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Table 2 A summary of studies covering blood biomarkers in headaches’ differentiation

From: Biomarkers in headaches as a potential solution to simplify differential diagnosis of primary headache disorders: a systematic review

Ref.

Year

Population

Comparison

Biomarker

Results

Methodology

Mauskop et al. [44]

1994

26 pts with daily MIG headache

21 pts with daily TTH

Mg

↑ serum ionized Mg in 30.8% MIG pts compared to 4.5% of TTH

↑ ionized Ca/Mg ratio in 61.5% MIG pts compared to 36.4% of TTH

ionized Mg with ion selective electrodes

total serum Mg by atomic absorption spectroscopy

ratios calculated

Sarchielli et al. [34]

1992

41 MO pts

29 MA pts

30 TTH pts

40 HC

Mg

↓ Mg in MA and MO than in TTH

↓ Mg in MA, MO, and TTH than in HC

serum Mg by atomic absorption spectroscopy

Leone et al. [35]

1994

12 MO pts

12 chronic TTH pts

12 HC

leukocytes subsets

↑ B-lymphocytes level in TTH than HC

↓ CD8 T-cells level in MIG than TTH and HC

↑ CD4/CD8 in MIG than TTH

cells counted by Coulter Counter

ratios calculated

Ferrari et al. [45]

1990

10 MA pts

21 MO pts

9 TTH pts

9 HC

MET in PLT and PLT-poor plasma MET

↑ PLT MET in MO than TTH and HC

↑ plasma-MET in TTH than in MIG

↑ MET ratio in MIG than in TTH and HC

↑ PLT and plasma-MET during MIG attacks than interictally

PLT counted electronically

MET determined by RIA

Cernuda-Morrolón et al. [46]

2013

103 CM female pts

43 EM female pts

14 CH pts

31 female HC

CGRP

↑ CGRP in CM than in EM, CH, and HC

CGRP by ELISA

absorption levels with a spectrophotometer

Cernuda-Morrolón et al. [47]

2015

119 CM female pts

51 EM female pts

18 CH pts

33 female HC

VIP

↑ VIP in CM than in CH and HC

↑ VIP in EM than in HC

NSD between EM and CM (numerically ↑ VIP in CM)

VIP by ELISA

absorption levels with a spectrophotometer

Forcelini et al. [36]

2011

17 MOH pts

17 MO/CM pts

leukocytes subsets, haemoglobin, haematocrit

↑ lymphocyte count in MOH pts than in MO pts

NSD between any other groups

WBC counted, haemoglobin, haematocrit in Cell Dyn 3000

Carlsen et al. [48]

2023

120 MOH pts

29 EM pts

28 HC

leukocytes subsets

↑ neutrophile/lymphocyte ratio in MOH than in control group

↑ reduction of headache days/month associated with ↓ neutrophile/lymphocyte ratio

by DNA extraction, bisulfite-convertion and analysis

Fan et al. [49]

2019

68 MIG paediatric pts

30 non-MIG headache paediatric pts

22 healthy children

CGRP

↑ CGRP in MIG pts than in non-MIG pts and HC (ictally and interictally)

CGRP by ELISA

Yang et al. [50]

2023

ML predictive model based on 121,241 pts

-

blood parameters

and their ratios, patient’s features

accuracy of 0.7405

sensitivity: 90%, specificity: 58%, false negative rate: 10%, false positive rate: 42%

data from the UK Clinical Practice Research Datalink

prediction model developed by using two ML-based approaches

data normalization and optimization by min–max scaling

Zhang et al. [51]

2019

46 spontaneous SAH pts

68 headache pts due to other causes

PT, INR, APTT, TT, fibrynogen and DD

NSD in PT, INR, TT, fibrynogen

APTT accuracy: 0.721; DD accuracy: 0.886

cut-off values: 25.2s (sensitivity: 73.53%, specificity: 60.87%) for APTT; 0.31 mg/L (sensitivity: 83.82%, specificity: 84.7%) for DD

data gathered from medical records from the Fourth Affiliated Hospital Zhejiang University School of Medicine

  1. ↑, increase; ↓, decrease; APTT, activated partial thromboplastin time; Ca, calcium; CGRP, calcitonin gene-related peptide; CH, cluster headache; CM, chronic migraine; DD, D-dimers; DNA, Deoxyribonucleic Acid; ELISA, enzyme-linked immunosorbent assay; EM, episodic migraine; HC, healthy controls; INR, international normalised ratio; MA, migraine with aura; MET, methionine-enkephalin; MET ratio, platelets to plasma MET; Mg, magnesium; MIG, migraine; ML, machine learning; MO, migraine without aura; MOH, medication overuse headache; NSD, no significant difference; PLT, platelets; pts, patients; PT, prothrombin time; Ref, reference; RIA, radioimmunoassay; SAH, subarachnoid haemorrhage; TT, thrombin time; TTH, tension-type headache; VIP, vasoactive intestinal peptide