J.Neurol.Sci.[Turk] Journal of Neurological Sciences [Turkish] 29:(1)# 30; 001-010, 2012 http://www.jns.dergisi.org/text.php3?id=491 Research Article Factors for Progression and Chronification of Episodic Migraine: One-year Face-to-face Follow-up Study Meral SEFEROĞLU1, Necdet KARLI1, Mehmet ZARIFOĞLU1, Çiğdem ŞEN1, Murat ALBAS1, Güven ÖZKAYA2, Özlem TAŞKAPILIOĞLU1 1Uludağ Üniversitesi Tıp Fakültesi, Nöroloji AB, Bursa, Türkiye 2Uludağ Üniversitesi Tıp Fakültesi, Biyoistatistik AB, Bursa, Türkiye Summary Objectives: To investigate the factors influencing progression and chronification of episodic migraine, we conducted a 12-month face to face follow-up study of episodic migraine patients. Methods: One hundred eighty patients with episodic migraine were enrolled. 120 parameters were analyzed including demographic factors, social and life-style features, comorbid medical illnesses and headache characteristics. After the first evaluation, all patients was scheduled to a structured face to face interview at 3-months interval for one-year. Results: Thirty-two (17,7%) patients developed chronic daily headache. Four out of 32 (2,2%) had definite chronic migraine. Low education level, obesity, greater tea consumption (≥4 cups/daily), predominantly hot and spicy diet, high headache frequency, long duration of headache and presence of allodynia at baseline, and more days with symptomatic drug intake were significant risk factors for progression and chronification of migraine. Cox regression analysis revealed triptan and NSAID intake, hot and spicy eating habit and allodynia as risk factors for chronification. Conclusion: Higher amount of tea consumption, hot and spicy diet appeared to be new risk factors for chronification of migraine. Weight gain is one of the most important risk factors. Patients should be warned about the risk factors to prevent chronification. Key words: Chronic daily headache, Chronic migraine, Migraine, Risk factors, Transformation Epizodik Migrenin Kronikleşmesinde ve Progresyonunda Etkili Faktörler: 1 Yıllık Yüz Yüze Takip Çalışması Özet Amaç: Epizodik migrenin kronikleşmesinde ve progresyonunda rolü olabilecek faktörleri araştırmak amacı ile epizodik migrenli hastaların 12 aylık yüz yüze takip çalışmasını gerçekleştirdik. Gereç ve yöntem: 180 epizodik migren hastası çalışmaya alındı. Demografik verileri, sosyal yaşam ve yaşam tarzı özellikleri, eşlik eden hastalıklar ve başağrısı özellikleri olmak üzere 120 parametre analiz edildi. İlk değerlendirmeyi takiben tüm hastalar bir yıl boyunca 3 ayda bir yüz yüze yapılandırılmış görüşmeye alındı. Bulgular: Otuz iki (17,7%) hastada kronik migren gelişti. Otuz iki hastanın dördüne (%2.2) kesin kronik migren tanısı kondu. Düşük eğitim seviyesi, obezite, yüksek miktarda çay tüketimi (≥4 bardak/gün), acılı ve baharatlı beslenme tarzı, yüksek başağrısı frekansı, uzun süreli başağrısı hikayesi, ilk değerlendirmede allodini varlığı ve fazla miktarda semptomatik ilaç alınması migrenin kronikleşmesi ve progresyonu için anlamlı risk faktörleri olarak 1 J.Neurol.Sci.[Turk] saptandı. Cox-regresyon analizinde fazla miktarda triptan ve NSAID alımı, acılı ve baharatlı beslenme tarzı ve allodini varlığı anlamlı risk faktörleri olarak bulundu. Sonuç: Fazla miktarda çay tüketimi, acılı ve baharatlı beslenme migrenin kronikleşmesi ve progresyonunda yeni risk faktörleri olarak ortaya kondu. Kilo alımı en önemli risk faktörlerinden biridir. Hastalar migrenin kronikleşmesinin ve progresyonunun önlenmesi için risk faktörleri konusunda uyarılmalıdırlar. Anahtar Kelimeler: Kronik günlük başağrısı, Kronik migren, Migren, Risk faktörleri, Transformasyon INTRODUCTION its use in studies. In most studies the required criterion for diagnosis of MOH, Migraine is a common disorder affecting waiting period of two months without any more than 10% of adult population(26). Its acute medication, make it difficult to lifetime prevalence in women and men has differentiate MOH from CM. The been reported to be 15 to 25%, and 6 to 9% prevalence of CM in the population based respectively(19,30). Ertaş et al. reported that studies has been reported as 2,4%. one-year migraine prevalence was 16.4% Medication overuse has accompanied to in Turkey(14). World Health Organisation CM in 30-80% of the cases(13,18,21,22). reported migraine as one of the world's top 20 most disabling diseases(35). Recent studies have focused on the risk factors that might influence incidence, Migraine which used to be seen as a purely prevalence, and prognosis of CDH. episodic disorder is now tended to be Recognizing risk factors might help to accepted as a chronic disorder with prevent the transformation of headache, episodic manifestations. Some migraine particularly migraine, into CDH and to sufferers may have attacks of increasing improve better management strategies for frequency over time leading to chronic each individual patient. Risk factors for migraine (CM) which, is termed as clinical CDH are classified into two groups as progression of migraine(22). CM was modifiable and non-modifiable (age, introduced in 2004 within the second gender, socioeconomic status, obesity, edition of the International Classification snoring, smoking, caffeine intake etc.)(2- of Headache Disorders (ICHD-II) under 5,27). Most of the reported studies about the the title “migraine complications”(16). The risk factors conducted by telephone or First Revision (ICHD-IIR) provides email and evaluated the subjects only diagnostic criteria for both CM and twice, at the beginning and at the end of medication overuse headache (MOH)(25). the follow-up period(6). CM forms an important part of the chronic In this face to face prospective, 12-month daily headache (CDH). CDH is follow-up study, we aimed to identify the characterized by a high frequency of risk factors and predictors leading to headaches with ≥15 headache days per progression and chronification of migraine. month. Worldwide prevalence of CDH is approximately 4%. Chronic headache MATERIAL AND METHODS patients with medication overuse should be This study was conducted at the headache diagnosed as both probable MOH and outpatient clinics of University of Uludag, probable CM. MOH diagnosis is not School of Medicine, Department of established until medication is withdrawn Neurology and approved by the Ethics for 2 months and the headache resolves or Committee of the Uludag University and reverts to its episodic pattern(27). As written informed consent was obtained criticized by many authors the diagnostic from all patients. criteria of MOH is not practical and detain 2 J.Neurol.Sci.[Turk] One-hundred eighty consecutive episodic following?” “combing your hair,” migraine patients (<15 headache “shaving,” “showering,” “exposure to cold days/month) were included in the study or heat”, “touching”. between September 2008 and September 2009. The study consisted of a baseline The patients were put on appropriate drug and five follow-up visits over twelve regimens (acute migraine attack treatment months. and/or preventive treatment for migraine). Preventive treatment was prescribed to the The questionnaire included questions about subjects who have 3 or more headache sociodemographic variables, headache days in a month. Propranolol, topiramate, characteristics, current depression and valproic acid and amitriptiline was anxiety, physician-diagnosed comorbid prescribed for preventive treatment. For conditions and life-style. acute attack treatment NSAIDs and triptans Baseline visit: All subjects were assessed were given to the subjects. During the by a fifth-year neurology resident (M.S.), baseline visit and follow-up visits only who completed one year headache out- medical treatment arrangements were patient clinic rotation. During the made and the subjects were told to avoid structured interview age, gender, BMI, triggers. Treatment was changed education, income level, marital status, whenever, unacceptable side effects by the family status, physical activity, social subjects or the physicians were reported. features, religious practices, exercise, No arrangements were made about their questioned. Participants were also diet or weight gain. Subjects continued to questioned about their medical history, take their previously prescribed duration of history of migraine, headache medications for concomitant diseases. characteristics; localization, duration (in Patients were asked to keep headache hours), headache intensity (0–10 scale), diaries on daily basis for each month until headache character (throbbing, aching, their next scheduled follow-up visit (3, 6, 9 pressure, stabbing), accompanying signs and 12 months after the initial assessment). and autonomic symptoms, aggravation of Headache diaries included data on headache by physical activity, medication headache frequency, headache duration responsiveness, disability, headache (hours-days), headache intensity (VAS), frequency (“low” 0 to 4, “intermediate” 5 menstrual period, accompanying to 9, and “critical” 10 to 14 days/month), symptoms (nausea, vomiting, photophobia acute headache medication (none, and phonophobia), and acute medication analgesics (simple, NSAIDs), ergots, intake. Patients with a current headache triptans, opioid), and regular intake (vs no frequency of ≥15 days/month, history of intake) of preventive migraine medication, chronic headache, accompanying serious allodynia, triggers of migraine attacks. systemic diseases and incapable of keeping Eating habits was evaluated based on diaries were excluded. subjects' answers by asking “What kind of Follow-up visits: The same resident (M.S.) food do you mostly eat?”; Mediterranean evaluated the patients at every visit and (vegetables, fish and fruit), Non- checked the pattern and characteristics of mediterrranean (meat, fast-food and the headache reported by the patients pastry). against the information reported in the For allodynia evaluation during a migraine diary. Headache diaries were collected at attack one question with multiple every follow-up visit and the new ones modalities was answered by the subjects; given to the subjects. Changes in the “Do you experience pain or any unpleasant management of headache were made when sensation on your skin-scalp during a necessary. The patients whose headaches migraine attack with any of the fulfilled CDH criteria during the follow-up 3 J.Neurol.Sci.[Turk] visits were excluded from the study. In univariate analysis high educational During the last visit, BMI were calculated level and cigarette smokers were again. significantly high in EM group (p ≤ 0.05). CDH was defined as headache frequency About 69% of CDH patients reported of ≥15 days/month for at least 3 months. allodynia during migraine attack (p ≤ The diagnosis of CM and MOH were made 0.05). There was no difference between the according to the ICHD-IIR(25). At the end groups in terms of income. Group 2 of the follow-up period, subjects were patients had significantly more psychiatric grouped into two groups; Group 1 – EM comorbidity (p<0.001) and depression was patients, Group 2 – CDH patients. the most common psychiatric diagnosis (63%) (p≤0.05) (Table 1). Psychiatric evaluation was made by psychiatrists or psychiatric comorbidities Hot and spicy eating habit and greater tea were recorded when the subjects reported a consumption (≥4 cups/daily) was psychiatrist diagnosed disorder. significantly more common where smoking was significantly less common in A total of 120 parameters were compared Group 2 (Table 1). between Groups 1 and 2. Parameters measured only at baseline visit defined as BMI of patients was calculated at initial predictors, where parameters continuously and last visits. There was no significant monitored during the year defined as risk difference between the groups in terms of factors. Descriptive statistics were obtained BMI at baseline. At the last visit, using SPSS version 13.0 Windows (SPSS significantly more subjects had higher BMI Inc., Chicago, IL, USA). Pearson chi- values in Group 2 (p≤0,05) (Table 1). BMI square and Fisher's exact chi-square tests of Group 2 patients were significantly were used for categorical variables. increased at the last visit when compared Multivariate analysis was conducted by the to baseline values (P= 0,019). Cox regression analysis. In all instances, p- Both ergotamine using subjects and the value ≤0.05 were considered significant. amount of ergotamine consumption were RESULTS significantly higher in group 2 than group 1 (p≤0,05). There was no difference One-hundred eighty episodic migraine between the groups according to headache patients were recruited in the study and characteristics other than allodynia which followed for 12 months. was reported to be more common in Group The mean age (18-65) was 39.6 (±10.4) 2. None of the subjects reported years. The majority of patients were medication overuse in Group 1. However, females (91%) and 83% of the study analgesic (78%) and triptan (9%) overuse subjects were married. More than half was present in Group 2 subjects (p≤0,05). (56.7%) of the subjects were housewives Subjects who developed CDH had a and almost 50% of the patients were high history of migraine more than 4 years. school or college graduates. Moreover, headache frequency was >4 No subject was lost during to follow-up. days/month in 72% of the subjects in All patients complied with the protocol and Group 2 during the last three months prior the acute attack or preventive treatment to the initial evaluation (Table 1). regimens. Thirty-two (17.7%) subjects' Significantly more patients were on migraine headache transformed to CDH. preventive treatment for migraine attacks Only four of them were CM. Rest of them at baseline in Group 2 (p=0,05). No were classified as MOH/CM. Predictors difference between groups in terms of and risk factors were analyzed separately. prophylactic treatment regimens was found. 4 J.Neurol.Sci.[Turk] Table 1: Predictors and risk factors for chronification of migraine headache (n=180) Group 1 Group 2 P n=148 (%) n=32(%) Predictors Illiterate 2(1,4) 1(3,1) Literate 0 3(9,4)* 0,005 ≤ 8 years of education 68(45,9) 18(56,3) > 8 years of education 78(52,7) 10(31,3)* 0,027 Headache history (>4 years) 128(86,5) 32(100) * 0,026 Baseline headache days/month 59(39,9) 23(71,8) * 0,001 (5-14 days/month) Allodynia 73(49,3) 22(68,8) * 0.046 Anxiety 12(8) 2(6) Depression 51(35) 20(63)* 0.003 Alcohol 8(5,4) 1(3,1) Coffee (≥4 cups/day) 85(57,4) 16(50) Tea (≥4 cups/day) 60(40) 22(69)* 0.003 Cigarette 38(26) 3(9)* 0.046 Exercise 17(11,6) 9(28,1) Regular praying 92(62,2) 19(59,4) Fasting 115(77,7) 26(81,3) Non-Mediterranean diet 75(50,7) 15(46,9) Mediterranean diet 131(88,5) 29(90,6) Hot-spicy diet 47(32) 17(53)* 0.022 Olive-oil use 88(59,9) 17(53,1) Other oil types 110(74,3) 23(71,9) Margarine 20(13,5) 5(15,6) Basal BMI <25 81 (54,7) 16(50,0) Basal BMI 25-30 39(26,9) 10(31,2) Basal BMI >30 28(18,9) 6(18,8) Risk factors Patients on preventive treatment 99(66,9) 27(84,4) * 0,050 BMI at last visit <25 83 (56,1)* 9 (28,1) 0,009 BMI at last visit 25-30 41(27,7) 12(37,5) * 0,010 BMI at last visit >30 24(16,2) 11(34,4) * 0,002 Analgesic overuse 7(4,7) 25(78,1) * <0,0001 Triptan overuse 0 3(9,4) * <0,0001 *p≤0,05 5 J.Neurol.Sci.[Turk] , In CDH group headache characteristics significant in the progression of EM in to showed significant differences as expected. CDH (Table 2). Both headache duration and monthly headache days were significantly increased Subjects with episodic migraine in Group 1 at the last visit (p‹0.001). On the other were divided in to two groups according to hand, headache severity decreased their headache days for further analysis; 0- compared to the first visit (p‹0.001). 4 days/month, ≥5 days/month. Those two groups were compared in terms of For multivariate analysis Cox Regression presence of MOH and BMI as given in analysis was made. Acute medication (both Table 3. NSAIDs and triptans), allodynia and hot and spicy food eating habit appeared to be Preventive medication data was given in Table 4. Table 2: Cox regression analyses of predictors and risk factors for chronification of migraine headache (n=180) (only significant ones shown in the table) Variable p HR %95 CI for HR Analgesic overuse <0,001 64,55 18,60-224,24 Triptan overuse <0,001 73,55 11,16-484,60 Allodynia 0,037 3,19 1,07-9,50 Hot and spicy diet 0,048 2,40 1,00-5,66 Table 3: Comparison of subgroups (according to headache days) of Group 1 patients in terms of presence of MOH and BMIs. headache days MOH MOH absent present BMI<25 BMI 25-30 BMI>30 0-4 days/m 112 0 70 25 17 (n=112) (100%) (0%) (62,5%) (22,3%) (15,2%) ≥5 days/m (n=36) 29 7 13 16 7 (80,6%) (19,4%)* (36,1%) (44,4%)* (19,4%) *MOH:p<0.001 and BMI p=0.014 6 J.Neurol.Sci.[Turk] Table 4: Use of preventive medications according to groups Group 1 Group 2 Medication n=148 (%) n=32 (%) Total Beta blockers 36(24,3) 6(18,8) 42(23,3) VPA 21(14,2) 7(21,9) 28(15,6) TPM 16(10,9) 4(12,5) 20(11,2) Amitriptilin 20(13,5) 6(18,8) 26(14,4) SSRI 22(14,9) 9(28,1) 31(17,2) SNRI 20(13,5) 7(21,9) 27(15,0) VPA: Valproic acid; TPM: Topiramate; SSRI: Selective serotonine selective re-uptake inhibitors; SNRI: Serotonine-Noradrenaline re-uptake inhibitor DISCUSSION The CM prevalence in our study is 2,2%, A total of 180 (91% female, 9% male) in line with the literature and the data of episodic migraine patients were enrolled in the last headache epidemiological study in Turkey(14,21,30)the study. Thirty-two (17,7%) patients . Nearly 18% of patients developed CDH. Four out of 32 (2,2%) with EM developed CDH (CM and CDH patients had definite chronic possible MOH/possible CM) during migraine headache. Twenty-eight subjects follow-up period, similar to the rates (27) received the diagnosis of CDH (possible reported by Scher et al . Our study CM or possible MOH) according to the population was based on tertiary headache ICHD-2R. In line with the literature outpatient clinic. Therefore, our results can univariate analysis revealed low not be generalized. educational level, high number of Like many other studies female subjects headache days at baseline, medication were predominant in our study. However, overuse, allodynia, comorbid psychiatric there was no significant difference between disease, increased body mass index was genders in terms of chronification. In most significantly more common in Group 2 of the studies, female gender has been than Group 1. Other than known risk accepted as a risk factor for migraine factors for chronification and progression chronification(3). On the other hand, hot and spicy diet, consumption of ≥4 cups Wiendels et al. identified female sex as a of tea/day were also determined as risk risk factor for headache, but not for the factors. On the other hand, Cox Regression chronification of headache(34). analysis showed acute medication (triptan and NSAID intake), allodynia and hot and High education level was significantly less spicy food eating habit as significant common in Group 2 when compared to predictors and risk factors. Group 1 (p<0,027). Low education level reported to be a risk factor both for 7 J.Neurol.Sci.[Turk] migraine and CDH(1,15,34). Low income neuromediators that play an important role level is also a risk factor both for migraine in migraine pathophysiology and might and CDH(1). However, in our study there cause peripheral and central sensitization was no difference in income levels which might lead increased attack between two groups. As our university frequency and chronification of migraine. hospital is a state run hospital, most of our Or simply, hot and spicy food might headache outpatient clinic subjects belong increase the appetite and result in more to middle economy class. This might have food in take and higher BMI, which might resulted in a selection bias. result in chronification of migraine. Sixty-nine percent of Group 2 patients had Further studies should be done to clarify psychiatric comorbidity (p<0,001), mostly this issue. depression 63(%) (p≤0,05). Our findings The BMI of Group 2 patients were show similarity with a number of studies significantly higher than Group 1 (p<0,05). reporting high rates of comorbid At the end of one-year follow-up, Group 2 psychiatric disorders in CDH(17,20,31). patients gained significantly more weight The role of dietary or medicinal caffeine in than Group 1. Primary headaches have the development of CDH has been previously been reported more frequent in investigated in many studies and has been obese cases. Additionaly, risk of CDH shown to be a risk factor in migraine development has been found to be higher (7-10,29) progression(27,28). On the contrary, tea in patients with BMI≥30 . Obesity consumption alone has not been evaluated. has been related with the severity and Subjects in Group 2 were found to frequency of headache attacks of consume significantly more tea (≥4 migraineurs in some studies (18). Frequent cups/day). The reason, we could not find headache attacks in obese will lead to any association between coffee and central sensitization which will eventually chronification may be tea consumption end up with both decrease in treatment being a cultural habit and more common response and increased risk of attack (7) than coffee consumption in Turkey. relapses . Increased headache frequency was correlated with increased BMI. In our study, hot and spicy food eating habit was significantly high in Group 2. To Similar to the previous studies, duration of the best of our knowledge, there is no data headache history, allodynia, number of in the existing literature about the impact days with headache at the baseline visit, of eating habits on migraine chronification. medication overuse, symptomatic Hot and spicy foods include capsaicine and ergotamine use without overuse were it is known that capsaicine selectively and found to be risk factors for chronification. potently increases the spontaneous release All 32 patients who developed CDH had a of Substance-P, calcitonin gene-related history of headache more than 4 years peptide, neuropeptide Y and neurokinin A (p=0,026). Frequency of attacks and as well as glutamate both in vitro and in number of days with headache has been vivo(24). Most of these neuromediators play reported among the most important risk an important role in migraine factors of migraine chronification. The risk pathophysiology. Recent publications of CM development increased in subjects suggest a role for transient receptor with three or more headaches per month at (5,29) potential vanilloid type 1 (TRPV1) baseline . In our study, 71,8 % of receptors, which capsaicine bind to, in patients in Group 2 were experiencing 5 - migraine pathophysiology(23). We can 14 headache days per month at the baseline speculate that paroxysmal capsaicine visit (p=0,001). As a result of increased intake may trigger migraine attacks by headache frequency, the use of preventive stimulating TRPV1 and secreting treatment was higher in Group 2 (p=0,05). 8 J.Neurol.Sci.[Turk] At the end of one year 88% of Group 2 increased the reliability of the study. On subjects developed medication overuse the other hand, relatively low number of (p<0,0001). The relation of medication the subjects and hospital based (tertiary overuse and CDH development is still care) study sample, which may introduce a under debate(11). bias, are the limitations of our study. One of the critical points in chronification As a conclusion, CDH is an important of migraine is the importance of frequency problem for the society and EM sufferers of headache at baseline. The high should be informed about the prognosis of frequency of headache at baseline is the headache and risk factors for suspected to carry risk of progression even chronificaiton. Together with the patients, in the absence of medication overuse(11,12). better management of migraine would In our study, medication overuse at the end decrease the burden of CDH to the of one year follow-up developed only in individual and to the society. Group 1 patients with a baseline headache frequency of ≥5 days/month. But these Conflict of Interest Statement: The patients, in line with the above mentioned authors declare that there is no conflict of literature, did not show progression. interest and have the full Access to the data presented in this study and take full Two (6%) of Group 2 patients in our study responsibility. reported to use ergotamine as a baseline symptomatic treatment. Their ergotamine use was significantly higher than Group 1 patients (p≤0,05). However, as the numbers of subjects with ergotamine use Correspondence to: was very small one must be cautious about Necdet Karlı the results. E-mail: nkarli@yahoo.com Central sensitization, the manifestation of physiological progression, shows itself frequently as cutaneous allodynia during Received by: 27 July 2011 migraine attacks(6,32). Cutaneous allodynia Revised by: 29 September 2011 was significantly more frequent in Group 2 Accepted: 26 October 2011 than Group 1 patients. Cox Regression analysis revealed four significant items in the chronification of EM; triptan and NSAID intake, hot and The Online Journal of Neurological spicy eating habit and allodynia (p≤0.05). Sciences (Turkish) 1984-2012 This e-journal is run by Ege University In our study, all subjects (100%) Faculty of Medicine, completed the study protocol and complied Dept. of Neurological Surgery, Bornova, with the given treatment. Face-to-face Izmir-35100TR interview, short follow-up intervals and as part of the Ege Neurological Surgery headache diaries all might have increased World Wide Web service. the compliance rate. Most of the studies Comments and feedback: about chronification of migraine are E-mail: editor@jns.dergisi.org retrospective. To best of our knowledge, a URL: http://www.jns.dergisi.org great proportion of prospective studies on Journal of Neurological Sciences (Turkish) this subject have used either e-mail Abbr: J. Neurol. Sci.[Turk] questionnaires or phone interviews to ISSNe 1302-1664 obtain follow-up data. We believe that face-to-face interviews might have 9 J.Neurol.Sci.[Turk] REFERENCES 19. Linde M. Migraine: a review and future directions for treatment. Acta Neurol Scand 2006; 114: 71-83. 20. Lipton RB. Tracing transformation chronic migraine 1. Atasoy HT, Unal AE, Atasoy N, Emre U, Sumer M. classification, progression, and epidemiology. Low income and education levels may cause Neurology 2009; 72 suppl 1: 3-7 medication overuse and chronicity in migraine 21. Lu SR, Fuh JL, Chen WT, Juang KD, Wang SJ. patients. Headache 2005; 45: 25-31. Chronic daily headache in Taipei, Taiwan: 2. Bigal ME, Lipton RB. The prognosis of migraine. prevalence, follow-up and outcome predictors. Curr Opin Neurol 2008; 21: 301-8. Cephalalgia 2001;21:980–986. 3. Bigal ME, Lipton RB. Modifiable Risk Factors for 22. Mathew NT. Transformed migraine. Cephalalgia Migraine Progression. Headache 2006; 46:1334-43 1993;13: 78-83. 4. Bigal ME, Lipton RB. What predicts the change 23. Meents JE, Neeb L, Reuter U. TRPV1 in migraine from episodic to chronic migraine? Curr Opin pathophysiology. Trends Mol Med 2010 Neurol 2009; 22: 269-76. Apr;16(4):153-9. 5. Bigal ME, Lipton RB. Clinical course in migraine: 24. Morgado-Valle C, Feldman JL.Depletion of conceptualizing migraine transformation. Neurology substance P and glutamate by capsaicin blocks 2008 ; 71: 848-55. respiratory rhythm in neonatal rat in vitro.J Physiol. 6. Bigal ME, Lipton RB. Concepts and Mechanisms of 2004 Mar 16;555(Pt 3):783-92. Migraine Chronification. Headache 2008;48: 7-15 25. Olesen J, Bousser MG, Diener HC, Dodick D, First 7. Bigal ME, Liberman JN, Lipton RB. Obesity and M, Goadsby PJ et al. New appendix criteria open migraine: a population study. Neurology 2006; 66: for a broader concept of chronic migraine. 545-50 Cephalalgia 2006;26(6):742-746. 8. Bigal ME, Lipton RB. Obesity is a risk factor for 26. Pietrobon D. Migraine: new molecular mechanisms. transformed migraine but not chronic tension-type Neuroscientist 2005; 11: 373-86. headache. Neurology. 2006 Jul 25;67(2):252-7 27. Scher AI, Midgette LA, Lipton RB. Risk factors for 9. Bigal ME, Gironda M, Tepper SJ, Feleppa M, headache chronification. Headache 2008; 48: 16- Rapoport AM, Sheftell FD, Lipton RB. Headache 25. prevention outcome and body mass index. 28. Scher AI, Stewart WF, Lipton RB. Caffeine as a risk Cephalalgia 2006; 26: 445-50 factor for chronic daily headache: A population 10. Bigal ME, Tsang A, Loder E, Serrano D, Reed ML, based study. Neurology 2004; 63: 2022-27 Lipton RB. Body mass index and episodic 29. Scher AI, Stewart WF, Ricci JA, Lipton RB. Factors headaches: a population-based study. Arch Intern associated with the onset and remission of chronic Med 2007; 167: 1964-70 daily headache in a population-based study. Pain 11. Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, 2003; 106: 81-9 Lipton RB. Acute migraine medications and 30. Stovner L, Hagen K, Jensen R, Katsarava Z, Lipton evolution from episodic to chronic migraine: a R, Scher A, et al.. The global burden of headache: a longitudinal population-based study. Headache documentation of headache prevalence and 2008; 48:1157–68 disability worldwide. Cephalalgia 2007; 27: 193- 12. Bigal ME, Lipton RB. Excessive acute migraine 210. medication use and migraine progression. 31. Tietjen GE, Brandes JL, Digre KB, Baggaley S, Neurology 2008; 71: 1821-8 Martin VT, Recober A et al. History of childhood 13. Castillo J, Munoz P, Guitera V, Pascual J. maltreatment is associated with comorbid Epidemiology of chronic daily headache in the depression in women with migraine. Neurology general population. Headache 1999;39:190–196. 2007;69: 959-68 14. Ertaş M, Baykan B, Orhan EK. Prevalance of 32. Tietjen GE, Brandes JL, Peterlin BL, Eloff A, Dafer migraine in Turkey: A nationwide home based study. RM, Stein MR et al. Allodynia in migraine: J Neurol Sci 2009; 148. association with comorbid pain conditions. 15. Hagen K, Vatten L, Stovner LJ, Zwart JA, Krokstad Headache 2009; 49:1333-44 S, Bovim G. Low socio-economic status is 33. Tribl GG, Schnider P, Wöber C, Aull S, Auterith A, associated with increased risk of frequent headache: Zeiler K, Wessely P. Are there predictive factors for a prospective study of 22718 adults in Norway. long-term outcome after withdrawal in drug-induced Cephalalgia 2002; 22: 672-79 chronic daily headache? Cephalalgia 2001; 21: 16. Headache Classification Subcommittee of the 691-6 International Headache Society. The International 34. Wiendels NJ, Knuistingh Neven A, Rosendaal FR, Classification of Headache Disorders, 2nd Edition. Spinhoven P, Zitman FG, Assendelft WJ, Ferrari Cephalalgia 2004; 24:1–160. MD. Chronic frequent headache in the general 17. Juang KD, Wang SJ, Fuh JL, Lu SR, Su TP. population: prevalence and associated factors. Comorbidity of depressive and anxiety disorders in Cephalalgia 2006; 26: 1434-42 chronic daily headache and its subtypes. Headache 35. World Health Organisation. The world health report 2000; 40: 818-23 2001, Chapter 2. Geneva: WHO 2001. Available at 18. Katsarava Z, Schneeweiss S, Kurth T, Kroener U, http://www.who.int/whr/2001/en/index.html Fritsche G, Eikermann A et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 9;62(5):788-90. 10