Chronic migraine in women is associated with insulin resistance: a ...

5 downloads 0 Views 465KB Size Report
Chronic migraine in women is associated with insulin resistance: a cross-sectional study. A. Favaa, D. Pirritanob, D. Consolic, M. Plastinob, F. Casalinuovob, ...
European Journal of Neurology 2014, 21: 267–272

doi:10.1111/ene.12289

Chronic migraine in women is associated with insulin resistance: a cross-sectional study A. Favaa, D. Pirritanob, D. Consolic, M. Plastinob, F. Casalinuovob, S. Cristofarob, C. Colicad, C. Ermioe, M. De Bartolof, C. Opiparib, R. Lanzob, A. Consolig and D. Boscob a

Department of Clinical and Experimental Medicine, University of Catanzaro, Catanzaro; bDepartment of Neuroscience, S. Giovanni di Dio Hospital, Crotone; cDepartment of Neuroscience, G. Jazzolino Hospital, Vibo Valentia; dInstitute of Neurological Science – National Research Council, Roccelletta di Borgia, Catanzaro; eDepartment of Neuroscience, S. Giovanni Paolo II Hospital, Lamezia Terme; f

Neurophysiology Unit, General Hospital, Rossano; and gDepartment of Radiology, ‘Careggi’ University Hospital, Florence, Italy

Keywords:

chronic migraine, episodic migraine, insulin resistance, metabolic syndrome Received 20 June 2013 Accepted 23 September 2013

Background and purpose: Migraine is a common neurological disorder. It can be divided into episodic migraine (EM) and chronic migraine (CM), based on headache frequency. Some studies have shown that insulin sensitivity is impaired in migraine; moreover, hypertension, diabetes and obesity are common in patients with CM. The aim of this study was to assess serum glucose, insulin levels and insulin resistance (IR) in a sample of episodic migraineurs, chronic migraineurs and non-pain healthy controls. Methods: Eighty-three women with EM, 83 with CM and 83 healthy controls were recruited. Headache was diagnosed according to the latest International Classification of Headache Disorders 2 criteria. Waist circumference, body mass index (BMI) and blood pressure were measured. Checked metabolic parameters included fasting glucose, the 2 h 75 g oral glucose tolerance test (2 h OGTT), serum HbA1c, blood lipid profile, C-reactive protein and prolactin. The homeostasis model assessment formula was used to calculate IR. Results: A significant prevalence of IR in CM was observed (P = 0.002). No significant associations were found with fasting glycaemia, the 2 h OGTT, HbA1c, blood lipid profile, C-reactive protein, prolactin and waist circumference. Obesity (BMI >30 kg/m2) was associated with an increased risk of CM [odds ratio (OR) 2.4]. When the outcome of interest was the association between IR and obesity, the OR was significantly increased compared with IR alone (OR = 13.2). Conclusion: This may suggest that CM is associated with IR status, particularly when it is in partnership with obesity.

Introduction Migraine is a common neurological disorder with a wide range of subtypes, many comorbidities and a variable prognosis [1]. It can be divided into episodic migraine (EM) and chronic migraine (CM), based on the headache frequency. EM refers to a headache occurring for less than 15 days per month on average, within the past 3 months. CM is listed as a complication of EM in the third edition of the International Classification of Headache Disorders (ICHD-3 beta) [2]. It is defined as ‘headache occurring on 15 or more *Correspondence: D. Bosco, Department of Neuroscience, S. Giovanni di Dio Hospital, Largo Bologna, 88900, Crotone, Italy (tel.: +39 0962 92 42 41; fax: +39 0962 92 45 61; e-mail: [email protected]).

© 2013 The Author(s) European Journal of Neurology © 2013 EFNS

days per month for more than 3 months, which has the features of migraine headache on at least 8 days per month’ [2]. Comorbidities of CM have been studied in population-based samples; clinical and population studies suggest that increased headache frequency is correlated with depression [3], anxiety [3], posttraumatic stress disorder [4], chronic pain [5] and fibromyalgia [6]. Hypertension, diabetes, high cholesterol level and obesity are more common in patients with CM [7]. The higher prevalence of migraine amongst morbidly obese women and the effect of obesity on transformation of EM into the chronic form suggest that similar factors may act on migraine and metabolic disorder pathogenesis [8]. Some studies supposed that migraine is more frequent in conditions of low insulin receptor activation [9,10]. Insulin

267

268

A. Fava et al.

resistance (IR) is considered a risk factor for hypertension [11] and stroke [12]. Insulin is also thought to influence brain metabolism and cerebral blood flow through insulin receptors, which have been found in many brain regions [13]. A recent study showed that insulin sensitivity is impaired in migraine and suggested a role for IR in the comorbidity of migraine and vascular disease [14]. Another study confirmed a significant association between IR and migraine in 60 non-obese migraine patients [15]. The aim of our study was to assess glucose metabolism and IR in a convenience sample of EM, CM and non-pain healthy controls.

Methods Participants

This study was approved by the Ethical Committee of S. Giovanni di Dio Hospital, Crotone, Italy (code: CNVF233A2401). All patients gave their informed consent, in accordance with the official standards of the 1964 Declaration of Helsinki, local laws and regulations. The present study was performed in Calabria, Italy. Eligible patients were selected from consecutive migraineur Caucasian women seen at the headache center of our hospital (S. Giovanni di Dio Hospital, Crotone, Italy) from February 2011 to March 2013 according to the ICHD-3 beta criteria. They were divided into three groups: (i) 83 with EM, (ii) 83 with CM and (iii) 83 non-pain healthy controls. To avoid iatrogenic alteration of glucose metabolism subjects using medications acting on IR and weight, such as corticosteroids, and valproic acid were excluded. Subjects suffering from endocrine and metabolic diseases, such as diabetes, thyroid dysfunction and hypothalamic-pituitary disorders, were also excluded, as well as subjects suffering from any other inflammatory, autoimmune and infectious disorder. The following data were recorded for each patient: age, headache type (EM or CM), smoking habits, medication use, education level, marital status and associated disorders. Education level was evaluated in scholastic years. Depressive symptoms were measured with the Beck Depression Inventory [16]. Patients and controls were matched for age, ethnic background, dietary habits and lifestyle. Control subjects were recruited from healthy volunteers. Clinical assessment

Patients and controls underwent general medical examination, neurological examination and general blood tests. Waist circumference (WC), body mass

index (BMI) and blood pressure were also assessed. Weight was recorded in kilograms using a calibrated digital scale; height was measured in meters without shoes; BMI was calculated as weight in kilograms divided by the square of the height in meters; criteria for obesity were BMI over 30 kg/m2 (for total obesity) and WC over 88 cm (for abdominal obesity), according to the World Health Organization recommendations [17]. Metabolic assessment

Checked metabolic parameters included fasting glucose level, 2 h 75 g oral glucose tolerance test (2 h OGTT), serum HbA1c, blood lipid profile, C-reactive protein (CRP) and prolactin (PRL). A standard 75 g OGTT was performed after a 10 h overnight fast. Plasma samples were obtained at 0, 30 and 120 min after glucose loading. The same laboratory performed all blood tests. Glucose was determined by an immune-enzymatic method with the oxidase technique (Roche Diagnostics, Mannheim, Germany); insulin was tested with an immunofluorometric assay (Tosoh Bioscience, Tokyo, Japan). The cholesterol esterase enzymatic assay (Roche Diagnostics) was used to measure total cholesterol and high-density lipoprotein cholesterol level, and the lipase technique (Roche Diagnostics) was used to measure triglyceride amount. The low-density lipoprotein cholesterol was calculated according to the Friedewald formula. The homeostasis model assessment (HOMA) formula was applied to calculate IR [HOMA index = basal glucose plasma (mg/dl) 9 basal insulin plasma (UI/ml)/405] [18]. A HOMA index score >2.77 was considered abnormal, indicating a condition of IR but not a metabolic syndrome (MetS), which must satisfy further criteria to be diagnosed, according to the International Diabetes Federation criteria [19]. An enzyme linked immunosorbent assay was used, according to the manufacturer’s instructions, to carry out a highly sensitive CRP test in a quantitative way. The intra-assay coefficient of variance was 277) Triglycerides, mg/dl Total cholesterol, mg/dl LDL-C, mg/dl HDL-C, mg/dl MetS, n, % CRP PRL basal, ng/ml BDI Marital status, n, % Unmarried Married Divorced Widowed Smoking habit, n, % Non-smoker Current smoker Blood pressure, mmHg Systolic Diastolic Drug use, mean/monthly NSAIDs Triptans Opiates

83 417 247 13 745 844 52 865 231 37 143 186 129 46 24 6 16 9

EM

(59) (68) (45) (101) (95) (11) (47) (23) (12) (192) (285) (161) (97) (29) (12) (34) (32)

42 32 6 4

(51) (38) (7) (48)

83 40 162 11 76 823 49 85 226 21 148 188 132 48 23 56 18 82

Controls

(47) (58) (35) (68) (89) (09) (42) (31) (09) (191) (346) (101) (109) (26) (08) (54) (36)

34 39 8 5

(41) (47) (96) (6)

32 (38) 39 (42)

33 (397) 34 (41)

145 (24) 88 (162)

120 (221) 84 (144)

28 21 12

9 7 2

83 402 (68) // 105 (51) 72 (56) 801 (102) 5 (12) 852 (56) 225 (34) 24 (06) 1474 (186) 178 (217) 130 (197) 41 (112) 19 (21) 57 (14) 17 (42) 8 (32) 24 24 4 1

(45) (45) (7) (18)

25 18 110 (164) 86 (109) 4 0 1

CM versus controls

EM versus controls

– 008 – 005 039 049 044 009 009 0002 061 071 074 012 0001 056 072 005

– 024 – 019 022 036 053 052 043 042 055 044 081 016 0003 023 056 042

009 009 031 026

032 044 062 017

008 008

009 009

003 023

009 021

0005 0001 052

008 0002 052

Value adjusted for age, depression, medication use, education level, hypertension, glycaemia, BMI, WC, blood profile, triglycerides, MS and Hb1Ac. Values are expressed as mean (SD). HOMA formula: HOMA index = basal glucose plasma (mg/dl) 9 basal insulin plasma (UI/ml)/ 405. P < 0.05 was considered statistically significant. OGTT, oral glucose tolerance test; WC, waist circumference; BMI, body mass index; HOMA index, homeostasis model assessment; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MetS, metabolic syndrome; CRP, C-reactive protein; PRL, prolactin; BDI, Beck Depression Inventory; NSAIDs, non-steroidal anti-inflammatory drugs.

© 2013 The Author(s) European Journal of Neurology © 2013 EFNS

270

A. Fava et al.

(CM 41.7  5.9 years vs. controls 40.2  5.8 years; P = 0.08) without any statistical difference. CM patients had longer disease duration than EM patients and higher education level versus controls. Clinical features

No significant difference was found between groups in fasting glycaemia, 2 h OGTT, HbA1c, triglycerides, blood lipid profile, CRP and WC. This analysis also showed no association with baseline PRL and BMI values. A significant difference was observed in IR between CM and controls (P = 0.002). Besides, MetS was significantly higher in migraineur groups versus controls. Out of five MetS diagnostic criteria, all were present in six patients of the CM group and in four of the EM group. Four criteria were satisfied in eight patients with CM and in eight patients with EM. Ten patients in the CM group and 11 in the EM group met just three criteria for MetS. Rescue medication use (triptans, non-steroidal anti-inflammatory drugs), expressed as average monthly intake, was significantly higher in the CM group (Table 1).

and obesity appeared to be independent CM predictors. In detail, a status of IR (HOMA index >2.77) was recorded in 20 patients (24%) with CM and in eight patients (9.6%) with EM, yielding an OR of 3.1 (95% CI 2.7–3.7). After adjustment for confounding variables (age, smoking habits, drug intake, hypertension, education level, depressive symptoms, MetS, blood lipid profile, BMI, WC, glycaemia and HbA1c), the association between HOMA index and CM remained significant. Migraine patients (CM and EM) were further stratified for BMI. Obesity was associated with an increased risk of CM (OR 2.4; 95% CI 2–2.6). In CM, the most common comorbidities were depression, hypertension and anxiety. Allergy, stroke, heart disease and MetS were equally distributed in the two groups. When the outcome of interest was considered to be the association between IR and obesity, the OR was significantly increased compared with IR alone (OR = 13.2; 95% CI 12.5–14.6). Indeed, when IR status was associated with hypertension or depression the risk of CM remained substantially unchanged.

Discussion Risk factors for chronic migraine

Risk factors are shown in Table 2. In multivariate analysis models, IR, depression, hypertension, MetS

In this study, performed in Calabria, Italy, CM was suggested to be strongly associated with IR status. Our data show that EM patients and controls have

Table 2 Risk factors by type of migraine

HOMA index WC, cm >88 cm 30 25–299 30 HOMA + WC > 88 cm HOMA + depression HOMA + hypertension HOMA + anxiety

CM (n°;%)

EM (n°;%)

Unadjusted OR (95% CI)

20; 24

8; 94

3 (26–34)

19 (228) 64 (77)

16; (192) 67; (807)

25 37 17 12 5 12 25

(30) (44) (204) (144) (6) (144) (30)

12 30 13 13 5 11 24

23 30 46 16 27 8 14 8

(277) (36) (554) (19) (32) (96) (168) (96)

15 27 58 3 27 5 11 8

Adjusted OR (95% CI)

P

P

0003

31 (27–37)

0001

112 (096–12) 1 (094–13)

082 091

095 (09–11) 098 (096–12)

065 034

(144) (36) (156) (156) (6) (13) (289)

2 14 12 115 1 11 09

(19–28) (12–18) (1–14) (1 –16) (098–12) (09–14) (08–12)

0001 005 008 092 056 054 034

21 14 13 12 1 11 088

0001 005 008 061 056 054 034

(18) (32) (698) (56) (32) (6) (132) (96)

22 (2–26) 12 (1–14) 05 (04–07) 132 (125–14) – 22 (18–24) 13 (11–16) 1 (09–11)

0005 061 052 0001 – 006 007 //

24 (2–26) 11 (1–13) 07 (04–09) 124 (11–146) – 24 (2–28) 15 (12–15) 1 (09–11)

(19–24) (11–17) (11–14) (11–14) (09–12) (08–13) (079–116)

003 062 0002 0001 – 006 006 //

Values adjusted for age, sex, depression, drug use, hypertension, glycaemia, BMI, WC, blood profile, triglycerides, MetS and Hb1Ac. Values are expressed as mean (SD) unless otherwise indicated. HOMA formula: HOMA index = basal glucose plasma (mg/dl) 9 basal insulin plasma (UI/ml)/405. P < 0.05 was considered statistically significant. HOMA index, homeostasis model assessment; WC, waist circumference; MetS, metabolic syndrome; BMI, body mass index.

© 2013 The Author(s) European Journal of Neurology © 2013 EFNS

Insulin resistance and chronic migraine

similar HOMA index value. Indeed, CM women were three times more likely to have IR than the EM group. MetS was significantly more common in patients than controls, whereas no difference between EM and CM patients was found. These observations are in agreement with previous studies reporting an association between MetS and migraine [21,22]. CM and EM also showed a significant difference in associated diseases (depression and hypertension), drug intake, education level and obesity. After adjustment for these parameters, a significant correlation was found between IR and CM. This association was unchanged also after adjustment for confounding variables commonly associated with higher IR status. The risk of CM was exponentially increased when IR was associated with obesity (OR 13.2), whereas when IR was associated with hypertension or depression OR remained substantially unchanged. Migraine headache is usually episodic, but sometimes it changes into a chronic form. Because migraine does not progress in most patients, identification of risk factors for progression has become an important goal in public health research [1,23]. Migraine frequency, diabetes mellitus, MetS and obesity are reported as the most important risk factors for migraine progression [1,7,22]. Migraine frequency and medication overuse play a role in the change to a chronic type [24]. Hypertension, central obesity, dyslipidemia, MetS and type 2 diabetes are all associated with IR and an increased risk of cardiovascular and cerebrovascular events [25,26]. In a small case control study, IR has been shown also to exist in non-obese migraine patients [14]. In this regard, it can be speculated that one of the shared underlying mechanisms between migraine and vascular disorders could be IR. Enhanced platelet aggregation and high levels of Von Willebrand factor that promote atherothrombosis have been reported in migraine and IR state [27,28]. However, the relationship between obesity and migraine is not clear. Several studies showed that obesity is associated with headache frequency but not with migraine prevalence [7,22]. The relationship between migraine and diabetes is still unclear, and there are conflicting results about migraine prevalence in patients with diabetes [29]. Some studies supposed that migraine is more common in susceptible people in a condition of low insulin receptor activation [10,30]. Rainero et al. suggested IR in patients with migraine, finding a higher glucose level and a similar insulin level in migraineurs compared with controls, 180 min after the OGTT [14]. Guldiken and colleagues found a significant association between IR and migraine in 60 non-obese migraine patients [15]. Recently, Bhoi et al. [21] reported that migraine was © 2013 The Author(s) European Journal of Neurology © 2013 EFNS

271

associated with MetS in 31.9% of patients and IR in 11.1% of patients from an Indian population, finding a correlation of IR with migraine attack duration. These results largely reflect ours except that there are important differences in the features of MetS between southeast Asian and western populations [31,32]. Also they did not differentiate between EM and CM. Hypothalamic-pituitary axis disorders have been implicated in primary headache pathogenesis. Cavestro et al. found higher insulin levels in patients with migraine compared with subjects with other kinds of headache. These authors suggested that high insulin levels may play a role in migraine pathogenesis, through an overstimulation of insulin receptors in hypothalamic and brainstem regions [33]. Migraine worsening in patients taking estro-progestinic drugs, inducing hyperinsulinism and hypoglycaemia, supports their hypothesis [34]. PRL physiologically stimulates pancreatic insulin-producing cells during pregnancy [35]. PRL is also implicated in some primary headaches and it is considered a worsening factor for headache [36,37]. However, similar PRL levels were found in all three groups. Our data suggest that medication acting on IR, glucose metabolism and weight gain, may be useful for preventing migraine from becoming chronic, along with current therapies. A drawback of our study may be the small sample size and consequently the number of patients with IR status. In addition, our study was cross-sectional, so it was not possible to determine the right sequence between BMI and migraine; more exactly, it was not possible to establish whether CM patients were already in an IR condition or, on the contrary, if this followed the chronic status of migraine. Nevertheless, the study shows that CM is strongly associated with IR and this suggests that high IR levels could play a significant role in CM pathogenesis, considering the amount of insulin receptors in the hypothalamic and brainstem regions. Another study limitation could be the selection of a pre-menopausal women sample; it is well known that hormonal factors influence migraine and therefore any bias due to that variable should be avoided. Further population-based studies are needed to confirm the association between IR and CM.

Acknowledgement None.

Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.

272

A. Fava et al.

References 1. Lipton RB, Bigal ME. Looking to the future: research design for study of headache disease progression. Headache 2008; 48: 58–66. 2. Headache Classification Committee of the International Headache Society (IHS). The international classification of headache disorders, 3rd edn (beta version). Cephalalgia 2013; 33: 629–808. 3. Zwart JA, Dyb G, Hagen K, et al. Depression and anxiety disorders associated with headache frequency. The Nord-Trondelag Health Study. Eur J Neurol 2003; 10: 147–152. 4. Peterlin BL, Tietjen G, Meng S, Lidicker J, Bigal M. Post-traumatic stress disorder in episodic and chronic migraine. Neurology 2008; 48: 517–522. 5. Hagen K, Einarsen C, Zwart JA, Svebak S, Bovim G. The co-occurrence of headache and musculoskeletal symptoms amongst 51,050 adults in Norway. Eur J Neurol 2002; 9: 527–533. 6. Peres MF, Young WB, Kaup AO, Zukerman E, Silberstein SD. Fibromyalgia is common in patients with transformed migraine. Neurology 2001; 57: 1326–1328. 7. Buse DC, Manack A, Serrano D, Turkel C, Lipton RB. Sociodemographic and comorbidity profiles of chronic migraine and episodic migraine sufferers. J Neurol Neurosurg Psychiatry 2010; 81: 428–432. 8. Bigal ME, Pipton RB. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology 2006; 67: 252–257. 9. Rose FC. Trigger factors and the natural history of migraine. Funct Neurol 1986; 1: 379–384. 10. Masters JB, Mortimer MJ, Hay KM. Glucose and diet in fasting migraineurs. Headache 1986; 1: 379–384. 11. Lind L, Berne C, Lithell H. Prevalence of insulin resistance in essential hypertension. J Hypertens 1995; 13: 1457–1462. 12. Kernan WN, Inzucchi SE, Viscoli CM, Brass LM, Bravata DM, Horwitz RI. Insulin resistance and risk for stroke. Neurology 2002; 59: 809–815. 13. Porte D, Baskin DG, Schwartz MW. Insulin signaling in the central nervous system. Diabetes 2005; 54: 1264–1276. 14. Rainero I, Limone P, Ferrero M. Insulin sensitivity is impaired in patients with migraine. Cephalalgia 2005; 25: 593–597. 15. Guldiken B, Guldiken S, Demir M, et al. Insulin resistance and high sensitivity C-reactive protein in migraine. Can J Neurol Sci 2008; 35: 448–451. 16. Beck AT, Ward C, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 561–571. 17. World Health Organization. Obesity: Preventing and Managing in Global Epidemic. Report of a WHO consultation on obesity. Geneva: World Health Organization, 1997. 18. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419.

19. Alberti KGMM, Zimmet P, Shaw J. Metabolic syndrome a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006; 23: 469–480. 20. Codwell EA, Ratcliff WA, Beastall GH, Ratcliff IG. Laboratory assessment of prolactin status. Ann Clin Biochem 1979; 16: 113–121. 21. Bhoi SK, Kalita J, Misra UK. Metabolic syndrome and insulin resistance in migraine. J Headache Pain 2012; 13: 321–326. 22. Guldiken B, Guldiken S, Taskiran B, et al. Migraine in metabolic syndrome. Neurologist 2009; 15: 55–58. 23. Bigal ME, Lipton RB. Modifiable risk factors for migraine progression. Headache 2006; 46: 1334–1343. 24. Katsarava Z, Schneeweiss S, Kurth T, et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 2004; 62: 788–790. 25. Yudkin JS. Insulin resistance and the metabolic syndrome or the pitfalls of epidemiology. Diabetologia 2007; 50: 1576–1586. 26. Chan JC, Tong PC, Critchley JA. The insulin resistance syndrome: mechanisms of clustering of cardiovascular risk. Semin Vasc Med 2002; 2: 45–57. 27. Mezei Z, Kis B, Gecse A, et al. Platelet arachidonate cascade of migraineurs in the interictal phase. Platelets 2000; 11: 222–225. 28. Tietjen GE, Al-Qasmi MM, Athanas K, Dafer RM, Khuder SA. Increased Von Willebrand factor in migraine. Neurology 2001; 57: 334–336. 29. Horev A, Wirguin I, Lantsberg L, Ifergane G. A high incidence of migraine with aura among morbidly obese women. Headache 2005; 45: 936–938. 30. Masters JB, Mortimer MJ, Hay KM. Glucose and diet in fasting migraineurs. Headache 1986; 26: 243–247. 31. Vega GL. Is intra-abdominal obesity a unique risk factor for metabolic syndrome in non-diabetics? Indian J Med Res 2010; 131: 603–605. 32. Winter AC, Berger K, Buring JE, Kurth T. Body mass index, migraine, migraine frequency, and migraine features in women. Cephalalgia 2009; 29: 269–278. 33. Cavestro C, Rosatello A, Micca G, et al. Insulin metabolism is altered in migraineurs: a new pathogenic mechanism for migraine? Headache 2007; 47: 1436–1442. 34. Kim C, Siscovick DS, Sidney S, et al. Oral contraceptive use and association with glucose, insulin, and diabetes in young adult women: the CARDIA study: Coronary Artery Risk Development in Young Adults. Diabetes Care 2002; 25: 1027–1032. 35. Nielsen JH, Svensson G, Galsgaard ED, Moldrup A, Billestrup N. Beta cell proliferation and growth factors. J Mol Med 1999; 77: 62–66. 36. Bosco D, Labate A, Mungari P, Vero S, Fava A. SUNCT and high nocturnal prolactin levels: some new unusual characteristics. J Headache Pain 2007; 8: 114– 118. 37. Bosco D, Belfiore A, Fava A, et al. Relationship between high prolactin levels and migraine attacks in patients with microprolactinoma. J Headache Pain 2008; 9: 103–107.

© 2013 The Author(s) European Journal of Neurology © 2013 EFNS