MicroRNA as diagnostic markers of epilepsy: systematic review and meta-analysis_Journal of Epilepsy

Authors：

LI An ¹ , CHEN Rui ¹ ,  XUE Guofang ²

1. The Second Clinical Medical College of Shanxi Medical University, Taiyuan 030001, China;
2. Department of Neurology, the Second Hospital of Shanxi Medical University, Taiyuan 030001, China;

Corresponding author：

XUE Guofang, Email: xueguofangty@163.com

Keywords：

Biomarkers; Diagnosis; Epilepsy; Meta-analysis; miRNA

DOI：

10.7507/2096-0247.202404009

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective The aim of this meta-analysis and systematic review is to assess the effectiveness of microRNAs as a diagnostic tool for individuals with epilepsy. Methods A systematic search of PubMed, EMBASE, the Cochrane Library, and Web of Science databases was performed to collect literature on miRNA diagnosis of epilepsy up to January 1, 2024. Two researchers independently screened and extracted the literature and resolved discrepancies by negotiation. The QUADAS-2 evaluation tool was used to assess the quality of the included studies. Statistical analysis was performed using Review Manager 5.4, Meta-Disc 1.4, and Stata 17.0. Results A total of 17 papers were included, including 942 patients with epilepsy and 932 healthy controls. miRNA in the diagnosis of epilepsy had a combined sensitivity of 0.76 [95%CI (0.71, 0.79)], combined specificity of 0.78 [95%CI (0.74, 0.82)], and area under the SROC curve of 0.84 [95%CI (0.80, 0.87)]. Subgroup analysis showed that miRNA had higher diagnostic value for temporal lobe epilepsy, especially medial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Conclusion The study suggests that miRNA may be a promising tool for the diagnosis of epilepsy, especially temporal lobe epilepsy, but more high-quality studies are needed to support it.

Citation： LI An, CHEN Rui, XUE Guofang. MicroRNA as diagnostic markers of epilepsy: systematic review and meta-analysis. Journal of Epilepsy, 2024, 10(4): 299-307. doi: 10.7507/2096-0247.202404009 Copy

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2.	Johnson EL. Seizures and epilepsy. The Medical Clinics of North America, 2019, 103(2): 309-324.
3.	Martinez B, Peplow PV. MicroRNAs as potential biomarkers in temporal lobe epilepsy and mesial temporal lobe epilepsy. Neural Regeneration Research, 2023, 18(4): 716-726.
4.	Ridley B, Marchi A, Wirsich J, et al. Brain sodium MRI in human epilepsy: disturbances of ionic homeostasis reflect the organization of pathological regions. NeuroImage, 2017, 157: 173-183.
5.	Engel J Jr, Pitkänen A, Loeb JA, et al. Epilepsy biomarkers. Epilepsia, 2013, 54(Suppl 4): 61-69.
6.	Iliescu C, Craiu D. Diagnostic approach of epilepsy in childhood and adolescence. Maedica, 2013, 8(2): 195-199.
7.	Grau-López L, Jiménez M, Ciurans J, et al. Clinical predictors of adverse events during continuous video-EEG monitoring in an epilepsy unit. Epileptic Disorders: International Epilepsy Journal with Videotape, 2020, 22(4): 449-454.
8.	Raoof R, Bauer S, El Naggar H, et al. Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. EBioMedicine, 2018, 38: 127-141.
9.	Henshall DC, Hamer HM, Pasterkamp RJ, et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol, 2016, 15(13): 1368-1376.
10.	Saugstad JA. MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J Cereb Blood Flow Metab, 2010, 30(9): 1564-1576.
11.	Ou S, Liu X, Xu T, et al. miRNA-let-7i modulates status epilepticus via the TLR4 pathway. Acta Epileptologica, 2022, 4(1): 20.
12.	Chen R, Xue G, Hölscher C. The role of the TNFα-mediated astrocyte signaling pathway in epilepsy. Acta Epileptologica, 2021, 3(1): 24.
13.	Wang L, Yue Y, Wang X, et al. Function and clinical potential of microRNAs in hepatocellular carcinoma. Oncology Letters, 2015, 10(6): 3345-3353.
14.	Ghafouri-Fard S, Hussen BM, Abak A, et al. Aberrant expression of miRNAs in epilepsy. Molecular Biology Reports, 2022, 49(6): 5057-5074.
15.	Sueri C, Gasparini S, Balestrini S, et al. Diagnostic biomarkers of epilepsy. Current Pharmaceutical Biotechnology, 2018, 19(6): 440-450.
16.	Ma Y. The challenge of microRNA as a biomarker of epilepsy. Current Neuropharmacology, 2018, 16(1): 37-42.
17.	Claudia Cava, Ida Manna, Antonio Gambardella, et al. Potential role of miRNAs as theranostic biomarkers of epilepsy. Mol Ther Nucleic Acids, 2018, 13: 275-290.
18.	Alsharafi WA, Xiao B, Abuhamed MM, et al. miRNAs: biological and clinical determinants in epilepsy. Frontiers in Molecular Neuroscience, 2015, 8: 59.
19.	Wang S, He X, Bao N, et al. Potentials of miR-9-5p in promoting epileptic seizure and improving survival of glioma patients. Acta Epileptologica, 2022, 4(1): 33.
20.	Cattani AA, Allene C, Seifert V, et al. Involvement of microRNAs in epileptogenesis. Epilepsia, 2016, 57(7): 1015-1026.
21.	Shao Y, Chen Y. Pathophysiology and Clinical Utility of Non-coding RNAs in Epilepsy. Frontiers in Molecular Neuroscience, 2017, 10: 249.
22.	Liu D, Zhu J, Shu Y, et al. Model-based assessment of a Northwestern Tropical Pacific moored array to monitor intraseasonal variability. Ocean Modelling, 2018, 126: 1-12.
23.	Rodriguez AS, Engel T, Palfi A, et al. Tubby-like protein 1 (Tulp1) is a target of microRNA-134 and is down-regulated in experimental epilepsy. International Journal of Physiology, Pathophysiology and Pharmacology, 2017, 9(6): 178-187.
24.	Nomair AM, Mekky JF, El-hamshary SA, et al. Circulating miR-146a-5p and miR-132–3p as potential diagnostic biomarkers in epilepsy. Epilepsy Research, 2023, 191: 107089.
25.	Zahra MA, Kamha ES, Abdelaziz HK, et al. Aberrant expression of serum MicroRNA-153 and -199a in generalized epilepsy and its correlation with drug resistance. Annals of Neurosciences, 2022, 29(4): 203-208.
26.	Liu Y, Yu G, Ding YY, et al. Expression of miR-155 in serum exosomes in children with epilepsy and its diagnostic value. Disease Markers, 2022, 22: 1-6.
27.	Guerra Leal B, Barros-Barbosa A, Ferreirinha F, et al. Mesial temporal lobe epilepsy (MTLE) drug-refractoriness is associated with P2X7 receptors overexpression in the human hippocampus and temporal neocortex and may be predicted by low circulating levels of miR-22. Frontiers in Cellular Neuroscience, 2022, 16: 910662.
28.	Yu Y, Du L, Zhang J. Febrile Seizure-related miR-148a-3p exerts neuroprotection by promoting the proliferation of hippocampal neurons in children with temporal lobe epilepsy. Developmental Neuroscience, 2021, 43(5): 312-320.
29.	Wu Y, Zhang Y, Zhu S, et al. MiRNA-29a serves as a promising diagnostic biomarker in children with temporal lobe epilepsy and regulates seizure-induced cell death and inflammation in hippocampal neurons. Epileptic Disorders, 2021, 23(6): 823-832.
30.	Niu X, Zhu HL, Liu Q, et al. MiR-194-5p serves as a potential biomarker and regulates the proliferation and apoptosis of hippocampus neuron in children with temporal lobe epilepsy. Journal of the Chinese Medical Association, 2021, 84(5): 510-516.
31.	Li R, Hu J, Cao S. The clinical significance of miR-135b-5p and its role in the proliferation and apoptosis of hippocampus neurons in children with temporal lobe epilepsy. Developmental Neuroscience, 2020, 42(5-6): 187-194.
32.	Moustafa M, Abokrysha NT, Eldesoukey NA, et al. Role of circulating miR 194-5p, miR 106b, and miR 146a as potential biomarkers for epilepsy: a case-control study. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 2020, 56(1): 82.
33.	Martins‐Ferreira R, Chaves J, Carvalho C, et al. Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel. European Journal of Neurology, 2020, 27(4): 660-666.
34.	Li N, Pan J, Liu W, et al. MicroRNA-15a-5p serves as a potential biomarker and regulates the viability and apoptosis of hippocampus neuron in children with temporal lobe epilepsy. Diagnostic Pathology, 2020, 15(1): 46.
35.	Ioriatti ES, Cirino MLA, Lizarte Neto FS, et al. Expression of circulating microRNAs as predictors of diagnosis and surgical outcome in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsy Research, 2020, 166: 106373.
36.	Shen CH, Zhang YX, Zheng Y, et al. Expression of plasma microRNA-145-5p and its correlation with clinical features in patients with refractory epilepsy. Epilepsy Research, 2019, 154: 21-25.
37.	Elnady HG, Abdelmoneam N, Eissa E, et al. MicroRNAs as potential biomarkers for childhood epilepsy. Open Access Macedonian Journal of Medical Sciences, 2019, 7(23): 3965-3969.
38.	Avansini SH, De Sousa Lima BP, Secolin R, et al. MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy. Plos One, 2017, 12(4): e0173060.
39.	Wang J, Tan L, Tan L, et al. Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy. Scientific Reports, 2015, 5(1): 10201.
40.	Wang J, Yu JT, Tan L, et al. Genome-wide circulating microRNA expression profiling indicates biomarkers for epilepsy. Scientific Reports, 2015, 5(1): 9522.
41.	Morris G, O’Brien D, Henshall DC. Opportunities and challenges for microRNA-targeting therapeutics for epilepsy. Trends in Pharmacological Sciences, 2021, 42(7): 605-616.
42.	Wang J, Zhao J. MicroRNA dysregulation in epilepsy: from pathogenetic involvement to diagnostic biomarker and therapeutic agent development. Frontiers in Molecular Neuroscience, 2021, 14: 650372.
43.	Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
44.	Lee YJ, Kang HC, Bae SJ, et al. Comparison of temporal lobectomies of children and adults with intractable temporal lobe epilepsy. Child’s Nervous System, 2010, 26(2): 177-183.

1. Thijs RD, Surges R, O’Brien TJ, et al. Epilepsy in adults. Lancet, 2019, 393(10172): 689-701.
2. Johnson EL. Seizures and epilepsy. The Medical Clinics of North America, 2019, 103(2): 309-324.
3. Martinez B, Peplow PV. MicroRNAs as potential biomarkers in temporal lobe epilepsy and mesial temporal lobe epilepsy. Neural Regeneration Research, 2023, 18(4): 716-726.
4. Ridley B, Marchi A, Wirsich J, et al. Brain sodium MRI in human epilepsy: disturbances of ionic homeostasis reflect the organization of pathological regions. NeuroImage, 2017, 157: 173-183.
5. Engel J Jr, Pitkänen A, Loeb JA, et al. Epilepsy biomarkers. Epilepsia, 2013, 54(Suppl 4): 61-69.
6. Iliescu C, Craiu D. Diagnostic approach of epilepsy in childhood and adolescence. Maedica, 2013, 8(2): 195-199.
7. Grau-López L, Jiménez M, Ciurans J, et al. Clinical predictors of adverse events during continuous video-EEG monitoring in an epilepsy unit. Epileptic Disorders: International Epilepsy Journal with Videotape, 2020, 22(4): 449-454.
8. Raoof R, Bauer S, El Naggar H, et al. Dual-center, dual-platform microRNA profiling identifies potential plasma biomarkers of adult temporal lobe epilepsy. EBioMedicine, 2018, 38: 127-141.
9. Henshall DC, Hamer HM, Pasterkamp RJ, et al. MicroRNAs in epilepsy: pathophysiology and clinical utility. Lancet Neurol, 2016, 15(13): 1368-1376.
10. Saugstad JA. MicroRNAs as effectors of brain function with roles in ischemia and injury, neuroprotection, and neurodegeneration. J Cereb Blood Flow Metab, 2010, 30(9): 1564-1576.
11. Ou S, Liu X, Xu T, et al. miRNA-let-7i modulates status epilepticus via the TLR4 pathway. Acta Epileptologica, 2022, 4(1): 20.
12. Chen R, Xue G, Hölscher C. The role of the TNFα-mediated astrocyte signaling pathway in epilepsy. Acta Epileptologica, 2021, 3(1): 24.
13. Wang L, Yue Y, Wang X, et al. Function and clinical potential of microRNAs in hepatocellular carcinoma. Oncology Letters, 2015, 10(6): 3345-3353.
14. Ghafouri-Fard S, Hussen BM, Abak A, et al. Aberrant expression of miRNAs in epilepsy. Molecular Biology Reports, 2022, 49(6): 5057-5074.
15. Sueri C, Gasparini S, Balestrini S, et al. Diagnostic biomarkers of epilepsy. Current Pharmaceutical Biotechnology, 2018, 19(6): 440-450.
16. Ma Y. The challenge of microRNA as a biomarker of epilepsy. Current Neuropharmacology, 2018, 16(1): 37-42.
17. Claudia Cava, Ida Manna, Antonio Gambardella, et al. Potential role of miRNAs as theranostic biomarkers of epilepsy. Mol Ther Nucleic Acids, 2018, 13: 275-290.
18. Alsharafi WA, Xiao B, Abuhamed MM, et al. miRNAs: biological and clinical determinants in epilepsy. Frontiers in Molecular Neuroscience, 2015, 8: 59.
19. Wang S, He X, Bao N, et al. Potentials of miR-9-5p in promoting epileptic seizure and improving survival of glioma patients. Acta Epileptologica, 2022, 4(1): 33.
20. Cattani AA, Allene C, Seifert V, et al. Involvement of microRNAs in epileptogenesis. Epilepsia, 2016, 57(7): 1015-1026.
21. Shao Y, Chen Y. Pathophysiology and Clinical Utility of Non-coding RNAs in Epilepsy. Frontiers in Molecular Neuroscience, 2017, 10: 249.
22. Liu D, Zhu J, Shu Y, et al. Model-based assessment of a Northwestern Tropical Pacific moored array to monitor intraseasonal variability. Ocean Modelling, 2018, 126: 1-12.
23. Rodriguez AS, Engel T, Palfi A, et al. Tubby-like protein 1 (Tulp1) is a target of microRNA-134 and is down-regulated in experimental epilepsy. International Journal of Physiology, Pathophysiology and Pharmacology, 2017, 9(6): 178-187.
24. Nomair AM, Mekky JF, El-hamshary SA, et al. Circulating miR-146a-5p and miR-132–3p as potential diagnostic biomarkers in epilepsy. Epilepsy Research, 2023, 191: 107089.
25. Zahra MA, Kamha ES, Abdelaziz HK, et al. Aberrant expression of serum MicroRNA-153 and -199a in generalized epilepsy and its correlation with drug resistance. Annals of Neurosciences, 2022, 29(4): 203-208.
26. Liu Y, Yu G, Ding YY, et al. Expression of miR-155 in serum exosomes in children with epilepsy and its diagnostic value. Disease Markers, 2022, 22: 1-6.
27. Guerra Leal B, Barros-Barbosa A, Ferreirinha F, et al. Mesial temporal lobe epilepsy (MTLE) drug-refractoriness is associated with P2X7 receptors overexpression in the human hippocampus and temporal neocortex and may be predicted by low circulating levels of miR-22. Frontiers in Cellular Neuroscience, 2022, 16: 910662.
28. Yu Y, Du L, Zhang J. Febrile Seizure-related miR-148a-3p exerts neuroprotection by promoting the proliferation of hippocampal neurons in children with temporal lobe epilepsy. Developmental Neuroscience, 2021, 43(5): 312-320.
29. Wu Y, Zhang Y, Zhu S, et al. MiRNA-29a serves as a promising diagnostic biomarker in children with temporal lobe epilepsy and regulates seizure-induced cell death and inflammation in hippocampal neurons. Epileptic Disorders, 2021, 23(6): 823-832.
30. Niu X, Zhu HL, Liu Q, et al. MiR-194-5p serves as a potential biomarker and regulates the proliferation and apoptosis of hippocampus neuron in children with temporal lobe epilepsy. Journal of the Chinese Medical Association, 2021, 84(5): 510-516.
31. Li R, Hu J, Cao S. The clinical significance of miR-135b-5p and its role in the proliferation and apoptosis of hippocampus neurons in children with temporal lobe epilepsy. Developmental Neuroscience, 2020, 42(5-6): 187-194.
32. Moustafa M, Abokrysha NT, Eldesoukey NA, et al. Role of circulating miR 194-5p, miR 106b, and miR 146a as potential biomarkers for epilepsy: a case-control study. The Egyptian Journal of Neurology, Psychiatry and Neurosurgery, 2020, 56(1): 82.
33. Martins‐Ferreira R, Chaves J, Carvalho C, et al. Circulating microRNAs as potential biomarkers for genetic generalized epilepsies: a three microRNA panel. European Journal of Neurology, 2020, 27(4): 660-666.
34. Li N, Pan J, Liu W, et al. MicroRNA-15a-5p serves as a potential biomarker and regulates the viability and apoptosis of hippocampus neuron in children with temporal lobe epilepsy. Diagnostic Pathology, 2020, 15(1): 46.
35. Ioriatti ES, Cirino MLA, Lizarte Neto FS, et al. Expression of circulating microRNAs as predictors of diagnosis and surgical outcome in patients with mesial temporal lobe epilepsy with hippocampal sclerosis. Epilepsy Research, 2020, 166: 106373.
36. Shen CH, Zhang YX, Zheng Y, et al. Expression of plasma microRNA-145-5p and its correlation with clinical features in patients with refractory epilepsy. Epilepsy Research, 2019, 154: 21-25.
37. Elnady HG, Abdelmoneam N, Eissa E, et al. MicroRNAs as potential biomarkers for childhood epilepsy. Open Access Macedonian Journal of Medical Sciences, 2019, 7(23): 3965-3969.
38. Avansini SH, De Sousa Lima BP, Secolin R, et al. MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy. Plos One, 2017, 12(4): e0173060.
39. Wang J, Tan L, Tan L, et al. Circulating microRNAs are promising novel biomarkers for drug-resistant epilepsy. Scientific Reports, 2015, 5(1): 10201.
40. Wang J, Yu JT, Tan L, et al. Genome-wide circulating microRNA expression profiling indicates biomarkers for epilepsy. Scientific Reports, 2015, 5(1): 9522.
41. Morris G, O’Brien D, Henshall DC. Opportunities and challenges for microRNA-targeting therapeutics for epilepsy. Trends in Pharmacological Sciences, 2021, 42(7): 605-616.
42. Wang J, Zhao J. MicroRNA dysregulation in epilepsy: from pathogenetic involvement to diagnostic biomarker and therapeutic agent development. Frontiers in Molecular Neuroscience, 2021, 14: 650372.
43. Fisher RS, Acevedo C, Arzimanoglou A, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia, 2014, 55(4): 475-482.
44. Lee YJ, Kang HC, Bae SJ, et al. Comparison of temporal lobectomies of children and adults with intractable temporal lobe epilepsy. Child’s Nervous System, 2010, 26(2): 177-183.

Journal of Epilepsy

MicroRNA as diagnostic markers of epilepsy: systematic review and meta-analysis

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