Table 1:

Findings on peripheral levels of cytokines and chemokines in migraineurs

Authors and year of publication (ref.)	Patients age range/mean age (years) F/M	Controls Age range/mean age (years) F/M	Headache Diagnostic criteria	Cytokine assessed	Method	Time of assessment	Main results	Comments
Martelletti et al 1997 [77]	20 MwA pts mean age: 36.5 ± 5.1 years 13 F and 7 M	20 healthy subjects mean age: 33.7 ± 8.4 years 13 F and 7 M 10 episodic TTH pts mean age: 37.0 ± 4.1 years 4 males and 6 females	IHS Criteria (1st edition)	serum IL-4 Other variables assessed: ICAM-1 expression IL-1R sICAM-1	ELISA method flow cytometry	Spontaneous attacks M crisis experimentally induced by the administration of isosorbide dinitrate	A sharp decrease in the expression of ICAM-1,, sICAM-1 and serum IL-4 were observed in experimentally induced and spontaneous M attacks. No change of IL-IR expression values.	M patients are more sensitive to exogenous NO than C. Experimental M crisis, induced by a NO donor, is mediated by the inhibition of IL-4 and subsequently of ICAM-1. ICAM-1 downregulation inhibits the critical step of transendothelial migration into the brain of activated leukocytes in line with the ‘sterile inflammation’ hypothesis of M..
Munno et al 1998 [76]	22 MwA patients Age range: 20 to 59 years (mean age: 34.2 years) M to F ratio: 9:23	32 sex- and age-matched blood donors as healthy controls	IHS Criteria (first edition)	Plasma IFN-γ, IL-4, IL-5, and IL-10	ELISAmethod	Interictal	No difference in the plasma levels of IFN-γ and IL-10 were between M patients and C. A strong increase of IL-5 level was found in 84.3% as well as increased IL-4 levels in 37.5% of pts with MwA.	These findings suggests a preferential enhancement of some Th2-type cytokines, and may support potential immune-allergic mechanism in M.
Munno et al., 2001 [79]	23 MwA patients Age range: from 19 to 58 years (mean, 38.5 years) M to F ratio: 9:14	23 subjects sex- and age- matched were included as healthy controls	IHS Criteria (first edition)	Plasma IL-4, IL-5, IL-10, and IFN-γ	ELISA method	Ictal and after acute treatment	Low to undetectable IL-5 and IL-4 levels were found. High IL-10 levels were seen in 52.2% of M pts. IFN-γ levels were undetectable in all pts. After treatment with sumatriptan, 10 pts showed a decrease in IL-10 and an increase in both IL-4 and IL-5 levels.	A preferential enhancement of TH2-type cytokine production may contribute to the mechanisms of M attacks.
Perini et al., 2005 [72]	25 MwA Patients (22 MwA, 4 MA, and 1 MwA and MA) Age range: 23 to 48years (mean age: 35 ± 7.2 years) 22 F and 3 M	18 healthy subjects Age range: 23 to 51 yrs (mean age: 34 ± 9.9 years) 13 F and 4 M	IHS criteria (second edition)	Plasma IL-1β, TNF-α, and IL-10	ELISAmethod	interictal and ictal	TNF-α, IL-1β and IL-10, during attacks were significantly higher in comparison to their levels outside attacks (P = 0.0003, P = 0.03, and P = 0.05, respectively). IL-10 and TNF serum levels were higher inpatients assessed soon after headache onset and lower over time.	These cytokines are suggested to be involved in M pathogenetic mechanisms.
Boćkowski et al., 2009  [73]	21 Children Age range: 10 to 18 years (mean, 14.04 ± 2.29) 12 MwA (6 F and 6 M) 9 MA (4 F and 5 M)	24 TTH patients Age range: 8 to 17 years (mean age: 12.11 ± 3.46 years) 18 girls, 6 boys	IHS Criteria (second edition)	Plasma IL-1β, TNF-α, and TNF receptor 1	ELISA method	Interictal	Soluble TNF receptor 1 in the M group were significantly higher than in the C group. M pts tended to have increased TNF-α, level, compared with C. IL-1β, level was significantly higher in MA than in MwA. TNF-α, and soluble TNF receptor 1 levels tended to be increased in MA subgroup.	Proinflammatory cytokines may be involved in the pathogenic events underlying M attacks, although fluctuations in cytokine levels may be different in children than in adults. Difference could be due to long medical history of M in adult pts and frequent intake of analgesic drugs or prophylactic treatment.
Boćkowski et al., 2010 [74]	35 M patients Age range: 10–18 years (mean age 14.04 ± 2.29 years) 21 MwA (9 F and 12 M) 14 MA (6 F and 8 M)	33 TTH patients Age range: 8–17 years old (mean age: 12.11 ± 3.46 years) 22 F and 11 M	IHS Criteria (second edition)	Plasma IL-4, IL10 and IL-13	ELISA method	Interictal	IL-4 was detected in 17.1% of pts with M and in 28.6% of pts with TTH. IL-13 was detected in 17.1% of pts with M and in 15.2% of pts with TTH. IL-10 was only detected in 3 of 68 (4.4%) pts. No significant correlations emerged between measurable cytokine levels and age, gender, aura, duration of disease, frequency and severity of headache inboth patient groups.	No changes of anti-inflammatory cytokines levels during the headache-free period, excluding their potential involvement in pathogenic mechanisms of M and TTH in children.
Uzar et al. 2011 [69]	64MwA and MA 25 assessed in ictal period and 39 in the interictal period mean age: 35.4 ± 11.5 years 45 F and 19 M	34 healthy subjects mean age: 34.7 ± 11.7 years 24 F and 10 M	IHS criteria (second edition)	Serum TNF-α, IL-1β, IL-2, IL-6, IL-10, and pro BNP levels	chemiluminescence assay.	Interictal and ictal	Significantly higher concentrations of IL-1β and IL-6 and conversely significantly lower Il-10 in M pts compared with the healthy C. No differences in the cytokine levels between interictal and ictal periods. M pts had higher concentrations of pro-BNP compared with healthy C .	These cytokines are proposed to be involved in neurogenic inflammation due to trigemino-vascular activation in M, Increased pro-BNP may indicate preclinical cardiac involvement in patients with M.
Duarte et al. 2015 [70]	49 MwA mean age: 40.5 ± 14.5 years 46 F and 3 M	49 healthy subjects mean age: 42.5 ± 14.3 years 46 F and 3 M	IIHS criteria (second edition)	Serum CXCL8/IL-8 CCL3/MIP-1α	ELISA method	Interictal	CXCL8/IL-8 and CCL3/MIP-1α levels were significantly higher among pts with M even after controlling for anxiety and depression scores.	CXCL8/IL-8 and CCL3/MIP-1 α levels were raised in M, independently of psychiatric comorbidities, migraine impact, and allodynia.
Oliveira et al. 2017 [71]	20 MwA and/or MwA mean age 33.8 ± 10.5 years All F	17 healthy controls mean age 33.7 ± 9.0 years All F	IIHS criteria (second edition)	Plasma TNF-α, IL-1β, IL-6, IL-8, IL-10, and IL-12p70	ELISA method	Interictal	TNF-α and IL-12p70 were significantly higher, while IL-6 (P < 0.01), IL-8 (P < 0.01), and IL-10 (P < 0.01) were decreased compared to C group. M was positively associated with TNF-α and IL-12p70, and negatively associated with IL-6, IL-8, and IL-10. Anxiety scores were positively associated with IL-12p70. VO2Peak was negatively associated with TNF-α.	An exaggeratedly skewed cytokine profile, in particular the TNF-α and 12p70/IL-10 balance may be related to M pathophysiologic mechanisms, and its psychiatric comorbidities andfunctional capacity.
Bougea et al. 2020 [86]	30 MwA pts Age range: 18–60 years 30 TTH pts Age range: 18–60 years Sex distribution not specified	30 healthy subjects Age range: 18–50 Sex distribution not specified	HIS criteria, (third edition, beta version)	Salivary CRP, IL-1β and IL-6	ELISA Method	Interictal	No significant differences were found in time variation of CRP, IL-1β, and IL-6 levels between M and TTH pts. IL1-β had the highest discriminative value followed by CRP and IL-6 in separating pts (M+TTH) and healthy C. CRP and IL-6 were negatively correlated with HAM-A and BDI scores.	L1-β had the highest discriminative value between headache pts and controls compared with CRP and IL-6. CRP and IL-6 were correlated with lower symptom scores of anxiety and depression prior or immediately after the headache period in both patient groups.

BDI, Beck Depression Inventory; CRP, C reactive protein; C, controls; HAM-A, Hamilton Anxiety Rating Scale; ICAM-1, intercellular adhesion molecule; IFN-γ, interferon-gamma; IL. interleukin; Interleukin1-Receptor, IL-1R; M, migraine; MA, migraine with aura; MwA, migraine without aura; Pro-BNP, pro-brain natriuretic peptide; pts, patients; s ICAM-1, soluble intercellular adhesion molecule 1; TNF, tumour necrosis factor; TTH, tension-type headache