10/07/18. Point-prevalence of migraine (women & men) COMORBIDITY MIGRAINE & COMORBIDITY

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1 10/07/18 CARDIOVASCULAR RISKS ASSOCIATED WITH MIGRAINE AND USE OF COMBINED HORMONAL CONTRACEPTION 1,2László Vécsei, 1János Tajti, 1Délia Szok 1 D e p a r tm e n t o f N e u r o lo g y, F a c u lty o f M e d ic in e, U n iv e r s ity o f S z e g e d, S z e g e d, H u n g a ry 2 N e u r o s c ie n c e R e s e a r c h G r o u p o f th e H u n g a r ia n A c a d e m y o f S c ie n c e s a n d U n iv e r s ity o f S z e g e d, H u n g a r y (M TA S Z T E N e u r o s c ie n c e R e s e a r c h G r o u p ) MIGRAINE Migraine is a common, episodic, multifactorial, neurovascular disorder with high socio-economic and personal impact. Point-prevalence of migraine (women & men) N e w sw e e k Ja n u a ry 11, Ferrari M. Cephalalgia 25: , 2005 Vetvik and MacGregor Lancet Neurol 2017 COMORBIDITY The term comorbidity is now used to refer to the greater than coincidental association of two conditions in the same individual. MIGRAINE & COMORBIDITY E p id e m io lo g ic a l s tu d ie s h a v e re p o rte d th a t MIGRAINE VASCULAR DISEASES: TRANSIENT ISCHAEMICATTACK (TIA) ISCHAEMIC STROKE HAEMORRHAGIC STROKE MIGRAINE DEPRESSION MIGRAINE EPILEPSY MIGRAINE ASTHMA MIGRAINE ALLERGIES MIGRAINE RESTLESS LEGS SYNDROME MIGRAINE CHRONIC PAIN SYNDROMES Feinstein AR. The pre-therapeutic classification of comorbidity in chronic disease. J. Chronic Dis., Lipton RB, Silberstein SD. Why study the comorbidity of migraine? Neurology, Vetvik and MacGregor Lancet Neurol., m ig ra in e is c o m o rb id w ith s e v e ra l d is o rd e rs : vascular diseases asthma allergies epilepsy restless legs syndrome various chronic pain syndromes psychiatric disorders 1

2 MIGRAINE - TIA (WOMEN S HEALTH STUDY) Migraine with aura (women) TIA RR: 1.55 (95% CI ) Migraine without aura (women) no change in risk of TIA RR: relative risk Rist et al. Migraine and functional outcome from ischemic cerebral events in women. Circulation 122: , MIGRAINOUS INFARCTION It is a rare condition. Incidence: 0.8/ Ischaem ic lesion in the left occipital lobe (M R I) Laurell et al. Migrainous infarction: a Nordic multicenter study. Eur. J. Neurol. 18: , Collaborative Group of the Study of Stroke in Young Women (1975) ISCHAEMIC STROKE ANY MIGRAINE It showed a doubling of the relative risk of stroke with women with migraine compared with controls. CVD: cardiovascular disease Collaborative Group of the Study of Stroke in Young Women. Oral contraceptives and stroke in young women. JAMA 231: , Sacco S, Ricci S, Carolei A. Migraine and vascular diseases: A review of the evidence and potential implications for management. Cephalalgia 32: ,

3 ISCHAEMIC STROKE MIGRAINE WITH and WITHOUT AURA ISCHAEMIC STROKE (AMERICAN MIGRAINE PREVALENCE AND PREVENTION STUDY) Any migraine OR (95% CI). Migraine with aura OR (95% CI) Migraine without aura OR (95% CI) STROKE (ischaemic) ( ) ( ) ( ) Association: No association: - any migraine and ischaemic stroke - migraine with aura and ischaemic stroke - migraine without aura and ischaemic stroke Sacco S, Ricci S, Carolei A. Migraine and vascular diseases: A review of the evidence and potential implications for management. Cephalalgia 32: , Bigal et al. Migraine and cardiovascular disease. Neurology 74: , ISCHAEMIC STROKE MIGRAINE (W OMEN vs. MEN) THE STROKE PREVENTION IN YOUNG WOMEN STUDY Greater risk among WOMEN: 2.08 ( ) compared with MEN: 1.37 ( ) Compared with women with no migraine history who were non smokers and non oral contraceptive users, women with migraine with aura who smoked and used oral contraceptives had 10.0-fold higher Odds of stroke (95% CI, 1.4 to 73.7). Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and metaanalysis. BMJ 339:b3914, Doi: /bmj.b3914, MacClellan L.R., Giles W., Cole J., Wozniak M., Stern B., Mitchell B.D., Kittner S.J. Probable migraine with visual aura and risk of ischemic stroke. The Stroke Prevention in Young Women Study. Stroke 38: , VENOUS THROMBOSIS MIGRAINE There are no data on the effect of migraine on risk of venous thrombosis in women who use combined hormonal contraception (CHC). Combined hormonal contraceptives and migraine: An update on the evidence. Calhoun AH, Batur P. Cleve Clin J Med Aug;84(8): Vetvik and M acgregor Lancet Neurol.,

4 MIGRAINE & HORMONAL CONTRACEPTION WHO consideration: migraine with aura contraindicates use of combined hormonal contraception Combined hormonal contraceptives and migraine: An update on the evidence. Calhoun AH, Batur P. Cleve Clin J Med Aug;84(8): Use nonestrogen contraception for smokers who are age 35 or older, or for women with multiple risk factors for stroke. WHO. Medical eligibility criteria for contraceptive use. 5th Edition (accessed Sept 3, 2016) Combined hormonal contraceptives and migraine: An update on the evidence. Calhoun AH, Batur P. Cleve Clin J Med Aug;84(8): Progestin-only pills are unlikely to help in reducing migraine since they prevent ovulation only about half the time. Menstrually-related migraine without aura Diagnostic criteria: A.Attacks, in a menstruating woman, fulfilling criteria for 1.1 Migraine without aura and criterion B below B.Documented and prospectively-recorded evidence over at least three consecutive cycles has confirmed that attacks occur on day 1 ± 2 (ie, days 2 to +3) of menstruation in at least two out of three menstrual cycles, and additionally at other times of the cycle. Calhaun et Batur. Cleve Cin J Med In women with menstrual-related migraine, any decrease in estrogen level greater than 10 ug of ethinyl estradiol may trigger an estrogen-withdrawal migraine. Postmenopausal hormone therapy Neither smoking nor migraine is a contraindication of to the use of postmenopausal hormone therapy, which is substantially lower in dosage than combined hormonal contraceptives. Desogestrel 75 mcg/day, progestin-only pill significantly but modestly reduces the number of migraine attacks and migraine days. Calhaun et Batur. Cleve Cin J Med Progestin-only pill should be considered in women with migraine, particularly those with common contraindications to combined oral contraceptives use such as migrainous aura and hypertension. 4

5 10/07/18 P A T E N T F O R A M E N O V A L E (P F O ) B R A IN W H IT E M A T T E R L E S IO N S (W M L s ) IN M IG R A IN E U R S W M L s : ty p ic a lly m u ltip le, s m a ll, p u n c ta te h y p e rin te n s itie s o c c u rin g in th e d e e p o r p e riv e n tric u la r w h ite m a tte r a n d o fte n s e e n o n T 2 w h e ig h te d o r F L A IR im a g e s. PFO an interatrial septal cardiac abnormality associated with increased risk of ischemic stroke in young adults. PFOis significantly more common in migraine with aura (general population: 7%, migraine with aura: 38%). Pezzini A et al. Current Molecular Medicine, Tepper et al. Neurol. Sci., Del Sette et al. Cerebrovasc. Dis., Anzola et al. Neurology, M i g r a i n e p a t ie n t s a r e a t in c r e a s e d r is k f o r W M L s ( O R 3. 9 ) m a in ly in t h e p o s t e r i o r c i r c u l a t i o n t e r r it o r y. Kundra et al. The prevalence of white matter abnormalities on magnetic resonanceimages in migraine. Ideggyogy Sz, Swartz and Migraine isischemic associated with magnestic resonancejimaging whiteflow matter abnormalities. Del Zotto etkern. al. Migraine and stroke: a debated question. Cereb Blood Metab, Arch Neurol, C E R E B E L L A R IN F A R C T -L IK E L E S IO N S (CAMERA STUDY) Prevalence (cerebellar lesions): Control: 0.7% Migraine without aura: 2.2% Migraine with aura: 7.5% Risk factors for WMLs: High attack frequency Sex (women) H A E M O R R H A G IC S T R O K E M IG R A IN E A meta-analysis found that any migraine was a significant risk factor for haemorrhagic stroke. WOMEN S HEALTH STUDY: Migraine without aura (women): 0.52 ( H a z a r d R a t io s, 9 5 % C I ) Migraine with aura (women): 2.31 ( H a z a r d R a t io s, 9 5 % C I ) META-ANALYSIS: Any migraine control: 1.48 ( p o o le d a d ju s t e d e ff e c t, 9 5 % C I ) Migraine with vs. aura: 1.62 (NS) ( a d ju s t e d e ff e c t, 9 5 % C I ) Any migraine (women) : 1.55 ( r e la t iv e e ff e c t 9 5 % C I ) Any migraine (women) < 45 years: 1.57 ( r e la t iv e e ff e c t 9 5 % C I ) (C A M E R A : C e re b ra l A b n o rm a litie s in M ig ra in e, a n E p id e m io lo g ic a l R is k A n a ly s is ) Kruit et al. Infarcts in the posterior circulation territory in migraine. The population-based MRI CAMERA stuy. Brain 128: , G E N E T IC IN F L U E N C E O N M IG R A IN E IS C H A E M IC S T R O K E R E L A T IO N M O N O G E N IC D IS O R D E R S Familial Hemiplegic Migraine (FHM) Kurth et al. Migraine and risk of haemorrhagic stroke in women: prospective cohort study. BMJ, Sacco et al. Migraine and haemorrhagic stroke: a meta-analysis. Stroke, Vetvik and MacGregor Lancet Neurol., FAMILIAL HEMIPLEGIC MIGRAINE (FHM) S tro k e o c c u rs in le s s th a n 5 % o f p a tie n ts w ith F H M. Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) Cerebroretinal Vasculopathy (CRV) Hereditary Endotheliopathy with Retinopathy, Nephropathy, and Stroke (HERNS) Pezzini A., Del Zotto E., Giossi A., Volonghi I., Grassi M., Padovani A. The migraine-ischemic stroke connection: potential pathogenic mechanisms. Current Molecular Medicine 9: , Thomsen et al. Brain 125: ,

6 Pezzinie et al. Current Molecular Medicine 9: , FHM1 CADASIL FHM1 CHROMOSOME 19p13 GENE CACNA1A CADASIL CHROMOSOME 19p13 GENE Notch-3 Migraine with aura is usually the first manifestation, presenting about 15 years before stroke and before the appearance of MRI signal abnormalities. GENETIC INFLUENCE ON MIGRAINE ISCHEMIC STROKE RELATION MELAS mtdna CRV Cerebroretinal Vasculopathy HERNS Hereditary Endotheliopathy with Retinopathy, Nephropathy, and Stroke Leber s Hereditary optic neuropathy, myoclonic epilepsy with ragged red fibers Osler-Weber-Rendu Hereditary hemorrhagic teleangiectasia Del Zotto E et al. Migraine and ischemic stroke: a debated question. J Cereb Blood Flow Metab, GENETIC INFLUENCE ON MIGRAINE ISCHAEMIC STROKE RELATION POLYGENIC FORMS Neurotransmitter-related pathway Dopamine D2 receptor (D R D 2) Human serotonin transporter (H SER T) Catechol-O -m ethyl-transferase (C O M T) Dopamine ß -hydroxylase (D B H ) Vascular function 5, 10-m ethylene-tetrahydrofolate reductase (M TH FR ) Angiotensin I-converting enzyme (A C E) Endothelin type A receptor (ETA ) Hormonal function Estrogen receptor1 (ESR 1) Progesterone receptor (PG R ) Androgen receptor (A R ) Del Zotto E et al. Migraine and ischemic stroke: a debated question. J Cereb Blood Flow Metab, CARDIOVASCULAR RISKS ASSOCIATED WITH MIGRAINE AND USE OF COMBINED HORMONAL CONTRACEPTION Take home message Migraine is a primary headache disorder with high socio-economic and personal impact One of the severe comorbid factors of migraine are vascular diseases Women with migraine with aura have 2-fold increased risk of ischemic stroke Women with migraine with aura who smoked and used combined hormonal contraception have 10-fold higher Odds of stroke Use non-estrogen contraception for smoker female migraineurs, who are age 35 or older, or with multiple risk factors for stroke Women with migraine with aura contraindicates use of combined hormonal contraception 6