorphism and vulvar pain in women with vulvodynia. Enzyme that metabolizes catecholamines -Neuromodulator that is involved with perception and sensitivity to pain Patanwala IY, Lamvu G, Ledger WJ, Witzeman K, Marvel R, Rapkin A, Bongiovanni AM, Feranec J, Witkin SS. American Journal of Obstetrics & Gynecology 2017;216(4):395.e1-395.e Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. 19

20 Hormonal Changes Controversy! Eva LJ, MacLean AB, Reid WM, Rolfe KJ, Perrett CW. American Journal of Obstetrics & Gynecology. 2003;189: Johannesson U, Sahlin L, Masironi B, et al. Steroid receptor expression and morphology in provoked vestibulodynia. Am J Obstet Gynecol. 2008;198(3):311 e1 6. Estrogen Receptor Expression Study group showed a significant decrease in estrogen receptor expression, and 50% of the samples did not exhibit any receptor expression Eva LJ, MacLean AB, Reid WM, Rolfe KJ, Perrett CW. American Journal of Obstetrics & Gynecology. 2003;189:

21 Steroid receptor expression and morphology in provoked vestibulodynia Ulrika Johannesson Karolinska Institutet, Danderyd Hospital, Sweden Co-authors;Lena Sahlin, Britt Masironi, Bo Blomgren, Marita Hilliges, Eva Rylander, Nina Bohm-Starke 70 Boxplot by Group Variable: ERa tot bv v vs 60 ERa tot bv vvs ERα stroma 10 0 Patients 1 2 Group Controls Median 25%-75% Min-Max 120 Boxplot by Group Variable: ERa tot vvs ERα epithelium ERa tot vvs Patients Group Controls Median 25%-75% Min-Max 21

22 Conclusion Increased expression of ERα in the vulvar vestibular mucosa in patients with provoked vestibulodynia in the absence of an altered epithelial morphology For women aged <50 years of age, OC use did not increase the risk of subsequent vulvodynia. 22

23 Polymorphisms of the Androgen Receptor Gene and Hormonal Contraceptive Induced Provoked Vestibulodynia Goldstein et al Risk of developing combined hormonal contraceptive (CHC)- induced vestibulodynia may be due to lowered free testosterone combined with an inefficient androgen receptor that predisposes women to vestibular pain 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. 23

24 Mast Cells Bornstein et al. (2004) found significant increase in inflammatory infiltrate, number of mast cells and degranulated mast cells in vestibulitis patients (N=40) compared to normal controls (N=7, ages 18-48) Regauer et al. (2015) evaluated 35 patients with vulvodynia -Median age was 24 years (ranged from 18 to 70 years). -Control tissues obtained from autopsies (? number) -Only 20/35 vulvodynia specimens showed a T-lymphocyte dominant inflammatory infiltrate on HE-stained sections, but all showed mast cells. 4/35 biopsies showed <10 mast cells/mm2, 15/35 specimens mast cells/mm2 and 16/35 specimens >60 mast cells/mm2 (average 80/mm2). Control tissue contained typically <10 mast cells. 24

25 Vestibular Mast Cell Density in Vulvodynia: A Case- Controlled Study No difference in mast cell density in biopsies of the vestibule found between white cases and racially matched controls Black control women have a lower mast cell density compared with white control women Papoutsis D, Haefner HK, Crum CP, Opipari AW, Reed BD. J Lower Genit Tract Dis 2016;20: Toll-Like Receptor Signaling Contributes to Proinflammatory Mediator Production in Localized Provoked Vulvodynia Human vulvar fibroblasts express a broad spectrum of TLRs A significantly higher TLR-mediated proinflammatory response was observed in LPV case vestibular fibroblasts Falsetta ML, Foster DC, Woeller CF, et al. Journal of Lower Genital Tract Disease. 22(1):52-57, January

26 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia Morin M, Binik YM, Bourbonnais D, Khalife S, Ouellet S, Bergeron S. J Sex Med 2017 Apr;14(4):

27 Heightened Pelvic Floor Muscle Tone and Altered Contractility in Women With Provoked Vestibulodynia Evaluated the passive component of the PFM tone in women with PVD Findings show that women with PVD sustaining quiescent muscle activity during stretching still presented greater passive forces, stiffness, and hysteresis than asymptomatic controls Women with PVD showed muscle over-activation as well as persistent alterations in muscle viscoelastic properties 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. 27

28 Vulvodynia as Neuropathic Pain Central Peripheral Vulvodynia and the Brain Augmented Central Pain Processing in Vulvodynia. J Hampson, BD Reed, DJ Clauw, R Bhavsar, RH Gracely, HK Haefner, RE Harris. Journal of Pain June, 2013;14:

29 Vulvodynia and the Brain On MRI, 24 vestibulodynia patients displayed greater levels of activation during thumb stimulation within the insula, dorsal midcingulate, posterior cingulate and thalamus compared to controls (P<0.005 corrected) The augmented brain activation in VVD patients in response to a stimulus remote from the vulva suggests central neural pathology in this disorder Mechanisms of Pain Brain A-delta 1 st sharp Stimulus C fiber 2 nd burning, throbbing Willis 1985 Spinal cord from Robert Bennett, MD 29

30 Mechanisms of Pain Acute pain Peripheral nociceptive input from thermal, chemical or mechanical nociceptors Chronic pain Central factors typically predominate Brain Stimulus Spinal cord from Robert Bennett, MD Question 3 The nerve which supplies the major portion of the vulva is the 1. Ilioinguinal nerve 2. Genitofemoral nerve 3. Perineal nerve 4. Pudendal nerve 30

31 Pudendal Nerve Originates from S2, S3, and S4 foramina Journal of Lower Genital Tract Disease: January 2017;21:

32 JLGTD April 2018 Volume 22: NGF increased in response to Candida Antigen stimulation in vulvodynia patients- NGF produces pain via direct effect on nerves, and indirect effect on mast cells neutrophils, and efferent neurons. 32

33 Proposed neuroimmunological mechanism of the allodynia/hyperpathia of vulvodynia IL-1ra Potentially inciting factors: Infections Irritants Toxins Medications Other Increased proinflammatory cytokines: IL-1, IL-6, IL-8 IFN- TNF- Nerve growth factor increased IL-4 Mast cell accumulation Allodynia and hyperpathia IL-12 and IL-18 Substance P CGRP Distal nerve sprouting Legend: = stimulatory = inhibitory A review of the available clinical therapies for vulvodynia management and new data implicating pro-inflammatory mediators in pain elicitation Fibroblasts isolated from the vestibule of LPV patients are sensitive to proinflammatory stimuli and copiously produce pain-associated pro-inflammatory mediators (IL 6 and PGE2) Falsetta ML, Foster DC, Bonham AD, Phipps RP. BJOG 2017 Jan;124(2):

34 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. A Prospective 2-Year Examination of Cognitive and Behavioral Correlates of Provoked Vestibulodynia Outcomes Changes in both cognitive and behavioral variables were significantly associated with improved pain and sexual satisfaction outcomes Davis SN, Bergeron S, Bois K, Sadikaj G, Binik YM, Steben M.Clinical Journal of Pain 2015;31(4):

35 2015 Consensus Terminology and Classification of Persistent Vulvar Pain and Vulvodynia Appendix: Potential Factors Associated with Vulvodynia a Comorbidities and other pain syndromes (e.g., painful bladder syndrome, fibromyalgia, irritable bowel syndrome, temporomandibular disorder; level of evidence 2) Genetics (level of evidence 2) Hormonal factors (e.g., pharmacologically induced; level of evidence 2) Inflammation (level of evidence 2) Musculoskeletal (e.g., pelvic muscle overactivity, myofascial, biomechanical; level of evidence 2) Neurologic mechanisms Central (spine, brain; level of evidence 2) Peripheral: neuroproliferation (level of evidence 2) Psychosocial factors (e.g., mood, interpersonal, coping, role, sexual function; level of evidence 2) Structural defects (e.g., perineal descent; level of evidence 3) a The factors are ranked by alphabetical order. New Concepts on Functional Chronic Pelvic and Perineal Pain: Pathophysiology and Multidisciplinary Management Dysregulation of nociceptive messages derived from the pelvis and perineum Ploteau S, Labat JJ, Riant T, Levesque A, Robert R, Nizard J. Discovery Medicine 2015;19(104):

36 Not One Disease F1000Research 2016,5. 36

37 The Human Dimension 37