Sex Differences in Migraine

Transcription

1 Sex Differences in Migraine European Before puberty (10-14 girls), migraine affects both sexes equally Following puberty, migraine has strikingly higher prevalence in females than in men Female:male ratio 2:1 to 3:1, peaks at midlife Female migraineurs have more symptoms (photophobia, nausea) and more migrainerelated disability than male migraineurs Female predominance consistent across racial groups American Migraine Prevalence and Prevention Study (160,000 participants) Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, Serrano D, Lipton RB. Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache Sep;53(8): Stovner LJ, Zwart JA, Hagen K, Terwindt GM, Pascual J. Epidemiology of headache in Europe. Eur J Neurol Apr;13(4):

2 Sexual Dimorphism in Familial Hemiplegic Migraine Rare autosomal dominant migraine with aura Danish study identified 147 affected FHM patients from 44 families Most often had all 4 typical aura symptoms: visual, sensor, aphasic, motor Headache present in 99% of FHM patients during attack Female (105) : male (42) = 2.5 Thomsen LL, Eriksen MK, Roemer SF, Andersen I, Olesen J, Russell MB. A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria. Brain Jun;125(Pt 6):

3 Menstrual Migraine >50% of women with migraine report an association between migraine and menstruation Only migraine without aura Incidence greatest 2 days before menstruation and continuing through day 2-3 of bleeding More severe, disabling, and refractory to abortive medications than non-menstrually related IHS Menstrual migraine = attacks of migraine without aura which occur on day 1 ± 2 (i.e. days 2 to +3) of menstruation in at least 2/3 menstrual cycles (affects approximately 20% female migraineurs) [1st day of menstruation is day 1; no day 0]

4 Sex Steroids During Menstrual Cycle and Menstrual Migraine Menstruation Somerville BW. The role of estradiol withdrawal in the etiology of menstrual migraine. Neurology Apr;22(4):

5 Treatment with Progresterone Does Not Affect Menstrual Migraine Daily injections of progesterone (25-75 mg) in sesame oil beginning 3-6 days before the expected onset of menstruation, adjusted to maintain plasma progesterone of 5-20 ng/ml (midluteal range) Somerville BW. The influence of progesterone and estradiol upon migraine. Headache Oct;12(3):

6 Treatment with Estradiol Delays Menstrual Migraine Estradiol valerate in oil (slowrelease estradiol), 10 mg, i.m., 3-6 days before expected onset of menstrual bleeding Plasma estradiol threshold = 0.05 ng/ml Somerville BW. The influence of progesterone and estradiol upon migraine. Headache Oct;12(3):

7 Incidence of Migraine Relative to Menstrual Cycle Phases Luteal Onset of menstruation Follicular 38 women with 1-4 migraine attacks/month, 1 of which occurred perimenstrually Urinary metabolites collected daily Higher number of attacks late luteal/early follicular phase Lower number of attack during rising estrogen No increased migraine in relation to postovulatory withdrawal MacGregor EA, Frith A, Ellis J, Aspinall L, Hackshaw A. Incidence of migraine relative to menstrual cycle phases of rising and falling estrogen. Neurology Dec 26;67(12):

8 Menopause Last menstrual period around age 51 In perimenopausal years, orderly pattern of estrogen and progesterone secretion is lost Following menopause, lower levels of hormones fluctuate for 4-5 years; migraine may worsen but often progressively improves over time Migraine with aura unaffected by menopause Freeman EW, Sammel MD, Lin H, Gracia CR, Kapoor S. Symptoms in the menopausal transition: hormone and behavioral correlates. Obstet Gynecol Jan;111(1):

9 In postmenopausal women, fall in estrogen after 5 mg depo-estradiol triggers migraine in those with history of severe menstrual migraine but not in normal controls Sustained estrogen exposure necessary for estrogen withdrawal to provoke migraine attacks. Threshold estrogen (0.05 ng/ml) same as in Somerville s studies. Lichten EM, Lichten JB, Whitty A, Pieper D. The confirmation of a biochemical marker for women's hormonal migraine: the depo-estradiol challenge test. Headache Jun;36(6):

10 Pregnancy Kvisvik EV, Stovner LJ, Helde G, Bovim G, Linde M. Headache and migraine during pregnancy and puerperium: the MIGRA-study. J Headache Pain. 2011;15(4):

11 Cortical Spreading Depression Depolarization Decreased blood flow [Dhir A, Lossin C, Rogawski MA. Neuroscience Lett 514: 67 70, 2012]

12

13 Reduced CSD Threshold in Female Mice KCl Stimulation Tetanic Stimulation Brennan KC, Romero Reyes M, López Valdés HE, Arnold AP, Charles AC. Reduced threshold for cortical spreading depression in female mice. Ann Neurol Jun;61(6):603-6.

14 Sex Differences in CSD in FHM Type 1 Mouse (R192Q mutation) Homozygous R192Q CACNA1A gene (α1a subunit of Cav2.1 channels) R192Q causes mild CSD Topical KCl used to evoke CSD Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C. Genetic and hormonal factors modulate spreading depression and transient hemiparesis in mouse models of familial hemiplegic migraine type 1. J Clin Invest Jan;119(1):

15 Testosterone Suppresses CSD in FHM Type 1 Mouse (R192Q mutation) Subcutaneous testosterone pellet (0.1 mg/pellet, 21-day release) Testosterone propionate (1.2 mg) Subcutaneous flutamide (25 or 50 mg/pellet, 21-day release Eikermann-Haerter K, Baum MJ, Ferrari MD, van den Maagdenberg AM, Moskowitz MA, Ayata C. Androgenic suppression of spreading depression in familial hemiplegic migraine type 1 mutant mice. Ann Neurol Oct;66(4):564-8.

16 Case Report: Menstrual Hemiplegic Migraine Cured by Oophorectomy 48-year-old woman with premenstrual right arm and leg weakness, expressive dysphasia TAH-BSO Completely well with no subsequent recurrence of symptoms Sood SV. Hemiplegic migraine associated with menstruation. J Obstet Gynaecol Br Commonw Aug;78(8):762-3.

17 MM Perimenstrual Prophylaxis (NSAIDs) Naproxen (550 mg) b.i.d., 7-14 days, starting during the week before expected onset of menstruation Risks: GI bleeding (consider gastroduodenal protection) Medication-overuse headache Fluid retention, edema hypertension

18 MM Perimenstrual Prophylaxis (triptans) Frovatriptan (load: 5 mg b.i.d. first day; 2.5 mg b.i.d. remaining days), 6 days, starting 2 days before expected onset of menstruation Naratriptan and zolmitriptan can also be used 2 hour recurrence MacGregor EA. A review of frovatriptan for the treatment of menstrual migraine. Int J Womens Health May 21;6:

19 MM Estrogen Supplements Maintains luteal phase estradiol levels, preventing late luteal phase drop Women must be menstruating regularly (endogenous progesterone following ovulation provides endometrial protection) Estradiol gel 1.5 mg (1.5 g) daily, 7 days, starting between 2-5 days before expected onset of menstruation Estradiol transdermal system Estradiol Gel Estradiol transdermal system (Vivelle Dot)

20 Contraceptives Progestin Only Ethinylestradiol-containing BCP s contraindicated in migraine with aura due to 2-fold increased stroke risk; also contraindicated in clotting disorder, history of DVT, or cardiovascular risk factors (lipids, obesity, smoking, CRP) Progesterone only BCPs ( mini-pill ) safe alternative Mini-Pill: Micronor, Nor-QD (norethindrone) Implant (3 year): Implanon, Nexplanon (etonogestrel) Depo: Depo-provera (medroxyprogesterone) Higher failure rate and slightly higher rate of ectopic pregnancy Alternatives: IUD, barrier contraceptives Levonorgestrel IUD (low systemic absorption) (Mirena, Skyla)

21 MM Oral Contraceptives Oral contraceptives can be used to prevent pregnancy in most women with migraine; do not prevent migraine Risks of endometrial and ovarian cancer reduced; possibly reduce colon cancer risk Risk of breast, cervical, and liver cancer increased Estrogen withdrawal during hormone-free interval can trigger migraine Estrogen supplements can prevent (0.01 mg oral ethinyl estradiol, 0.9 mg oral conjugated equine estrogens, 0.1 mg/day estradiol patch, 2 g estradiol gel) Endometrial protection from progestagen in BCP

22 MM Monophasic (Continuous) Low-Dose Combination Oral Contraceptives Reduced Withdrawal Bleeds / Amenorrhea Contraceptive-induced amenorrhea reduces migraine frequency 84/7 regimen (4 withdrawal bleeds; Seasonique) No withdrawal bleeds (Lybrel; unscheduled bleeding in early cycles resolves with time; may break with the bleed - stop BCP for 3 days); by months continuous use, % of women are amenorrheic Vetvik KG, MacGregor EA, Lundqvist C, Russell MB. Contraceptive-induced amenorrhoea leads to reduced migraine frequency in women with menstrual migraine without aura. J Headache Pain May 17;15:30.

23 MM Chemical Menopause: Leuprolide + add-back Leuprolide acetate 3.75 mg IM monthly Last 6 months estrogenprogestin add-back transdermal estradiol (E2) patches (0.1 mg/d) and oral medroxyprogesterone acetate (2.5 mg daily Provera) Murray SC, Muse KN. Effective treatment of severe menstrual migraine headaches with gonadotropinreleasing hormone agonist and add-back therapy. Fertil Steril 1997;67(2):390Y393.

24 Perimenopause Many women require treatment for vasomotor symptoms, usually with hormone replacement Oral estrogen can exacerbate migraine Non-oral routes: estradiol gel, estradiol transdermal system Endometrial protection with progestin necessary for women who have not had hysterectomy Medroxyprogesterone acetate (2.5 mg/day) Natural progesterone ( mg/day) Levonorgestrel IUD (low systemic absorption) (Mirena, Skyla) 4% vaginal progesterone (Crinone) -- must apply daily, expensive MacGregor EA. Migraine Management During Menstruation and Menopause. Continuum (Minneap Minn) Aug;21(4 Headache): Hampton NR, Rees MC, Lowe DG, Rauramo I, Barlow D, Guillebaud J. Levonorgestrel intrauterine system (LNG-IUS) with conjugated oral equine estrogen: a successful regimen for HRT in perimenopausal women. Hum Reprod Sep;20(9): Levonorgestrel-releasing intrauterine system (LNG-IUS; Mirena) Copper IUD (Paragard)

25 The End